Conditions: Healthy Volunteers
Keywords: Healthy volunteers Monoclonal antibody AV-1 Safety Dengue
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 42
Healthy volunteers: yes

Brief summary:
AV-1 is a human monoclonal antibody (mAb) being investigated as a potential therapy for dengue, a mosquito-borne viral disease with extensive global public health impact. Globally, over 2 billion people are thought to be at risk of infection from the dengue virus and there are an estimated 390 million infections each year. Current treatment options for dengue are limited to supportive care, so a safe and effective treatment would provide substantial public health benefits. AV-1 has not previously been tested in humans. This study aims to determine the safety of AV-1 in healthy adult volunteers, when administered as a single IV infusion. The results of the study are based on the clinical study report and statistical analysis plan.

Detailed description:

Arms:
arm 1: Participants received a single intravenous (IV) infusion (infusion duration: 1 hour) of AV-1 30 mg on Day 1. arm 2: Participants received a single IV infusion (infusion duration: 1 hour) of AV-1 90 mg on Day 1. arm 3: Participants received a single IV infusion (infusion duration: 1 hour) of AV-1 250 mg on Day 1. arm 4: Participants received a single IV infusion (infusion duration: 1 hour) of AV-1 500 mg on Day 1. arm 5: Participants received a single IV infusion (infusion duration: 1 hour) of AV-1 1000 mg on Day 1. arm 6: Participants received a single IV infusion (infusion duration: 1 hour) of placebo matched to AV-1 on Day 1.

Interventions: intervention 1: AV-1 intervention 2: Placebo
Intervention descriptions: intervention 1: Single dose, administered by IV infusion (volume: 250 mL) intervention 2: 0.9% sterile saline. Administered by IV infusion (volume: 250 mL)

Protocol document:
Prot_000.pdf: 
 
A PHASE 1A, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
SINGLE ASCENDING DOSE STUDY TO DETERMINE THE 
SAFETY AND PHARMACOKINETICS OF AV-1 IN HEALTHY 
MALE AND FEMALE ADULT SUBJECTS 
Sponsor Protocol Number:   
 
AV1-PPD-0005 
DMID Protocol Number: 
 
 
18-0016 
NIAID Contract Number:  
 
HHSN272201600028C 
IND Sponsor: 
AbViro LLC 
 
Principal Investigator: 
 
 
 
Sponsor Representative: 
 
 
 
Version Number: 
 
 
 
5.0 
Protocol Date: 
 
 
 
06 November 2019 
Protocol Amendment 1 Date: 
 
25 March 2020 
Protocol Amendment 2 Date: 
 
07 May 2020 
Protocol Amendment 3 Date: 
 
25 February 2021 
Protocol Amendment 4 Date: 
 
23 April 2021 
 
 


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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) registered with OHRP, for which the 
research will be reviewed and approved by the IRB and will be subject to continuing review 
(45 CFR 46.103[b]). The IRB designated under an FWA may include an institution’s IRB, an 
independent IRB, or an IRB 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 (US) 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 (IRBs), 21 CFR Part 11, and 21 CFR Part 312 (Investigational New Drug 
Application) 
• 
International Council for Harmonisation (ICH) E6 (R2) GCP: Integrated Addendum to ICH 
E6 (R1) Guidance for Industry, published in the Federal Register (83 Federal Register 8882 
[2018]) 
• 
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 Clinical Terms of Award, as applicable 
• 
Applicable federal, state, and local regulations and guidance 




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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Date of Amendment 1: 
25 March 2020 (Version 2.0) 
The reasons for this protocol amendment are summarized below: 
• DMID Medical Monitor name, address, phone number, and email address were updated in 
Section 1. 
• Modified the screening period from 28 days to 35 days in the protocol summary, Section 3.1, 
Section 5.1.2, and schedule of events (Section 17.1 Appendix A). 
• A pharmacokinetic blood draw was added on Day 43 (±3) and Day 57 (±3) throughout the 
protocol. 
• To clarify the duration of nonclinical studies in mice from the survival perspective, the 
following text “for the duration of the study (10 days)” was added in Section 2.2. 
• Text was added to clarify subject retesting of laboratory parameters that are outside the 
acceptable range in Section 5.1. 
• Clarified inclusion criterion 3.b.II “A pre-existing medical condition that is not exclusionary 
but has worsened in terms of clinical outcome within 3 months of enrollment” in 
Section 5.1.1. 
• Removed “will” and “unless otherwise specified” and replaced with “may” in Section 5.2.2. 
• Respiratory rate was added as part of vital sign measurements in Section 7.1.1 and footnote 
“j” in the schedule of events (Section 17.1 Appendix A). 
• Added “alkaline phosphatase, aspartate aminotransferase” to Section 7.2.1 to match the 
safety laboratory tests that will be performed. 
• Text was added to clarify when dosing escalation should be halted in Section 8.6.1. 
• Clarified when the infusion should be halted and adjusted language to allow reductions in 
infusion rate for symptom management in Section 8.6.2. 


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• Clarified that the physical examination performed at Check-in (Day –1) will be a focused 
examination in Section 7.1.4 and footnote “i” in the schedule of events (Section 17.1 
Appendix A). 
• Updated “immunogenicity” to “anti-AV-1 antibody” in Section 3.1, Section 7.2.3, and the 
schedule of events (Section 17.1 Appendix A). 
• Removed “Water is permitted as desired except for the period of 1 hour prior to the start of 
the IP infusion until 1 hour after the end of the infusion.” in footnote “s” in the schedule of 
events (Section 17.1 Appendix A). There is no restriction for water prior to and after dosing. 
• Removed reference range from the title and removed the reference ranges column for 
laboratory values in Table 17-3 Laboratory Toxicity Grading. 
• Administrative changes were made throughout the protocol. 
Details of the changes within the protocol can be found in the tracked-changes document, which 
accompanies the amended protocol. 
Date of Amendment 2: 
07 May 2020 (Version 3.0) 
The reasons for this protocol amendment are summarized below: 
• The approximate study duration was updated from 16 to 22 weeks in the protocol summary 
and Section 3.1. 
• The number of follow-up visits was updated from 7 to 8 in the protocol summary and 
Sections 2.3.1 and 3.1. 
• A Day 120 study visit was added to include safety activities as well as pharmacokinetic and 
anti-AV-1 antibody sampling throughout the protocol. 
• The schedule of events table (Section 17.1 Appendix A) was updated to add the Day 120 
visit, to reflect that Day 120 is the end of study (EOS) visit, as well as procedures to be 
performed in the event of early termination from the study. The abbreviation EOS and 
definition was added to the schedule of events table abbreviation list.  
• Final follow-up visit in footnote “c” in the schedule of events (Section 17.1 Appendix A) was 
updated from “Day 85 (Week 12)” to “Day 120 (approximately Week 17)”. 


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• AV-1 product stability and planned stability study duration was updated in Section 4.1.2. 
• Typographical error corrected in Section 5.1 to change “hepatitis B surface antibody” to 
“hepatitis B surface antigen”. 
• For clarity, “Anti-drug antibody” was changed to “Anti-AV-1 antibody” in the schedule of 
events table (Section 17.1 Appendix A). 
• A urine drug screen test was added to Day 85 and the text was updated in Section 7.2.1 and 
the schedule of events table (Section 17.1 Appendix A). 
Details of the changes within the protocol can be found in the tracked-changes document, which 
accompanies the amended protocol. 
Date of Amendment 3: 
25 February 2021 (Version 4.0) 
The reasons for this protocol amendment are summarized below: 
• The Principal Investigator for this study changed. The Principal Investigator’s name was 
updated on the title page and the signature page. The Principal Investigator’s name, 
telephone number, and email address were updated in the key roles in Section 1. 
• The lead statistician for this study changed. The lead statistician’s name and email address 
were updated in the key roles in Section 1. 
Date of Amendment 4: 
23 April 2021 (Version 5.0) 
The reasons for this protocol amendment are summarized below: 
• The Principal Investigator for this study changed. The Principal Investigator’s name was 
updated on the title page and the signature page. The Principal Investigator’s name, 
telephone number, and email address were updated in the key roles in Section 1. 
• Updated exclusion criterion 23 to include language prohibiting receipt of any COVID-19 
vaccine within 14 days prior to or after Day 1 in Section 5.1.2. 
 
 


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TABLE OF CONTENTS 
STATEMENT OF ASSURANCE ...................................................................................................2 
STATEMENT OF COMPLIANCE .................................................................................................3 
SIGNATURE PAGE .......................................................................................................................4 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ..........................................................5 
TABLE OF CONTENTS .................................................................................................................8 
LIST OF ABBREVIATIONS ........................................................................................................12 
PROTOCOL SUMMARY .............................................................................................................14 
 
KEY ROLES.........................................................................................................................16 
 
BACKGROUND AND SCIENTIFIC RATIONALE ..........................................................18 
 
Background .................................................................................................................18 
 
Scientific Rationale .....................................................................................................19 
2.2.1 Purpose of Study ............................................................................................19 
2.2.2 Rationale for Study ........................................................................................19 
2.2.3 Study Population ............................................................................................20 
 
Potential Risks and Benefits .......................................................................................21 
2.3.1 Potential Risks ...............................................................................................21 
2.3.2 Potential Benefits ...........................................................................................21 
2.3.3 Risk-Benefit Ratio .........................................................................................21 
 
STUDY DESIGN, OBJECTIVES, AND ENDPOINTS ......................................................23 
 
Study Design Description ...........................................................................................23 
 
Study Objectives .........................................................................................................24 
3.2.1 Primary ...........................................................................................................24 
3.2.2 Secondary .......................................................................................................24 
 
Study Endpoints ..........................................................................................................24 
3.3.1 Primary Endpoint ...........................................................................................24 
3.3.2 Secondary Endpoints .....................................................................................25 
 
INVESTIGATIONAL PRODUCT.......................................................................................26 
 
Investigational Product Description ...........................................................................26 
4.1.1 Formulation, Packaging, and Labeling ..........................................................26 


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4.1.2 Product Storage and Stability .........................................................................26 
 
Acquisition ..................................................................................................................27 
 
Preparation and Administration of Investigational Product .......................................27 
 
Accountability Procedures for the Investigational Product ........................................27 
 
SELECTION OF SUBJECTS AND STUDY ENROLLMENT AND WITHDRAWAL ....28 
 
Eligibility Criteria .......................................................................................................28 
5.1.1 Inclusion Criteria ...........................................................................................28 
5.1.2 Exclusion Criteria ..........................................................................................30 
 
Withdrawal from the Study, Discontinuation of Investigational Product, or Study 
Termination ...............................................................................................................33 
5.2.1 Withdrawal from the Study or Discontinuation of the Investigational Product
 ........................................................................................................................33 
5.2.2 Subject Replacement ......................................................................................34 
5.2.3 Study Termination .........................................................................................34 
 
STUDY PROCEDURES ......................................................................................................35 
 
DESCRIPTION OF CLINICAL AND LABORATORY EVALUATIONS .......................36 
 
Clinical Evaluations ....................................................................................................36 
7.1.1 Vital Signs ......................................................................................................36 
7.1.2 Twelve-lead ECG ...........................................................................................36 
7.1.3 Medical History .............................................................................................36 
7.1.4 Physical Examination .....................................................................................37 
7.1.5 Assessment of Concomitant Medications/Treatments other than the 
Investigational Product ..................................................................................37 
 
Laboratory Evaluations ...............................................................................................38 
7.2.1 Clinical Laboratory Evaluations ....................................................................38 
7.2.2 Pharmacokinetic Sampling ............................................................................39 
7.2.3 Anti-AV-1 Antibody Sampling ......................................................................39 
7.2.4 Hypersensitivity Testing ................................................................................40 
7.2.5 Laboratory Specimen Preparation, Handling, and Storage ............................40 
7.2.6 Laboratory Specimen Shipping ......................................................................40 
 
ASSESSMENT OF SAFETY ...............................................................................................41 
 
Assessing and Recording Safety Parameters ..............................................................41 


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8.1.1 Adverse Events ..............................................................................................41 
8.1.2 Serious Adverse Events .................................................................................42 
 
Specification of Safety Parameters .............................................................................43 
8.2.1 Solicited and Unsolicited Events ...................................................................44 
8.2.2 Dose Escalation Criteria ................................................................................44 
8.2.3 Sentinel Subjects ............................................................................................44 
 
Reporting Procedures ..................................................................................................45 
8.3.1 Reporting Serious Adverse Events ................................................................45 
8.3.2 Regulatory Reporting .....................................................................................45 
8.3.3 Reporting of Pregnancy .................................................................................46 
 
Type and Duration of Follow-up of Subjects after Adverse Events ...........................46 
 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings......................................................................................46 
 
Halting Rules ..............................................................................................................47 
8.6.1 Dose Escalation Halting Criteria ...................................................................47 
8.6.2 Halting Criteria for Subject Infusions ............................................................47 
8.6.3 Study Halting Criteria ....................................................................................48 
 
Safety Oversight .........................................................................................................48 
8.7.1 Safety Review Committee .............................................................................48 
8.7.2 Safety Monitoring Committee .......................................................................49 
 
HUMAN SUBJECTS PROTECTION .................................................................................50 
 
Institutional Review Board .........................................................................................50 
 
Informed Consent Process ..........................................................................................50 
 
Subject Confidentiality ...............................................................................................51 
 
Certificate of Confidentiality ......................................................................................51 
 
Costs, Subject Compensation, and Research-Related Injuries ...................................52 
 
STATISTICAL CONSIDERATIONS .................................................................................53 
 Study Hypotheses .......................................................................................................53 
 Sample Size Considerations .......................................................................................53 
 Treatment Assignment Procedures .............................................................................53 
10.3.1 Randomization Procedures ............................................................................53 
10.3.2 Blinding ..........................................................................................................53 


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10.3.3 Breaking the Blind .........................................................................................54 
 Final Analysis Plan .....................................................................................................54 
10.4.1 Populations for Analysis ................................................................................54 
10.4.2 Statistical Analyses ........................................................................................54 
10.4.3 Pharmacokinetic Analyses .............................................................................55 
10.4.4 Anti-AV-1 Antibody Analyses ......................................................................56 
10.4.5 Safety Analyses ..............................................................................................56 
 Handling of Missing Data ...........................................................................................57 
 Interim Analyses .........................................................................................................57 
 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ..............58 
 
QUALITY CONTROL AND QUALITY ASSURANCE ...................................................59 
 
DATA HANDLING AND RECORD KEEPING ................................................................60 
 Data Management Responsibilities ............................................................................60 
 Data Coordinating Center/Biostatistician Responsibilities ........................................60 
 Data Capture Methods ................................................................................................60 
 Types of Data ..............................................................................................................60 
 Study Records Retention ............................................................................................60 
 Protocol Deviations ....................................................................................................61 
 
CLINICAL MONITORING .................................................................................................62 
 
PUBLICATION POLICY ....................................................................................................63 
 
LITERATURE REFERENCES ............................................................................................64 
 
APPENDICES ......................................................................................................................65 
 Appendix A. Schedule of Events ................................................................................65 
 Appendix B. Toxicity Tables ......................................................................................68 
 
 


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LIST OF ABBREVIATIONS 
λz 
apparent terminal elimination rate constant 
%AUCexp 
percentage of the area extrapolated for calculation of area under the 
serum concentration-time curve from time 0 extrapolated to infinity 
AE 
adverse event 
AUC0-∞ 
area under the serum concentration-time curve from time 
0 extrapolated to infinity 
AUC0-48 
area under the serum concentration-time curve from time 0 to 
48 hours postdose 
AUC 
area under the serum concentration-time curve 
AUC0-tlast 
area under the serum concentration-time curve from time 0 to the 
last quantifiable concentration 
BLQ 
below the limit of quantification 
bpm 
beats per minute 
CFR 
Code of Federal Regulations 
CL 
total serum clearance 
Cmax 
maximum observed serum concentration 
Ct 
last observed serum drug concentration 
CV 
coefficient of variation 
DENV 
dengue virus 
DHHS 
Department of Health and Human Services 
DMID 
Division of Microbiology and Infectious Diseases 
ECL 
electrochemiluminescence 
eCRF 
electronic case report form 
ECG 
electrocardiogram 
ELISA 
enzyme-linked immunosorbent assay 
ET 
early termination 
FDA 
Food and Drug Administration 
FWA 
Federal Wide Assurance 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IFN 
interferon 
IP 
investigational product 
IRB 
Institutional Review Board 
IV 
intravenous 
mAb 
monoclonal antibody 
NaCl 
sodium chloride 
NIH 
National Institutes of Health 
NOAEL 
no observed adverse effect level 


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OHRP 
Office for Human Research Protections 
PK 
pharmacokinetic(s) 
QTcF 
QTc interval corrected by Fridericia’s formula 
SAE 
serious adverse event 
SD 
standard deviation 
SMC 
safety monitoring committee 
SRC 
safety review committee 
t1/2 
apparent terminal half-life 
Tmax 
time to reach maximum observed serum concentration 
US 
United States 
Vz 
volume of distribution during the terminal phase 


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PROTOCOL SUMMARY 
Title: 
A Phase 1a, Double-Blind, Placebo-Controlled, Single 
Ascending Dose Study to Determine the Safety and 
Pharmacokinetics of AV-1 in Healthy Male and Female Adult 
Subjects 
Design of the Study: 
 
Double-blind, randomized, placebo-controlled, sequential-group, 
single ascending dose study in healthy adult subjects. Five 
different doses will be tested in sequential cohorts of 8 subjects 
each (randomly assigned 6:2 to receive a single intravenous dose 
of AV-1 or placebo) 
Study Phase: 
1a 
Study Population: 
40 healthy male and female subjects between 18 and 55 years of 
age 
Number of Sites: 
One site as follows: 
PPD Phase 1 Clinic 
 
 
Description of the 
Investigational Product: 
AV-1 is a fully human anti-flavivirus IgG1K monoclonal 
antibody to be administered intravenously in fixed single doses 
of 30, 90, 250, 500, and 1000 mg. 
Study Objectives: 
 
Primary: 
• 
To determine the safety of a single intravenous dose of AV-1 
in healthy adult subjects. 
Secondary: 
• 
To characterize the pharmacokinetics of AV-1 following a 
single intravenous dose. 
• 
To evaluate if subjects develop anti-AV-1 antibodies 
following a single intravenous dose of AV-1. 


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Duration of Individual 
Subject Participation: 
Subject participation will include an up-to-35-day screening 
period, admission to the clinic for a 5-day period, and 
8 follow-up visits through Day 120 (±5). 
Estimated Time to Last 
Subject/Last Study Day: 
Approximately 22 weeks 
 
 


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KEY ROLES 
Principal Investigator: 
 
PPD Phase 1 Clinic 
 
 
Tel: 
 
Email: 
  
Sponsor Medical Monitor: 
 
Sponsor Chief Scientist: 
Sponsor Representative: 
DMID Clinical Project 
Manager: 
Mountside Consulting, LLC 
Tel: 
 
Email: 
 
 
AbViro, LLC. 
 
Tel: 
 
Email: 
 
 
AbViro, LLC 
 
Tel: 
 
Email: 
 
 
Office of Biodefense, Research Resources, and Translational 
Research 
Division of Microbiology and Infectious Diseases, National 
Institute of Allergy and Infectious Diseases, National 
Institutes of Health, Department of Health and Human 
Services 
 
Tel: 
 
Email: 
 


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DMID Medical Officer: 
DMID Medical Monitor: 
Statistical and Data 
Coordinating Center: 
Bioanalytical Laboratory: 
 
Office of Clinical Research Resources 
Division of Microbiology and Infectious Diseases, National 
Institute of Allergy and Infectious Diseases, National 
Institutes of Health, Department of Health and Human 
Services 
 
 
Tel: 
 
Email: 
 
 
Office of Clinical Research Affairs 
Division of Microbiology and Infectious Diseases, National 
Institute of Allergy and Infectious Diseases, National 
Institutes of Health, Department of Health and Human 
Services 
 
 
Tel: 
 
Email: 
 
 
PPD 
 
 
Tel: 
 
Email: 
 
 
PPD 
 
Tel: 
 
Email: 
 


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BACKGROUND AND SCIENTIFIC RATIONALE 
 
Background 
AV-1 is a human monoclonal antibody (mAb) being investigated as a potential therapy for 
dengue, a mosquito-borne viral disease with extensive global public health impact. Current 
treatment options for dengue are limited to supportive care. Thus, a safe and effective therapeutic 
treatment would provide substantial public health benefits. 
Dengue virus (DENV) is a flavivirus transmitted by mosquitos of the Aedes genus and a major 
cause of disease in tropical and subtropical areas (Henchal and Putnak 1990). Over 2 billion 
people are thought to be at risk of DENV infection globally (Brady et al 2012) with an estimated 
390 million infections annually (95% credible interval 284 to 528 million), resulting in 
96 million clinical cases (95% credible interval 67 to 136 million) and 500,000 severe cases 
(Bhatt et al 2013; Guzman et al 2010).  
There are 4 known DENV serotypes (DENV-1, -2, -3, and -4). Exposure to any one serotype 
confers lifelong immunity to that serotype, however; subsequent exposure to a different serotype 
is associated with increased risk of severe disease. Data suggests that antibody-dependent 
enhancement due to subneutralizing antibodies may contribute to severe disease resulting from 
exposure to a second serotype (Schmidt 2010; Dejnirattisai et al 2010). 
While the majority of DENV infections are asymptomatic or result in a mild flu-like illness 
lasting 4 to 10 days, the disease known as dengue can be severe and life-threatening. Signs and 
symptoms of dengue disease include fever (≥38.5°C), headache, retro-orbital or ocular pain, 
muscle and joint pain, macular or petechial rash, bruising, vomiting, abdominal pain, and 
enlarged liver. Clinical laboratory features typically include thrombocytopenia, leukopenia, and 
elevated aminotransferases (Simmons et al 2012). The condition of some patients rapidly 
deteriorates after a 3- to 7-day febrile phase around the time of defervescence. During this 
critical period, which lasts 48 to 72 hours, some patients develop a systemic vascular leakage 
syndrome with hemoconcentration, hypoproteinemia, pleural effusions, and ascites. Patients with 
clinically significant vascular leakage may develop persistent vomiting, severe abdominal pain, 
tender hepatomegaly, serosal effusions, mucosal bleeding, and lethargy or restlessness. These 
severe dengue cases may develop hemorrhage, hypovolemic shock, respiratory distress, and 
organ failure, requiring prompt supportive care measures and judicious intravascular 
resuscitation. Other complications include liver failure, myocarditis, and encephalopathy but 
these are less frequent (Simmons et al 2012). 
AV-1 specifically recognizes a conformational epitope in the fusion loop of Domain II of the 
flavivirus envelope protein. The highly conserved epitope gives AV-1 the potential for 
broad-spectrum antiviral activity against flaviviruses, including DENV-1, -2, -3, and -4, and 
limits the emergence of viral resistance. It is thought that AV-1 elicits its antiviral effects by 
reduction in viral load through inhibition of virus membrane fusion with the host cell, although 


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mechanism of action studies to confirm this have not yet been performed. AV-1 has leucine to 
alanine substitutions at amino acid positions 234 and 235 in its Fc component (LALA 
substitutions), rendering it unable to bind to Fcγ receptors and complement.  
AV-1 is manufactured from a stable Chinese hamster ovary master cell bank. The drug product is 
aseptically filled into vials with closure, resulting in a sterile injectable buffered solution suitable 
for clinical use. AV-1 will be administered in the Phase 1a clinical study as a single intravenous 
(IV) dose prepared in United States Pharmacopeia grade sterile 0.9% sodium chloride (NaCl) in 
water for injection (0.9% NaCl). 
The target population for AV-1 is anticipated to include those with suspected or confirmed 
dengue. 
 
Scientific Rationale 
2.2.1 Purpose of Study 
AV-1 has not previously been tested in humans. The primary objective of this study is to 
determine the safety of AV-1 in healthy male and female adult subjects when administered as a 
single IV infusion. Additionally, the pharmacokinetics (PK) and the incidence of anti-AV-1 
antibody responses will be studied. This first-in-human clinical safety study will provide 
important information to help guide further development of AV-1 as a potential countermeasure 
against dengue. 
2.2.2 Rationale for Study 
There are currently no approved treatments for dengue. AV-1, a fully human mAb, is being 
developed to address this unmet medical need. The nonclinical studies supporting the potential of 
AV-1 are briefly summarized. A more detailed summary of the nonclinical studies is available in 
the investigator’s brochure (AbViro, LLC 2019). 
AV-1 safety studies were conducted in compliance with Title 21 Code of Federal Regulations 
(CFR) Part 58 Good Laboratory Practice (GLP) for Nonclinical Laboratory Studies, including a 
human tissue cross-reactivity study and a 2-week IV dose toxicity and toxicokinetic study in 
Sprague-Dawley rats with a 1-week interim necropsy and an 8-week recovery. The human tissue 
cross-reactivity study showed AV-1 does not bind to normal human tissue. No AV-1-related 
deaths or adverse effects from AV-1 administered as either a single dose or multiple doses were 
observed in rats up to the highest tested dose of 300 mg/kg/day, which was the determined 
no-observed-adverse-effect level (NOAEL) dose. 
Nonclinical results suggest AV-1 has potential for treatment of dengue. In vitro studies showed 
AV-1 neutralizes all 4 DENV serotypes (DENV-1, -2, -3, -4), including 2 strains from each 
serotype prepared from recent clinical cases (2008 to 2016) and support the conclusion that 
DENV does not develop resistance to AV-1. In vivo, AV-1 protected 90 to 100% of AG129 mice 
(129/Sv, lacking receptors for interferon [IFN]-α, IFN-β, and IFN-γ, while keeping the adaptive 


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immune system intact) from death for the duration of the study (10 days) when administered at a 
dose as low as 7.5 mg/kg prior to or 1 day after lethal challenge with DENV. These doses, given 
prophylactically, also resulted in reduction of virus levels in serum and tissues and reduced 
tumor necrosis factor alpha levels in serum. AV-1 protected 80% of mice from death for the 
duration of the study (10 days) when administered 2 days following the virus challenge at a dose 
of 37.5 mg/kg. Results from both in vitro and in vivo studies indicate AV-1 avoid 
antibody-dependent enhancement of DENV as a result of the LALA substitutions. 
The initial starting dose of 30 mg considers the standard maximum starting dose calculations as 
described in the FDA Guidance for Industry Estimating the Maximum Safe Starting Dose in 
Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers (DHHS 2005), which 
indicates a minimum 10 times safety margin for selection of an initial clinical dose. The 
proposed initial starting dose provides a >90-fold safety margin when compared to the human 
equivalent dose NOAEL identified from the nonclinical safety study. The highest planned dose 
of 1000 mg was selected as it provides an approximately 3-fold safety margin compared with the 
NOAEL. 
Doses will be increased approximately 3-fold for the initial lower doses (30, 90, and 250 mg) and 
then increased 2-fold at the higher dose levels (500 and 1000 mg). No drug-related toxicity is 
anticipated based on nonclinical safety data; however, the more conservative dose increases at 
higher doses will provide greater opportunity to assess and identify safety risks. 
The nonclinical data supports AV-1 safety and potential efficacy and justifies the planned 
Phase 1a clinical study to assess AV-1 safety in a healthy adult population. The first step will be 
to conduct a Phase 1a safety trial. The study will be a double-blind, randomized, 
placebo-controlled, sequential-group, single-ascending dose study in healthy adult subjects. Five 
different doses will be tested in sequential cohorts of 8 subjects each, of which, 6 subjects will 
receive AV-1 and 2 subjects will receive placebo per cohort. 
2.2.3 Study Population 
Because this is an exploratory Phase 1a study to assess the safety and PK of a single IV dose of 
AV-1, and to determine if subjects develop anti-AV-1 antibodies, the most relevant population is 
healthy subjects as recommended by the FDA (ICH 1997). A combination of factors have been 
used to select the study population, including consideration of the patient population for AV-1, 
the estimated blood sample volume, and the stage of development. 
Both males and females aged 18 to 55 years will be enrolled in this study to represent the 
potential patient population who may receive AV-1 in future clinical studies. 


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Potential Risks and Benefits 
2.3.1 Potential Risks 
No clinical trials in humans have been conducted. Nonclinical GLP-compliant safety studies 
have indicated no safety concerns. However, as this is a first-in-human for AV-1, unexpected 
adverse events (AEs) are possible in humans. 
Potential theoretical risks associated with the clinical evaluation of AV-1 in humans include 
immune reactions to AV-1 or its excipients or unintended adverse effects related to the 
specificity of the antibody. Potential AEs may occur immediately following infusion or be 
delayed and may range from mild to severe. 
Consideration to these potential risks was included in the design of both the AV-1 product and 
the first-in-human clinical study. Subjects will be screened to ensure enrollment of only healthy 
adult subjects without significant underlying medical issues or history of hypersensitivity. 
AV-1 is a fully human mAb that reduces the risk of immunogenicity-related complications. 
Additionally, subjects will receive only a single dose of AV-1, further limiting risk of 
immunogenicity more likely to result from repeated exposures. A single dose will also limit 
exposure and allow reversibility of any treatment-related adverse effects. The initial fixed 
starting dose of 30 mg allows for a >90-fold safety margin based on nonclinical data based on 
the FDA guidance (DHHS 2005). Sentinel dosing will be employed for each dose level to further 
limit the impact of unforeseen drug-related adverse safety outcomes. 
Risk of acute reactions will be managed through close monitoring of subjects during and 
following administration of the investigational product (IP) infusion. Subjects will be admitted 
and remain in the clinical site beginning the day prior to the IP infusion (Day –1) through 
discharge on Day 5 to allow for regular monitoring for hypersensitivity and both laboratory or 
systemic adverse effects of IP dosing. Eight planned outpatient visits will follow subjects for 
approximately 120 (±5) days after dosing to afford an appropriate amount of time to observe 
delayed AV-1-related AEs prior to subject completion of the study. Review of cumulative safety 
data will be performed prior to dose escalations. 
2.3.2 Potential Benefits 
There are no benefits to the subjects from taking part in this study. This study is necessary to 
characterize the initial safety of AV-1 prior to additional clinical studies to further evaluate the 
safety and efficacy of AV-1 for treatment of dengue, an unmet medical need. 
2.3.3 Risk-Benefit Ratio 
AV-1 is a fully human mAb that lacks human tissue targets and has an unremarkable nonclinical 
safety profile. The nonclinical profile of AV-1 indicated no safety signals and supports 
evaluation in humans starting at an initial dose of 30 mg. The clinical study design includes 
monitoring for potential risks of AV-1. No therapy is currently approved for treatment of DENV 


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disease, leaving an unmet medical need. Therefore, the overall risk-benefit balance for 
evaluating the safety, PK, and incidence of anti-AV-1 antibody responses to AV-1 in healthy 
subjects is considered to be acceptable. 


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STUDY DESIGN, OBJECTIVES, AND ENDPOINTS 
 
Study Design Description 
This is a Phase 1a, first-in-human, single-center, double-blind, randomized, placebo-controlled, 
sequential-group, single ascending dose study in healthy adult subjects. Five sequential cohorts 
of 8 subjects each (Cohorts 1 to 5) are planned for this study. The starting dose of AV-1 will be 
30 mg and the planned doses for subsequent cohorts are 90, 250, 500, and 1000 mg. All 
references to the IP within the content of the protocol apply to AV-1 and placebo. 
The study will consist of a screening period, check-in, a treatment period, and 8 follow-up visits 
for each cohort. 
Potential subjects will be screened to assess their eligibility to enter the study within 35 days 
prior to IP administration. Study site staff will obtain written consent per the standard informed 
consent process outlined in Section 9.2 before conducting protocol-specific screening activities. 
Eligible subjects will check in to the clinical site on Day –1 (the day before dosing). After 
reverification of eligibility, subjects will be randomly assigned before dosing on Day 1 to AV-1 
or placebo in a 6:2 ratio. In each cohort, subjects will fast overnight (nothing to eat or drink 
except water) for at least 10 hours before the start of the IP infusion. Subjects will remain fasted 
for 4 hours after dosing with the IP. Subjects will be randomly assigned to receive AV-1 or 
placebo as follows: 
• Cohort 1: AV-1 30 mg (n = 6) or placebo (n = 2) administered as an IV dose 
• Cohort 2: AV-1 90 mg (n = 6) or placebo (n = 2) administered as an IV dose 
• Cohort 3: AV-1 250 mg (n = 6) or placebo (n = 2) administered as an IV dose 
• Cohort 4: AV-1 500 mg (n = 6) or placebo (n = 2) administered as an IV dose 
• Cohort 5: AV-1 1000 mg (n = 6) or placebo (n = 2) administered as an IV dose 
Sentinel dosing will be used in each cohort as discussed in Section 8.2.3. In each cohort, the 
Investigator will review safety data for the sentinel subjects and notify the Sponsor of intent to 
proceed with dosing the rest of the cohort with a minimum of 72 hours between dosing of the 
sentinel subjects and dosing the rest of the cohort. Safety data through Day 8 will be reviewed in 
a blinded fashion by the safety review committee (SRC) (Section 8.7.1) for each dose cohort 
before escalating to the next dose cohort (Section 8.2.2). Based on the review of safety and PK 
data, the Sponsor and the Investigator may choose to repeat a dose level, administer a dose less 
than the previous dose, escalate to a dose lower than the next planned dose, or prolong the 
duration of the infusion. 
On Day 5, subjects will be discharged after all protocol-specified assessments have been 
completed. Subjects will return for 8 follow-up visits on Days 8 (+2), 15 (±2), 22 (±2), 29 (±2), 
43 (±3), 57 (±3), 85 (±5), and 120 (±5). Subjects will be asked to attend an early termination 


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(ET) visit if they withdraw or are withdrawn from the study prior to the final follow-up visit on 
Day 120 (±5).  
Safety, PK, and anti-AV-1 antibody endpoints will be evaluated in the study. Clinical laboratory 
evaluations, physical examination findings, vital sign measurements, safety 12-lead 
electrocardiograms (ECGs), incidence and severity of AEs, and incidence of serious AEs (SAEs) 
will be monitored to assess safety (Section 7 and Section 8).  
Blood samples for PK analysis of AV-1 will be collected predose (within 15 minutes); at 0.5, 
1 (end of infusion), 1.25, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours after the start of infusion; Day 5 
prior to discharge; and at the follow-up visits on Days 8 (+2), 15 (±2), 22 (±2), 29 (±2), 43 (±3), 
57 (±3), 85 (±5), and 120 (±5) (or ET) (Section 7.2.2). 
Blood samples for anti-AV-1 antibody analysis will be collected on Day –1 and on Days 29 (±2) 
85 (±5), and 120 (±5) (or ET) to evaluate for the presence of pre-existing or treatment-emergent 
anti-AV-1 antibodies. 
A blood sample will be collected at baseline for hypersensitivity testing and additional samples 
will be collected if a suspected hypersensitivity reaction or anaphylactic response occurs 
(Section 7.2.4). 
Subjects will be confined to the clinical unit from Day –1 until discharge on Day 5. The planned 
duration for each cohort (screening to final follow-up visit) is approximately 22 weeks. 
 
Study Objectives 
3.2.1 Primary  
The primary objective of this study is to determine the safety of a single IV dose of AV-1 in 
healthy adult subjects. 
3.2.2 Secondary 
The secondary objectives of the study are the following: 
• 
To characterize the PK of AV-1 following a single IV dose. 
• 
To evaluate if subjects develop anti-AV-1 antibodies following a single IV dose of AV-1. 
 
Study Endpoints 
3.3.1 Primary Endpoint 
The primary safety endpoints are clinical laboratory evaluations (hematology, chemistry, 
urinalysis), physical examination findings, vital sign measurements, safety 12-lead ECG 
parameters, incidence and severity of AEs, and incidence of SAEs. 


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3.3.2 Secondary Endpoints 
The secondary endpoints of the study are the following: 
• 
Single dose PK including area under the serum concentration-time curve (AUC) from time 
0 to infinity (AUC0-∞), AUC from time 0 to 48 hours postdose (AUC0-48), AUC from time 
0 to the time of the last quantifiable concentration (AUC0-tlast), maximum observed serum 
concentration (Cmax), time of the Cmax (Tmax), apparent serum terminal elimination half-life 
(t1/2), total serum clearance (CL), and volume of distribution during the terminal phase (Vz) 
calculated from serum AV-1 levels measured using an electrochemiluminescence (ECL) 
enzyme-linked immunosorbent assay (ELISA). 
• 
Incidence of anti-AV-1 antibodies as measured by the proportion of subjects with detectable 
anti-AV-1 antibody signal in serum, including treatment-emergent anti-AV-1 antibodies, 
using an ECL ELISA. 


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INVESTIGATIONAL PRODUCT 
 
Investigational Product Description 
AV-1 
AV-1 is a fully human IgG1K mAb that targets the conserved fusion loop structure of the virus 
envelope protein. AV-1’s Fc portion has been engineered with leucine to alanine substitution of 
amino acids at positions 234 and 235 to avoid dengue antibody-dependent enhancement. Clinical 
doses will be prepared at the study site pharmacy in sterile 0.9% NaCl. AV-1 is being developed 
for treatment of dengue. 
Placebo 
The placebo is commercially available sterile 0.9% NaCl. 
4.1.1 Formulation, Packaging, and Labeling 
The AV-1 drug substance is formulated in 20 mM citrate (pH 5.6), 150 mM NaCl, and 
0.025% polysorbate 80 to a nominal concentration of 25 mg/mL of the AV-1 antibody. 
AV-1 will be supplied as a sterile, clear, colorless to pale yellow solution filled in a primary 
glass container with coated stopper and aluminum seal. The lower end of the fill volume range is 
controlled to ensure at least 4 mL recovery (100 mg total) from each vial during use.  
The AV-1 drug product will be labeled according to manufacturer or regulatory specifications 
and include the statement “Caution: New Drug – Limited by Federal Law to Investigational 
Use.” 
4.1.2 Product Storage and Stability 
AV-1 
AV-1 must be stored in a secure area at 2°C to 8°C (36°F to 46°F). The study site pharmacy has 
continuous temperature monitoring with alarm notification. Vials should not be shaken. 
Current stability data shows AV-1 is stable when stored at 2°C to 8°C (36°F to 46°F) for at least 
18 months. Stability testing is ongoing and planned for at least 24 months. Infusion set 
compatibility and stability testing was performed using the same materials intended for the 
conduct of the clinical study. 
Placebo 
Placebo solution will be stored at room temperature within the study site pharmacy. 


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Acquisition 
The Sponsor will provide the Investigator and clinical unit with adequate quantities of AV-1 and 
placebo. AV-1 will be stored and shipped from the AbViro-specified distribution center to the 
clinical site. Once received, AV-1 will be stored in the study site pharmacy and dispensed by the 
study site pharmacy to the study site staff. Unused product may be destroyed.  
 
Preparation and Administration of Investigational Product 
The IP will be aseptically prepared as per the pharmacy manual by delegated unblinded 
pharmacy personnel in INTRAVIA bags with pre-primed infusion set with a blunt tip cannula 
prior to IV infusion.  
AV-1 will be diluted to the appropriate dose in sterile 0.9% NaCl. Diluted AV-1 should be clear 
and colorless. 
The IP will be administered on the morning of Day 1 as a single IV infusion at planned nominal 
doses of 30, 90, 250, 500, and 1000 mg delivering the full product volume in 60 minutes. The 
exact dose will be determined following a safety data review after each cohort. 
Complete instructions for the preparation of the IP are described in the pharmacy manual. 
 
Accountability Procedures for the Investigational Product 
The FDA requires accountability of the IPs. The pharmacist is responsible for ensuring that a 
current record of IP accountability is maintained, and that the IP is dispensed only at an official 
clinical site by authorized personnel as required by applicable regulations and guidelines. 
Records of IP accountability will consist of the date received, date administered, quantity 
administered, and the subject number to whom the drug was administered.  
The pharmacist will be responsible for maintaining accurate records of the shipment and 
dispensing of the IP. The pharmacy records must be available for inspection by the Division of 
Microbiology and Infectious Diseases (DMID) monitoring contractors and is subject to 
inspection by a regulatory agency (eg, the FDA) at any time. An assigned blinded study monitor 
will review the pharmacy records. 
Unused AV-1 vials will be stored upright at 2oC to 8oC in the study site pharmacy until clinical 
trial accountability is completed. At study termination, all unused AV-1 will be disposed of in 
accordance with the pharmacy manual. 


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SELECTION OF SUBJECTS AND STUDY ENROLLMENT 
AND WITHDRAWAL 
 
Eligibility Criteria 
Eligible subjects unable to participate in the study due to a scheduling conflict or if the group 
they are screening for has completed enrollment may be rescreened for participation in a later 
group.  
A subject who has failed screening may also be rescreened for participation in a later group at 
the discretion of the Investigator and with Sponsor agreement based on the following criteria: 
1. In the opinion of the Investigator, the parameter value does not represent a chronic condition 
that otherwise will preclude the volunteer from enrolling in the study; and  
2. In the opinion of the Investigator, the abnormality is not likely to recur. 
Tests that do not allow for a rescreen include the following: 
• 
Positive human immunodeficiency virus, hepatitis B surface antigen, or hepatitis C virus 
antibody 
• 
Positive flavivirus screen 
• 
Positive urine drug screen 
In these cases, a new screening number must be assigned for each subject who is rescreened, and 
a new informed consent form (ICF) must be signed. 
5.1.1 Inclusion Criteria 
Each volunteer must meet all the following criteria to be enrolled in this study: 
1. Is a male or nonpregnant, nonlactating female, of any race, between 18 and 55 years of age, 
inclusive, at Screening. 
2. Has a body mass index between 18.5 and 29.9 kg/m2, inclusive, at Screening. 
3. Is in good health at Screening and reaffirmed on Day –1. 
a. Good health is defined by the absence of a medical condition described in the exclusion 
criteria and based on screening medical history, physical examination, vital signs, and 
12-lead ECG.  
b. If the subject has another current, ongoing chronic medical condition, the condition 
cannot meet any of the following criteria:  


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I. 
First diagnosed within 3 months of enrollment; or 
II. 
A pre-existing medical condition that is not exclusionary but has worsened in 
terms of clinical outcome within 3 months of enrollment; or 
III. 
Involves need for medication that may pose a risk to the subject’s safety or 
impede assessment of AEs or anti-AV-1 antibody response if they participate 
in the study. 
4. Female subjects must have a negative serum beta-human chorionic gonadotropin pregnancy 
test at Screening and Check-in on Day –1 and, on admission to the unit, must not be 
lactating. 
5. Female subjects must fulfill one of the following criteria as confirmed at Screening: 
a. Postmenopausal women must have had ≥12 months of spontaneous amenorrhea with 
follicle-stimulating hormone concentration consistently ≥40 mIU/mL and must have a 
negative pregnancy test result at Screening and Check-in on Day –1. 
b. Surgically sterile women, defined as those who have had a hysterectomy, bilateral 
ovariectomy (oophorectomy), or bilateral tubal ligation. Women who are surgically 
sterile must provide documentation of the procedure by an operative report or relevant 
medical records, and must have a negative pregnancy test result at Screening and 
Check-in. 
c. Be willing to remain abstinent (not engage in sexual intercourse) from Check-in on 
Day -1 until the final follow-up visit on Day 120 (±5). 
d. Be willing to use one of the following acceptable methods of birth control until the final 
follow-up visit on Day 120 (±5): intrauterine device with spermicide; a female condom 
with spermicide; contraceptive sponge with spermicide; an intravaginal system (eg, 
NuvaRing®); a diaphragm with spermicide; a cervical cap with spermicide; or oral, 
implantable, transdermal, or injectable hormonal contraceptives beginning 3 months 
prior to dosing. 
6. Male subjects who are biologically capable of fathering children must agree and commit to 
use of an adequate form of double-barrier contraception and refrain from sperm donation 
from Check-in on Day –1 until the final follow-up visit on Day 120 (±5). A male subject is 
considered capable of fathering children even if his sexual partner is sterile or using 
contraceptives. 
7. Has not traveled outside the US within 60 days prior to Day –1 and agrees to not travel 
outside the US through the final follow-up visit on Day 120 (±5). 


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8. Agrees to abide by the study restrictions and is willing to sign an ICF. 
5.1.2 Exclusion Criteria 
Volunteers meeting any of the following criteria will be excluded from the study: 
1. Has any significant medical condition that, in the opinion of the Investigator or Sponsor, 
would interfere with the subject’s ability to participate in the study or increase the risk of 
participating for that subject based on the investigator’s brochure and the safety profile of 
AV-1. 
a. Significant medical condition includes, but is not limited to, kidney disease with 
creatinine clearance <90 mL/min/1.73 cm2 (CKD-EPI method), known active liver 
disease (including steatosis), ischemic heart disease, cardiac conduction disorder, 
chronic intestinal disease, hypertension (including treated), arrythmia requiring 
treatment, diabetes requiring insulin, neuropathy, myopathy, and malignancy (not 
including squamous cell skin cancer, basal cell skin cancer, or cervical low-grade 
squamous intraepithelial lesions).  
b. Congenital nonhemolytic hyperbilirubinemia syndromes (eg, Gilbert’s syndrome) are not 
acceptable. 
2. Has one or more symptoms of a urinary tract infection (eg, dysuria, frequent, urgency, or 
suprapubic pain) at Screening or Check-in on Day –1. 
3. Has a 12-lead ECG with: 
a.  Any clinically important abnormalities in rhythm, conduction, or morphology of the 
resting ECG and any clinically important abnormalities in the 12-lead ECG that, in the 
Investigator’s opinion, may interfere with the interpretation of QTc interval changes, 
including abnormal ST-T-wave morphology. 
b. QT interval corrected by Fridericia’s formula (QTcF) of >450 msec in men or 
>460 msec in women.  
c. PR >220 msec. 
d. Second or third degree atrioventricular block or atrioventricular dissociation.  
e. Complete left or right bundle branch block. 
f. Ventricular or atrial premature contractions in couplets or higher in grouping. 
4. Has abnormal laboratory values for any of the hematology, serum chemistry, coagulation, or 
urinalysis tests outlined in Section 7.2.1 at Screening or Check-in on Day –1.  


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5. Is positive for hepatitis B surface antigen, hepatitis C virus antibody, or human 
immunodeficiency virus antibody types 1 and 2 within 35 days of enrollment. 
6. Has any psychiatric condition or history of psychiatric condition that, in the opinion of the 
Investigator or Sponsor, would interfere with the subject’s ability to participate in the study 
or increase the risk of the participation for that subject.  
7. Is unwilling to abstain from alcohol, caffeine-, or other xanthine-containing foods or 
beverages, tobacco or nicotine-containing products, and all bergamottin-containing fruits and 
fruit juices (eg, Seville-oranges, grapefruit or grapefruit juice, pomelos, pomegranate or 
pomegranate juice, cranberry or cranberry juice) 72 hours prior to Day –1 and through 
discharge on Day 5. 
8. Is unwilling to abstain from strenuous exercise 7 days before Day –1 through Day 15. 
9. Has a history of alcoholism or drug/chemical abuse within 6 months prior to Day –1. 
10. Has excessive alcohol consumption (regular alcohol intake >21 units per week for male 
subjects and >14 units of alcohol per week for female subjects) (1 unit is equal to 
approximately ½ pint [200 mL] of beer, 1 small glass [100 mL] of wine, or 1 measure 
[25 mL] of spirits). 
11. Has a positive urine drug screen at Screening or Check-in on Day –1.  
12. Has a positive cotinine urine test at Check-in on Day –1. 
13. Has any confirmed or suspected immunosuppressive or immunodeficient condition, 
including, but not limited to, human immunodeficiency virus infection, or use of anti-cancer 
chemotherapy or radiation therapy (cytotoxic) in the 3 years prior to Screening. 
14. Provides verbal history of vaccination with a licensed or investigational flavivirus vaccine for 
any of the following diseases: Zika virus, DENV, yellow fever virus, Japanese encephalitis 
virus, West Nile virus, St. Louis encephalitis virus, or tick-borne encephalitis virus or 
reportedly diagnosed with a flavivirus infection or disease. 
15. Plans to receive a licensed flavivirus vaccine or participate in a flavivirus vaccine trial during 
the study. 
16. Is positive for DENV or West Nile virus by immunoglobulin M, or immunoglobulin G, or 
Zika by immunoglobulin M serology testing within 35 days of enrollment. 
17. Has a history of significant hypersensitivity, intolerance, or allergy to any drug compound, 
food, or other substance, unless approved by the Investigator (or designee). 


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18. Has had major surgery within 3 months prior to Screening or plans to have a major surgery 
during the study through the final follow-up on Day 120 (±5). 
19. Has been previously treated for a medical condition with a licensed monoclonal or polyclonal 
antibody any time in the past. 
20. Has been dosed in a clinical study involving administration of an investigational monoclonal 
or polyclonal antibody in the 18 months (550 days) prior to IP administration on Day 1. 
21. Has received an investigational drug within 28 days of IP administration on Day 1. 
22. Has used any prohibited medication within 30 days prior to Day –1 or plans to use prohibited 
medication during the study. 
a. Prohibited medications include immunosuppressive drugs, immune modulators (except 
acetaminophen), oral corticosteroids, inhaled or intranasal steroids (<800 µg/day 
beclomethasone is acceptable), and anti-neoplastic agents. Topical steroids are 
acceptable. 
23. Has received or plans to receive any live vaccination, experimental or otherwise, within 
28 days prior to or after Day 1; and receipt or planned receipt of an inactivated vaccination 
(or any COVID-19 vaccine), experimental or otherwise, within 14 days prior to or after 
Day 1. 
24. Has received blood products within 60 days prior to Day –1. 
25. Has donated or lost more than 450 mL of blood or plasma within 56 days of IP infusion on 
Day 1. The subject must also agree to refrain from donating blood or plasma during the 
study. 
26. Has poor peripheral venous access. 
27. Has previously completed or withdrawn from this study. 
28. Is a current study site staff paid entirely or partially by the contractor for this trial, or staff 
who are supervised by the Investigator or subinvestigators. 
29. In the opinion of the Investigator (or designee), the subject is not suitable for entry into the 
study. 


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Withdrawal from the Study, Discontinuation of Investigational Product, 
or Study Termination  
5.2.1 Withdrawal from the Study or Discontinuation of the Investigational Product  
Subjects are free to withdraw from the study at any time upon request. Subject participation in 
the study may be stopped at any time at the discretion of the Investigator or at the request of the 
Sponsor.  
The Sponsor will be notified in advance whenever possible if subjects are stopped at the 
discretion of the Investigator. When a subject withdraws from the study or is stopped, the 
reason(s) are to be recorded by the Investigator on the relevant page of the electronic case report 
form (eCRF). Whenever possible, any subject who withdraws or is stopped from the study 
prematurely will undergo all ET assessments. Any subject who fails to return for final 
assessments will be contacted by the clinical site in an attempt to have them comply with the 
protocol. The status of subjects who fail to complete final assessments will be documented in the 
eCRF.  
The reasons for stopping subject participation by the Investigator or Sponsor include, but are not 
limited to the following: 
• 
The subject meets individual halting criteria (Section 8.6.2). 
• 
Subject noncompliance based on any of the following criteria after IP administration and 
before completion of all follow-up visits through Day 120 (±5):  
• 
Positive urine drug screen 
• 
Has major surgery 
• 
Received another IP 
• 
Uses prohibited medication 
• 
Receives blood products or donates blood or plasma 
• 
An AE 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. 
• 
The subject is lost to follow-up. 
• 
Subjects becoming pregnant prior to or following IP administration prior to the final 
follow-up visit on Day 120 (±5). Subject becoming pregnant after IP administration will not 
be included in data analysis but will be followed for safety. 
If the subject consents, every attempt will be made to follow all AEs through resolution 
including those subjects that elect to withdraw. The procedures that collect safety data for the 


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purposes of research must be inclusive in the original ICF or the Investigator may seek 
subsequent informed consent using an IRB-approved consent form with the revised procedures. 
The Investigator will inform the subject that already collected data will be retained and analyzed 
even if the subject withdraws from this study. 
5.2.2 Subject Replacement 
Any subject who withdraws before completing the study but after receiving IP may be replaced 
at the discretion of the Investigator and in consultation with the Sponsor. Any replacement 
subject will be assigned to receive the same treatment as the subject he or she is replacing. 
5.2.3 Study Termination  
Although the Sponsor has every intention of completing the study, they reserve the right to 
discontinue it at any time for clinical or administrative reasons. 
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 therapy or follow-up for the subjects, as necessary. The Investigator will provide a 
detailed written explanation of the termination to the IRB. 
The end of the study is defined as the date on which the last subject completes the last visit 
(including the ET visit and any additional long-term follow-up). Any additional long-term 
follow-up that is required for monitoring of the resolution of an AE or finding may be appended 
to the clinical study report. 


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STUDY PROCEDURES 
Before performing any study procedures, all potential subjects will sign an ICF as outlined in 
Section 9.2. 
A complete schedule for all study procedures is detailed in the schedule of events (Section 17.1). 
The IP will be administered in the clinical unit under direct observation of clinic personnel and 
will be recorded in the eCRF. Clinic personnel will confirm that the subject has received the 
entire dose of the IP. Complete information regarding any partial or interrupted infusions will be 
documented. The date and time (start and stop) of IP dosing will be recorded on the appropriate 
page in the eCRF. 
A study physician will be present at the time of IP administration and the subject will be under 
observation during the 60-minute infusion. Vital signs will be monitored, and an ECG will be 
recorded prior to, during, and after the infusion as outlined in the schedule of events 
(Section 17.1). The study site staff will observe the subjects closely for signs and symptoms of 
infusion-related reactions, including anaphylaxis and anaphylactoid type reactions. Should an 
adverse reaction of this type occur, the subject will be treated using the standard protocol at the 
clinical site. Infusion-related AEs and suspected hypersensitivity reactions will be documented, 
including the clinical presentation and severity (based on the grading scales in Section 17.2) of 
the event. 
For the specified time points, PK sample collection will take precedence over all other study 
sampling procedures and will therefore occur at the nominal time as described in Section 7.2.2. 
Multiple non-PK study procedures scheduled at the same time point should be performed as 
close as possible to the nominal time point (within 60 minutes predose and within 30 minutes for 
postdose time points). When procedures overlap or occur at the same time point, all blood draws 
should follow ECGs or vital signs, and PK sampling should be timed to occur last and as close to 
the scheduled time window as possible. The total amount of blood collected from each subject 
over the duration of the study, including any extra assessments that may be required, will not 
exceed 500 mL. Refer to the laboratory manual for specific details on blood volumes used for 
laboratory testing. 


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DESCRIPTION OF CLINICAL AND LABORATORY 
EVALUATIONS 
The timing and frequency of all safety assessments are listed in the schedule of events 
(Section 17.1). 
 
Clinical Evaluations 
Safety endpoints will include monitoring and recording of AEs and SAEs, clinical laboratory test 
results (hematology, chemistry, and urinalysis), vital sign measurements, 12-lead ECG results, 
and physical examination findings. 
For all safety assessments, the Investigator will determine whether results are clinically 
significant, which is defined as any variation in a result that has medical relevance and may 
result in an alteration in medical care (eg, active observation, diagnostic measures, or therapeutic 
measures). If clinical significance is noted, the result and reason for significance will be 
documented on the AE page in the subject’s eCRF and the Investigator will monitor the subject 
until the result has reached the reference range or the result at Screening, or until the Investigator 
determines that follow-up is no longer medically necessary. 
7.1.1 Vital Signs 
Vital sign measurements will include systolic and diastolic blood pressure, oral body 
temperature, heart rate, and respiratory rate. The subject will have rested comfortably in a seated 
or supine position for at least 5 minutes before all measurements are taken. For time points when 
ECGs and vital signs occur at the same time point, it is acceptable to perform the vital sign 
measurements approximately 2 minutes after the ECG as long as the subject remains resting in 
the supine position. Additional vital signs may be measured for safety of the subjects at the 
discretion of the Investigator. All measurements will be recorded in the subject’s eCRF. 
7.1.2 Twelve-lead ECG 
Twelve-lead ECG recordings will be obtained after the subject has rested comfortably in a supine 
position, for at least 10 minutes. The Investigator should review and sign the ECG for any 
immediate issues. Electrocardiogram assessments will include comments on whether the tracings 
are normal or abnormal, rhythm, presence of arrhythmia or conduction defects, morphology, any 
evidence of myocardial infarction, or ST-segment, T-wave, and U-wave abnormalities. In 
addition, measurements of the following intervals will be measured and reported: RR interval, 
PR interval, QRS width, and QTcF. 
7.1.3 Medical History 
Medical history will be obtained by direct interview and include a history of significant medical 
disorders of the head, eyes, ears, nose, throat, cardiovascular system, lungs, gastrointestinal tract, 


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liver, kidney, urologic, nervous system, blood, lymph glands, endocrine system, musculoskeletal 
system, skin, and genital/reproductive tract. A history of any allergies, cancer, 
immunodeficiency, psychiatric illness, substance abuse, and autoimmune disease will be 
solicited. The medical history will include current and past medical diagnoses, hospitalizations, 
and major surgical procedures. 
At each visit, subjects will be asked about any changes in health, new or worsening symptoms, 
or medications taken since their last visit. Any new adverse health changes will be recorded as an 
AE. 
7.1.4 Physical Examination 
A full physical examination will be performed at Screening (skin, head, ears, eyes, nose, throat, 
neck, thyroid, lungs, heart, cardiovascular, abdomen, lymph nodes, and musculoskeletal 
system/extremities). Focused examination (lungs, cardiovascular, abdomen, and skin) will be 
performed at Check-in (Day –1) and on Days 5, 8, and 15. Targeted, symptom-directed physical 
examinations will be performed at all other follow-up visits. 
7.1.5 Assessment of Concomitant Medications/Treatments other than the Investigational 
Product 
Restrictions for prior and concomitant medications and therapies are provided in Section 5.1.1 
and Section 5.1.2. Prior and concomitant medications and therapies will be coded using the latest 
version of the World Health Organization Drug Dictionary. 
7.1.5.1 
Prior Medications 
Information regarding prior medications taken by the subject within the 30 days before signing 
the ICF will be recorded in the subject’s eCRF. 
7.1.5.2 
Concomitant Medications 
The Investigator is responsible for ensuring that details regarding the medication are adequately 
recorded in the subject’s source documents and in the eCRF. Medication information will be 
recorded at the Screening visit for the prior 30 days and at Day –1. At each follow-up study visit, 
new concomitant medication and changes to existing medications will be recorded. Any 
concomitant medication deemed necessary for the welfare of the subject during the study may be 
given at the discretion of the Investigator. If a concomitant medication is taken, except for those 
specified in the protocol, a joint decision will be made by the Investigator and the Sponsor to 
continue or discontinue the subject based on the time the medication was administered, its 
pharmacology and PK, and whether the use of the medication will compromise the safety of the 
subject or the interpretation of the data. 


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Laboratory Evaluations 
7.2.1 Clinical Laboratory Evaluations 
The following clinical laboratory assessments will be performed at the time points indicated in 
the schedule of events (Section 17.1): 
Hematology 
Absolute neutrophil count, hemoglobin, platelet count, and white 
blood cell count 
Serum Chemistry 
Alanine aminotransferase, albumin(a), alkaline phosphatase, aspartate 
aminotransferase, bicarbonate(b), blood urea nitrogen, calcium(a), 
chloride(b), creatinine(c), glucose (fasted), potassium, sodium, and 
total bilirubin 
Coagulation(a) 
Prothrombin time and activated partial thromboplastin time 
Urinalysis 
Blood, glucose(a), and protein 
Serology (IgG)(a) 
Hepatitis B surface antigen, hepatitis C virus antibody, and human 
immunodeficiency virus antibody types 1 and 2 
Flavivirus Screening 
(IgM and IgG)(a) 
DENV antibody, Zika virus antibody (IgM only), and West Nile virus 
antibody 
Urine Drug Screen(d) 
Amphetamines (includes methamphetamines and 
ecstasy/methylenedioxymethamphetamine), barbiturates, 
benzodiazepines, cannabinoids, cocaine metabolites, cotinine, ethyl 
alcohol, methadone, methamphetamines, opiates (including heroin, 
codeine, and oxycodone/oxymorphone) 
Pregnancy Test 
(female subjects 
only)(e) 
Follicle-stimulating hormone, serum pregnancy test (human 
chorionic gonadotropin) 
Abbreviations: IgG, immunoglobulin G; IgM, immunoglobulin M. 
Note: Results of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, blood urea nitrogen, 
creatinine, and total bilirubin that are below the reference ranges are acceptable and will not exclude 
participation. 
(a) Clinical laboratory assessments will be performed at Screening and Check-in on Day –1 only, except serology 
and flavivirus screening will occur only at Screening. 
(b) Bicarbonate and chloride will only be used for calculation of anion gap ([sodium + potassium] - 
[chloride + bicarbonate)]. Volunteers with an anion gap greater than the upper limit of normal at Screening and 
Check-in on Day –1 will be excluded from participation in the study. 
(c) Volunteers with an estimated creatinine clearance (calculated using CKD-EPI method) <90 mL/min/1.73 cm2 at 
Screening will be excluded from participation in the study. 
(d) Urine drug screening will be performed at Screening, Check-in on Day –1, on Day 22 (±2), on Day 43 (±3), and 
on Day 85 (±5) except cotinine screening will occur only on Day –1.  
(e) For females in menses, screening urinalysis may be postponed or repeated, but a result should be available prior 
to Day 1. 


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Results of the absolute neutrophil count, hemoglobin, platelet count, white blood cell count, 
alanine aminotransferase, albumin, anion gap, aspartate aminotransferase, blood urea nitrogen, 
calcium, creatinine, creatinine clearance, glucose (fasting), potassium, sodium, prothrombin time 
and activated partial thromboplastin time, and urinalysis for blood, glucose, and protein must be 
normal at Screening and Check-in on Day –1 for eligibility. A repeat is allowed for out-of-range 
values, when not considered clinically significant by the Investigator, for the purpose of 
determining eligibility. The Investigator may choose to run addition clinical laboratory 
assessments at Screening or Check-in to assess volunteer eligibility to enroll. Results of these 
tests that fall outside of the reference ranges will be evaluated for inclusion into the study at the 
discretion of the Investigator. 
Laboratory assessments for monitoring safety and determining dose escalation include absolute 
neutrophil count, hemoglobin, platelet count, white blood cell count, alanine aminotransferase, 
alkaline phosphatase, aspartate aminotransferase, anion gap, blood urea nitrogen, creatinine, 
glucose (fasted), potassium, sodium, and total bilirubin. Instruments will be programmed to only 
generate results for hematology (including % relative neutrophils used to calculate absolute 
neutrophil count) and chemistry tests (including chloride and bicarbonate used to calculate anion 
gap) used to monitor safety and dose escalation after enrollment. Results of % relative 
neutrophils, chloride and bicarbonate will not individually be reviewed for evaluation of dose 
escalation or study halting criteria. 
Instruments will be programmed to only generate results for hematology and chemistry tests 
used to monitor safety and determining dose escalation include absolute neutrophil count, 
hemoglobin, platelet count, white blood cell count, alanine aminotransferase, anion gap, blood 
urea nitrogen, creatinine, glucose (fasted), potassium, sodium, and total bilirubin.  
The clinical laboratory that performs the tests will provide the reference ranges for all clinical 
laboratory parameters. Clinical laboratory tests that are thought to be due to a laboratory error 
may be repeated once at the discretion of the Investigator for assessment of inclusion and 
exclusion criteria or evaluation of clinical laboratory abnormalities. 
7.2.2 Pharmacokinetic Sampling 
Blood samples for PK analysis of concentrations of AV-1 in serum will be collected predose 
(within 15 minutes) and at 0.5, 1 (end of infusion), 1.25, 1.5, 2, 3, 4, 6, 8, 12, 24 and 48 hours 
after the start of the infusion, on Day 5 prior to discharge, and at the follow-up visits on 
Days 8 (+2), 15 (±2), 22 (±2), 29 (±2), 43 (±3), 57 (±3), 85 (±5), and 120 (±5) (or ET). A 
validated ECL ELISA method will be used to quantify AV-1 in serum samples for PK analyses 
as outlined in Section 10.4.3. 
7.2.3 Anti-AV-1 Antibody Sampling 
Blood samples for anti-AV-1 antibody analysis will be collected at Check-in (Day –1) and on 
Days 29 (±2), 85 (±5), and 120 (±5) (or ET). A validated ECL ELISA method will be used for 
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serum samples based on the MesoScale Discovery platform that utilizes labeled AV-1 for 
detection of anti-AV-1 antibodies and treatment-emergent antibodies. 
7.2.4 Hypersensitivity Testing 
Subjects will be monitored closely for signs and symptoms of hypersensitivity during and 
following infusion of the IP. A blood sample will be collected for all subjects on Day –1 and 
tested only if a suspected hypersensitivity reaction occurs during or following IP infusion on 
Day 1 at the discretion of the Investigator in consultation with the Sponsor. The subject will be 
treated using the standard site procedures if a subject develops a suspected hypersensitivity 
reaction. At the discretion of the Investigator, an additional blood sample will be drawn as soon 
as possible after the event occurs (Day 1) and again the following day (Day 2). Hypersensitivity 
testing of the Day –1, Day 1, and Day 2 samples will only occur in the event of a suspected 
hypersensitivity reaction at the discretion of the Investigator and in consultation with the 
Sponsor. Refer to the manual of procedures for further details. 
7.2.5 Laboratory Specimen Preparation, Handling, and Storage 
Details for the collection, processing, and storage of samples for assessment of PK and 
anti-AV-1 antibody will be provided to the clinical unit separately and outlined in the laboratory 
manual. 
7.2.6 Laboratory Specimen Shipping 
Details for the shipping of samples for the assessment of PK and anti-AV-1 antibody will be 
provided to the clinical unit separately and outlined in the laboratory manual. 


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ASSESSMENT OF SAFETY 
 
Assessing and Recording Safety Parameters 
Subjects will be monitored throughout the duration of the study to assess safety of a single IV 
infusion of AV-1 as per the schedule of events (Section 17.1). 
Safety assessments will include:  
• 
Incidence and severity of AEs 
• 
Incidence of SAEs 
• 
Physical examinations 
• 
Clinical safety laboratory tests 
• 
Vital sign measurements 
• 
12-lead ECGs 
8.1.1 Adverse Events 
An AE is defined by ICH E6(R2) 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. The FDA defines an AE as any untoward medical occurrence associated 
with the use of a drug in humans, whether or not considered drug related. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of 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 AEs, including solicited local (infusion site) and systemic (subjective and quantitative) 
reactions, will be captured on the appropriate data collection form and in the eCRF. Information 
to be collected for AEs includes event description, date of onset, assessment of severity, 
relationship to the IP and alternate etiology (assessed only by those with the training and 
authority to make a diagnosis and listed on Form FDA 1572 as an Investigator), date of 
resolution, seriousness, and outcome. Adverse events occurring during the study collection and 
reporting period will be documented appropriately regardless of relationship. Adverse events will 
be followed through resolution. 
Any medical condition that is present at the time that the subject is screened will be considered 
as baseline and not reported as an AE. However, if the severity of any pre-existing medical 
condition increases, it will be recorded as an AE. 


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8.1.1.1 Adverse Events Grading 
All AEs (laboratory and clinical symptoms) will be graded for severity and assessed for 
relationship to the IP (see definitions below). Adverse events characterized as intermittent 
require documentation of onset and duration of each episode. The start and stop date of each 
reported AE will be recorded on the appropriate data collection form and eCRF. Changes in the 
severity of an AE will be documented to allow an assessment of the duration of the event at each 
level of intensity. 
Severity of Event: Adverse events will be assessed by the Investigator using a protocol-defined 
grading system (toxicity table included in Section 17.2). For events not included in the 
protocol-defined grading system, the following guidelines will be used to quantify severity: 
• 
Mild (Grade 1): Events that are transient and may require only minimal or no treatment or 
therapeutic intervention and do not interfere with the subject’s usual activities of daily living. 
• 
Moderate (Grade 2): Events that are alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing discomfort but 
poses no significant or permanent risk of harm to the subject. 
• 
Severe (Grade 3): Events interrupt usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. Severe events are usually 
incapacitating. 
Relationship to Investigational Product: The assessment of the AE’s relationship to the IP will 
be done by the licensed study physician indicated on Form FDA 1572 and the assessment will be 
part of the documentation process. Whether the AE is related or not, is not a factor in 
determining what is or is not reported in this study. If there is any doubt as to whether a clinical 
observation is an AE, the event should be reported. 
In a clinical trial, the IP must always be suspect. The relationship to the IP will be assessed for 
AEs using the terms related or not related: 
• 
Related – There is a reasonable possibility that the IP caused the AE. Reasonable possibility 
means that there is evidence to suggest a causal relationship between the IP and the AE. 
• 
Not Related – There is not a reasonable possibility that the administration of the IP caused 
the event. 
8.1.2 Serious Adverse Events 
An AE or suspected adverse reaction is considered an SAE if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes:  
• 
Death 
• 
A life-threatening AE1 


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• 
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 subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition. Examples of such medical events include, but are not 
limited to, 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. 
1An AE or suspected adverse reaction is considered “life-threatening” if, in the view of either the 
Investigator or Sponsor, its occurrence places the subject at immediate risk of death. It does not 
include an AE or suspected adverse reaction that, had it occurred in a more severe form, might 
have caused death. 
Serious AEs will be: 
• 
Assessed for severity and relationship to the IP and alternate etiology (if not related to the IP) 
by a licensed study physician listed on Form FDA 1572 or by the Investigator or 
subinvestigator. 
• 
Recorded on the appropriate SAE data collection form and in the eCRF. 
• 
Followed through resolution by a licensed study physician (a physician listed on Form 
FDA 1572 as the Investigator or subinvestigator). 
• 
Reviewed and evaluated by the SRC, the safety monitoring committee (SMC) (if related), 
and the IRB. 
 
Specification of Safety Parameters 
Safety will be assessed by the frequency and severity of: 
• 
Occurrence of SAEs from the administration of AV-1 to final follow-up visit on 
Day 120 (±5). 
• 
Occurrence of unsolicited AEs from the administration of AV-1 to the final follow-up visit 
on Day 120 (±5). 
• 
Occurrence of solicited AEs from the administration of AV-1 to Day 8. 


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• 
Occurrence of changes from baseline in physical examination, vital sign measurements, and 
clinical safety laboratory values from the administration of AV-1 to the final follow-up visit 
on Day 120 (±5). 
• 
Occurrence of changes from baseline in ECG parameters in the 48 hours after starting the 
AV-1 infusion and at Days 8 (+2), 43 (±3), 85 (±5), and 120 (±5). 
8.2.1 Solicited and Unsolicited Events 
Solicited events are AEs that are common and known to occur following administration of the 
IP. Solicited events are defined in Table 17-1. 
Unsolicited events are any other AEs that occur following administration of the IP. 
8.2.2 Dose Escalation Criteria 
This study is designed such that dose escalation is allowed only after a blinded safety data review 
of each cohort by the SRC has occurred as outlined in Section 8.7.1. Study assessments (eg, AEs, 
clinical laboratory test results, vital sign measurements, and 12-lead ECG results) will be used to 
evaluate safety of a given dose level. Dose escalation will be dependent on review of the safety 
data. Clinically significant results will be discussed with the Sponsor before dose escalation 
continues. Data from a minimum of 6 subjects dosed per cohort must be reviewed before each 
dose escalation.  
Based on the review of safety data and recommendations by the SRC, SMC, or both, the Sponsor 
and the Investigator may choose to repeat a dose level, administer a dose less than the previous 
dose, escalate to a dose lower than the next planned dose, or prolong the duration of the infusion. 
Before implementing any change, the IRB will be notified and provided with the rationale for 
approval. 
8.2.3 Sentinel Subjects 
As a safety precaution in this first-in-human study, each cohort is divided into 2 groups with 
each group being dosed at least 72 hours apart. On the first day of dosing in all cohorts, the first 
group in each cohort will be comprised of 2 sentinel subjects. The randomization schedule will 
be constructed such that one of the sentinel subjects dosed on the first day will be randomly 
assigned to receive AV-1 and one of the sentinel subjects will be randomly assigned to receive 
placebo. After Investigator review of the safety data from the 48-hour postdose period for the 
sentinel subjects, which includes review of any AEs, abnormalities in ECGs, safety laboratory 
assessments, and vital signs, the remainder of the cohort (5 subjects randomly assigned to AV-1; 
one subject randomly assigned to placebo) will be dosed at least 72 hours after the sentinel 
subjects. Continuation from the sentinel subjects to dose the remaining 6 subjects will proceed if 
no study halting criteria are met as outlined in Section 8.6.3. 


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Reporting Procedures 
8.3.1 Reporting Serious Adverse Events 
Serious AEs will be followed until resolution even if this extends beyond the study-reporting 
period. Resolution of an AE is defined as the return to pretreatment status or stabilization of the 
condition with the expectation that it will remain chronic. 
Any AE that meets a protocol-defined serious criterion must be submitted immediately 
(within 24 hours of site awareness) on an SAE form to: 
PPD PVG Safety: 
Telephone (24 hour): 
 
Fax: 
 
Email: 
  
PPD PVG Safety will notify and submit to the DMID Pharmacovigilance Group within 
1 business day to: 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support 
 
 
SAE Hot Line: 
 
SAE FAX Number: 
 
SAE Email Address: 
 
In addition to the SAE form, select SAE data fields must also be entered into the Electronic Data 
Capture system. 
Other supporting documentation of the event may be requested by the Sponsor Representative or 
DMID Pharmacovigilance Group and should be provided as specified in the safety management 
plan. 
The Sponsor’s Representative, Sponsor’s Medical Monitor, and DMID Clinical Project Manager 
will also be notified of the SAE by the PPD Pharmacovigilance Group within 1 business day and 
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 Investigator or subinvestigator becomes aware 
of an SAE that is suspected to be related to the IP, the Investigator or subinvestigator will report 
the event to the Sponsor Representative and DMID Pharmacovigilance Group. 
8.3.2 Regulatory Reporting 
Following notification from the Investigator, PPD will report events that are both serious and 
unexpected that are related to the IP to the FDA on behalf of AbViro, LLC (the Sponsor) and 


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within the required timelines as specified in 21 CFR Part 312.32: fatal and life-threatening events 
within 7 calendar days (by telephone or fax). All written reports will be sent to the FDA within 
15 calendar days. All SAEs designated as “not related” to the IP, will be reported to the FDA at 
least annually in a summary format. 
8.3.3 Reporting of Pregnancy 
Subjects will be instructed that if they or their partner becomes pregnant during the study, this 
should be reported to the Investigator. The Investigator should also be notified of a pregnancy 
occurring during the study but confirmed after completion of the study. In the event that a 
subject or a subject’s partner is subsequently found to be pregnant after the subject is enrolled in 
the study and has received the IP, the pregnancy will be followed through its resolution, and the 
status of the mother and child will be reported to the Sponsor after delivery.  
A pregnancy notification form and follow-up will be completed. 
 
Type and Duration of Follow-up of Subjects after Adverse Events 
Adverse events will be assessed and followed from initial recognition of the AE through 
resolution even if the duration of follow-up goes beyond the final follow-up visit. 
Serious AEs will be followed through resolution even if duration of follow-up goes beyond the 
final follow-up visit. 
Resolution of an AE is defined as the return to pretreatment status or stabilization of the 
condition with the expectation that it will remain chronic. 
 
Procedures to be Followed in the Event of Abnormal Laboratory Test 
Values or Abnormal Clinical Findings 
Results of laboratory values collected during the conduct of the study will be reviewed by the 
Investigator or designee within 24 hours of receipt at the clinical site. As this study will be 
conducted in healthy subjects, assessment of laboratory abnormalities will be performed in 
accordance with the grading scale provided in Section 17.2, which is adapted from the FDA 
guideline, “Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials” (DHHS 2007). The adaptation is applied to account for local 
laboratory normal values and for compliance with the Clinical Data Interchange Standards 
Consortium. Any findings meeting Grade 3 criteria must be repeated immediately to rule out 
spurious values. All abnormal laboratory test values and findings on physical examination will 
be included in the study data and summarized in the safety analyses as described in 
Section 10.4.5. Any treatment-emergent AEs that are appropriately graded according to the 
toxicity scale in Section 17.2 will be captured as AEs in the eCRF. 


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Abnormal laboratory values occurring during the study will be followed until repeat test results 
return to normal, stabilize, or a cause is identified. If the laboratory abnormality is identified at 
the final scheduled visit, the subject will be requested to return for additional testing. 
 
Halting Rules 
8.6.1 Dose Escalation Halting Criteria 
If either of the following criteria is met, escalation to the next planned dose cohort will not 
proceed until all available study data have been reviewed by the SMC. 
• 
Two or more subjects in the same cohort experience a Grade 2 related AE (laboratory or 
systemic) that is attributed to the study drug and coded under the same high-level term per 
the Medical Dictionary for Regulatory Activities coding, throughout the duration of the 
study. 
• 
Two or more subjects in the same cohort experience a Grade 3 AE (laboratory or systemic) 
that is coded under the same high-level term per the Medical Dictionary for Regulatory 
Activities coding, regardless of causality assessment by the Investigator, throughout the 
duration of the study.  
If dose escalation is halted, the study may resume if deemed acceptable by the SMC following 
review of all available study data. 
8.6.2 Halting Criteria for Subject Infusions 
The Investigator and study site staff must carefully observe the subjects for any AE during the 
infusion.  
The infusion will be halted for an individual subject and will not resume if any of the following 
manifestations occur during the 1-hour infusion: 
• 
Occurrence during dosing that, in the opinion of the Investigator, results in the inability to 
have confidence that the intended dose of IP was delivered. 
• 
Infusion-related reaction of Grade 2 or higher. 
In case of a suspected infusion-related reaction, at the discretion of the Investigator, the 
infusion rate may be slowed from a rate of 250 mL/hour to a rate of 125 mL/hour for 
symptom management. The infusion may also be stopped. The subject will be observed to 
determine the severity of the reaction for a period of up to 15 minutes. Depending on the 
assessment of the subject, supportive care can be administered, and the infusion may 
permanently be stopped. If the Investigator determines that there is no infusion reaction, no 
ongoing supportive care is required after dosing is stopped, or if the symptoms of the clinical 
reaction have been improved after 15 minutes, the infusion may be restarted. The decision to 


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continue the infusion is based on the assessment by the Investigator. The infusion will be 
halted if there is a reoccurrence after a pause in dosing. 
• 
Symptomatic low blood pressure of <90 mm Hg systolic or >30% decrease from baseline in 
systolic or diastolic blood pressure at predose. 
• 
Confirmed tachycardia with an increase in resting heat rate to ≥130 beats per minute (bpm), 
or development of ventricular dysrhythmia, or bradycardia (<45 bpm, or <40 bpm in subjects 
with baseline of <60 bpm) associated with complaints of dizziness, nausea, or feeling faint. 
• 
Syncope. 
• 
Confusion. 
• 
Suspected Grade 3 AE or SAE. 
8.6.3 Study Halting Criteria 
Study dosing must be stopped, and a review of available safety data will be conducted by the 
SMC if any of the following occur: 
• 
Death of a dosed subject following infusion and prior to the subject’s last follow-up visit that 
was not the result of trauma or accident, regardless of relatedness to the IP. 
• 
Occurrence of a life-threatening allergic/hypersensitivity reaction (eg, anaphylaxis) in any 
subject, manifested by bronchospasm with or without urticaria, or angioedema requiring 
hemodynamic support with pressor medications or mechanical ventilation. 
• 
One subject with an IP-related SAE of any grade. 
• 
Two or more subjects with a Grade 3 AE in the same system organ class (systemic toxicity, 
clinical laboratory tests, or vital sign measurements) considered related to the IP, except 
scenarios where there are acceptable physiological explanations for a Grade 3 abnormality 
(eg, Grade 3 hematuria in a menstruating female). 
• 
One or more subjects experience a confirmed Grade 3 QTcF (≥500 msec or increase 
≥60 msec), or 2 or more subjects cumulatively have experienced a Grade 2 change in QTcF 
(≥480 msec). 
 
Safety Oversight 
8.7.1 Safety Review Committee 
The SRC is composed of the DMID Medical Monitor, Sponsor Medical Monitor, and the 
Investigator at the clinical site. Objective dose escalation criteria and safety evaluations will be 
utilized. The Investigator will evaluate safety data from the sentinel group and notify the Sponsor 
Representative of intent to proceed if no study halting criteria (Section 8.6.3) are met. The SRC 
will evaluate the safety data through Day 8 for each cohort to determine whether dose escalation 


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can occur. These reviews do not necessitate formal meetings. The SRC will inform the Sponsor 
Representative that the study can proceed to begin dosing the next cohort if none of the events 
described in the study halting criteria (Section 8.6.3) or dose escalation criteria (Section 8.2.2) 
are met. 
Should any of the study halting criteria or dose escalation halting criteria be met, the SMC will 
meet to evaluate the data and recommend appropriateness of further dosing. The decision to 
advance to the next dosing cohort will be documented and provided to the SRC and Sponsor 
Representative. 
8.7.2 Safety Monitoring Committee 
The SMC is an independent group of experts (at least 3 members) that monitor subject safety and 
advises the Sponsor. The 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 all available safety data during all scheduled ad hoc meetings: 
• 
When study halting criteria or dose escalation criteria are met. 
• 
At the request of the Sponsor to review a potential safety concern identified by the 
Investigator, Sponsor Medical Monitor, or DMID Medical Monitor. 
• 
When an SAE occurs. 
Procedures for the SMC reviews and meetings will be defined in the SMC charter. The SMC will 
review applicable aggregate data including, but not limited to, enrollment, demographics, dosing, 
laboratory, and safety data at scheduled time points during the study as defined in the charter. 
The SMC may request to receive data by AV-1 versus placebo in a closed session. The SMC 
may also request that the blind be broken for individual subjects, as needed, to assess safety 
issues. The SMC will make a recommendation to the Sponsor Representative in writing to 
continue, modify, or terminate the study as an outcome of each review or meeting. 


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HUMAN SUBJECTS PROTECTION 
 
Institutional Review Board 
The Investigator will obtain IRB approval for this protocol to be conducted at the clinical site 
and send supporting documentation to the Sponsor Representative 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 and 21 CFR 50 (Protection of Human Subjects), other federal, state, and 
local regulations. The IRB must be registered with OHRP as applicable to the research. The 
DMID Clinical Project Manager 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. Institutional review board 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 and the IRB. The Investigator will notify the IRB of 
deviations from the protocol and reportable SAEs, as applicable to the IRB policy. 
Each institution engaged in this research will hold a current FWA issued by the OHRP for 
federally funded research. 
 
Informed Consent Process 
Written informed consent in compliance with US Title 21 CFR Part 50 shall be obtained from 
each subject before he or she enters the study or before performing any unusual or nonroutine 
procedure that involves risk to the subject. If any institution-specific modifications to 
study-related procedures are proposed or made by the clinical site, the consent should be 
reviewed by the Sponsor before IRB submission. Once reviewed, the Investigator will submit the 
ICF to the IRB for review and approval before the start of the study. If the ICF is revised during 
the course of the study, all active participating subjects must sign the revised form. 
Before recruitment and enrollment, each prospective subject will be given a full explanation of 
the study and will be allowed to read the approved ICF. Once the Investigator is assured that the 
subject understands the implications of participating in the study, the subject will be asked to 
give his or her consent to participate in the study by signing the ICF. A copy of the ICF will be 
provided to the subject. 


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Subject Confidentiality 
Subject confidentiality is strictly held in trust by the participating Investigator, their study site 
staff, and the Sponsor and their agents. This confidentiality includes documentation, 
investigational 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 
Sponsor and the subject. Subject confidentiality will be maintained when study results are 
published or discussed in conferences. The study monitor, 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 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 specimens, evaluation 
forms, reports, and other records that leave the clinical site will be identified only by a coded 
number. 
 
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 US 
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 


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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 IP 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 may be compensated for their participation in this study. Compensation 
will be in accordance with the local IRB’s policies and procedures, and subject to IRB approval. 
If it is determined by the Investigator that an injury occurred to a subject as a direct result of the 
tests or treatments that are done for this study, then referrals to appropriate health care facilities 
will be provided to the subject. Study personnel will try to reduce, control, and treat any 
complications from this study. Immediate medical treatment may be provided by the 
participating clinical site. No financial compensation will be provided to the subject by the 
National Institute of Allergy and Infectious Diseases, the National Institutes of Health (NIH), or 
by the participating clinical site for any injury suffered due to participation in this study. 


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STATISTICAL CONSIDERATIONS 
 Study Hypotheses 
No hypothesis will be formally tested. 
 Sample Size Considerations 
This study will enroll a total of 40 subjects in 5 cohorts of 8 subjects each and up to 8 subjects 
for replacements as necessary. Each cohort will consist of 6 AV-1 treated and 2 placebo treated 
subjects. 
 Treatment Assignment Procedures 
The PPD randomization statistician will generate the randomization schedule. The PPD 
randomization statistician will not directly be involved in study conduct, data management, or 
data analysis. The first group will be comprised of 2 eligible subjects (sentinel subjects), with 
1 subject randomly assigned to receive AV-1 and 1 subject randomly assigned to receive 
placebo. The second group will be comprised of 6 eligible subjects (remaining cohort), with 
5 subjects randomly assigned to receive AV-1 and 1 subject randomly assigned to receive 
placebo with an overall ratio of 6:2 in each cohort. Continuation to dose the remaining 6 subjects 
in the second group will be at the discretion of the Investigator following consultation with the 
Sponsor Representative. 
10.3.1 Randomization Procedures 
This is a double-blind study. Neither the subjects, the Investigator, nor the Sponsor will be aware 
of the treatment assignment. Subjects will be randomly assigned to receive AV-1 or placebo in a 
6:2 randomization ratio. Access to the randomization code will be strictly controlled according to 
the standard operating procedures of PPD. 
10.3.2 Blinding 
The randomization list, as well as individual, subject-specific blind breaking documents, will be 
generated by the PPD randomization statistician and transferred to the unblinded study 
pharmacist prior to the start of the study. Pharmacy staff will store the subject-specific blind 
breaking documents in a tamper-evident container for afterhours access per standard clinic 
procedures. Study site staff participating in the administration of the IP and assessment of the 
subjects will not be aware of the contents of the IV bag. It is not anticipated that AV-1 and 
placebo will be distinguishable; however, masking overlays will be employed to maintain 
blinding and ensure the study site staff and the subject cannot determine whether AV-1 or 
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To maintain the study blind, AV-1 and placebo doses will be labeled with subject number, 
expiration date, expiration time, and volume. If the dose is not administered before the expiration 
time, a new dose should be requested from the unblinded pharmacy, if needed. The prepared 
dose, AV-1 or placebo, will be administered by appropriately trained neutral study site dosing 
staff as a single IV infusion over approximately 60 minutes by a controlled infusion device. 
10.3.3 Breaking the Blind 
Blind breaking envelopes will be prepared. A subject or subjects may be unblinded in the event 
of a dose-limiting toxicity, SAE, or other event, or if there is a medical emergency where the 
identity of the drug must be known to properly treat a subject. A cohort may be unblinded to 
determine if dose escalation to the next dose level will terminate. If a subject becomes seriously 
ill or pregnant during the study, the blind will be broken only if knowledge of the administered 
study drug will affect that subject’s treatment options. In the event of a medical emergency 
requiring identification of the IP administered to an individual subject, the Investigator will make 
every attempt to contact the Sponsor Medical Monitor to explain the need for opening the code 
within 24 hours of opening the code. The Investigator will be responsible for documenting the 
time, date, reason for the code break, and the names of the personnel involved. 
 Final Analysis Plan 
Prior to clinical database lock for this study, a statistical analysis plan will be finalized. The 
statistical analysis plan will detail the analyses to be conducted, the statistical methods that will 
be employed, and the formats and content of the final tables, listings, and figures to be produced. 
10.4.1 Populations for Analysis 
The analysis populations are as follows: 
• 
The safety population will include all subjects who receive the full dose of the IP. 
• 
The PK population will include subjects who receive the full dose of AV-1 and have at 
minimum all samples from predose through 1.5 hours from the start of infusion to have 
sufficient concentration data to support accurate estimation of at least 1 PK parameter. 
10.4.2 Statistical Analyses 
Details of all statistical analyses will be described in a separate statistical analysis plan. All data 
collected will be presented in data listings. Data from subjects excluded from an analysis 
population will be presented in the data listings, but not included in the calculation of summary 
statistics. 
For categorical variables, frequencies and percentages will be presented. Continuous variables 
will be summarized using descriptive statistics (number of subjects, mean, standard deviation 
[SD], minimum, median, and maximum). 


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All subjects receiving placebo across cohorts will be pooled into 1 treatment group for summary 
purposes. 
Baseline demographic and background variables will be summarized overall for all subjects. The 
number of subjects who enroll in the study and the number and percentage of subjects who 
complete the study will be presented. Frequency and percentage of subjects who withdraw or 
discontinue from the study, and the reason for withdrawal or discontinuation, will also be 
summarized. 
10.4.3 
Pharmacokinetic Analyses 
Serum concentration data will be listed and summarized by time point for each dose level using 
descriptive statistics (number of subjects, mean, SD, coefficient of variation [CV], minimum, 
median, and maximum). Serum concentration versus time profiles for each subject will be 
presented graphically. The mean serum concentrations versus scheduled time profiles will be 
presented graphically by dose. 
The PK parameters of AV-1 will be analyzed based on the actual sampling times. All parameters 
will be calculated using the latest version of Phoenix® WinNonlin® (Certara USA Inc., 
Princeton, New Jersey) or SAS® (SAS Institute Inc., Cary, North Carolina). Pharmacokinetic 
parameters will be summarized by time point for each dose level using descriptive statistics 
(number of subjects, arithmetic mean, SD, CV, minimum, median, and maximum). Geometric 
means and geometric CV will be reported for AUC0-tlast, AUC0-∞, and Cmax. The following serum 
PK parameters will be calculated as data permit: 
Cmax 
Maximum observed serum concentration 
Tmax 
Time to reach maximum observed serum concentration 
AUC0-48 
Area under the serum concentration-time curve from time 0 to 48 hours 
postdose, calculated using the linear trapezoidal rule method 
AUC0-tlast 
Area under the serum concentration-time curve from time 0 to the last 
quantifiable concentration, calculated using the linear trapezoidal method 
AUC0-∞ 
Area under the serum concentration-time curve from time 0 extrapolated to 
infinity, calculated as [AUC0-tlast + (Ct/λz)] where Ct is the last observed 
serum drug concentration. %AUCexp must be <0.20 to retain AUC0-∞ in the 
summary and statistical tables 
t1/2 
Apparent terminal half-life, calculated as ln(2)/λz 
CL 
Total serum clearance, calculated as Dose/AUC0-∞ 
Vz 
Volume of distribution during the terminal phase, calculated as Dose/AUC0-∞ 
* λz 


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In addition to the above PK parameters, which will be listed and summarized, the following 
parameters will also be listed to document the selection of data points used to estimate t1/2 using 
noncompartmental procedures: 
%AUCexp 
Percentage of the area extrapolated for calculation of AUC0-∞ 
λz 
Apparent terminal elimination rate constant  
Number of 
points 
Number of data points used to estimate λz; a minimum of 3 data points must 
be used, and Cmax must not be included 
λz lower (h) 
Lower bound used for the estimation of λz 
λz upper (h) 
Upper bound used for the estimation of λz 
Rsq 
r2, the coefficient of determination (goodness of fit statistic); visual inspection 
of the terminal slope will be performed. In general, λz may only be retained if 
r2 ≥ 0.80 
Where data are available, AV-1 dose proportionality will be examined across the dose groups. 
The PK parameters will be analyzed for dose proportionality using a power model approach or 
analysis of variance model as appropriate. Additional analysis may be conducted if deemed 
appropriate. 
Dose proportionality will be tested using the power regression model for AUC0-tlast, AUC0-∞, and 
Cmax, defined as: 
ln[PK parameter] = β0 + β1 ln[dose] 
where the PK parameter is an AUC or Cmax. The null hypothesis being tested is that the AUC and 
Cmax values are dose proportional, or slope (β1) = 1. 
10.4.4 
Anti-AV-1 Antibody Analyses 
Serum samples for measurement of anti-AV-1 antibody levels collected on Days –1, 29, 85, and 
120 (±5) (or ET) will be analyzed by an ECL ELISA method. The proportion of subjects with 
detectable anti-AV-1 antibody responses prior to AV-1 dosing and treatment-emergent 
anti-AV-1 antibodies will be reported. 
10.4.5 
Safety Analyses 
Adverse events will be coded by preferred term and system organ class using the latest version of 
the Medical Dictionary for Regulatory Activities and summarized by treatment and overall. All 
AE data will be presented in a data listing. Treatment-emergent AEs will be summarized by 
treatment and overall, as well as by severity and relationship to the IP. Serious AEs and AEs 
leading to discontinuation of the IP will also be presented in the data listings and summarized by 
treatment and overall. 


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Actual values and changes from baseline for clinical laboratory test results, vital sign 
measurements, and 12-lead ECG results will be summarized by treatment at each time point 
using descriptive statistics (number of subjects, mean, SD, minimum, median, and maximum). 
Shift tables will be generated for clinical laboratory test results. Physical examination findings 
will be presented in a data listing. 
 
Handling of Missing Data 
Concentrations that are below the limit of quantification (BLQ) will be treated as zero for 
descriptive statistics. Mean BLQ concentrations will be presented as BLQ, and the SD and CV 
will be reported as not applicable. Missing concentrations will be excluded from the calculations. 
For the PK analysis, BLQ values will be treated as zero with the exception that a BLQ value 
between 2 quantifiable concentrations will be set as missing. Missing concentrations will be 
treated as missing from the PK parameter calculations. If consecutive BLQ concentrations are 
followed by quantifiable concentrations in the terminal phase, those concentrations after BLQ 
concentrations will be treated as missing. 
 
Interim Analyses 
No formal interim analyses will be performed in this study. A blinded safety data review will be 
performed for each cohort before dose escalation is allowed (Section 8.2.2). 


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SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
The clinical 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 clinical site will permit authorized representatives of the Sponsor, 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 clinical site pharmacy, at the 
laboratories, and medico-technical departments involved in the clinical trial.  


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QUALITY CONTROL AND QUALITY ASSURANCE 
This study will be conducted using the quality processes described in applicable procedural 
documents. The quality management approach to be implemented will be documented and will 
comply with current ICH guidance on quality and risk management. All aspects of the study will 
be monitored for compliance with applicable government regulatory requirements, current GCP, 
the protocol, and standard operating procedures. The monitor will maintain current personal 
knowledge of the study through observation, review of study records and source documentation, 
and discussion of the conduct of the study with the Investigator and study site staff. Electronic 
CRFs and electronic data capture will be utilized. The electronic data capture system is validated 
and compliant with US Title 21 CFR Part 11. Each person involved with the study will have an 
individual identification code and password that allows for record traceability. There may be an 
internal quality review audit of the data and additional reviews by the clinical monitor. 


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DATA HANDLING AND RECORD KEEPING 
 Data Management Responsibilities 
All source documents and laboratory reports must be reviewed by the clinical team and data 
entry staff who will ensure that they are accurate and complete. Adverse events must be graded, 
assessed for severity and causality, and reviewed by the Investigator or designee.  
Data collection is the responsibility of the study site staff at the clinical site under the supervision 
of the Investigator. During the study, the Investigator must maintain complete and accurate 
documentation of the study.  
PPD, the contract research organization, will serve as the statistical and data coordinating center 
for this study and will be responsible for data management, quality review, analysis, and study 
data reports. The Investigator is responsible to ensure the accuracy, completeness, legibility, and 
timeliness of the data reported.  
 Data Coordinating Center/Biostatistician Responsibilities 
Data collection is the responsibility of the study site staff at the participating clinical site under 
the supervision of the Investigator. During the study, the Investigator must maintain complete 
and accurate documentation for the study. 
The statistical and data coordination center for this study will be responsible for data 
management, quality review, analysis, and reporting of the study data. 
 Data Capture Methods 
Clinical (including AE/SAEs, concomitant medications, medical history, and physical 
assessments) and clinical laboratory values 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 PPD. The data system includes password protection and internal quality checks, 
such as automatic range checks, to identify data that appear inconsistent, incomplete, or 
inaccurate.  
 Types of Data 
Data for this trial will include clinical, safety, and outcome measures. 
 Study Records Retention 
Study records and reports must be maintained for a minimum of 2 years after a marketing 
application is approved for AV-1 for the indication for which it is being investigated; or, if no 


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application is to be filed or if the application is not approved for AV-1, until 2 years after the 
investigation is discontinued and the FDA has been notified. These documents will be retained 
for a longer period, however, if required by local regulations. Informed consent forms will be 
maintained as long as the sample/specimen exists. 
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.  
 Protocol Deviations 
The Investigator or designee must document and explain in the subject’s source documentation 
any deviation from the approved protocol. The Investigator may implement a deviation from, or 
a change to, the protocol to eliminate an immediate hazard to study subjects without prior IRB 
approval. As soon as possible after such an occurrence, the implemented deviation or change, the 
reasons for it, and any proposed protocol amendments should be submitted to the IRB for review 
and approval, to the Sponsor Representative for agreement, and to the regulatory authorities, if 
required. 
A protocol deviation is any change, divergence, or departure from the study design or procedures 
defined in the protocol. An important deviation (sometimes referred to as a major or significant 
deviation) is a subset of protocol deviations that leads to a subject being discontinued from the 
study, or significantly affects the subject’s rights, safety, or well-being or the completeness, 
accuracy, and reliability of the study data. An important deviation can include nonadherence to 
inclusion or exclusion criteria or nonadherence to FDA regulations or ICH E6(R2) guidelines. 
Protocol deviations will be documented by the clinical monitor throughout the course of 
monitoring visits. The Investigator will be notified in writing by the monitor of deviations. The 
IRB should be notified of all protocol deviations, if appropriate, in a timely manner. 


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CLINICAL MONITORING 
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 and applicable standard operating procedures. PPD, 
the Sponsor, 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 the Sponsor and may be made more 
frequently as directed by the Sponsor. Monitoring visits will include, but are not limited to, 
review of regulatory files, accountability records, eCRFs, ICFs, medical and laboratory reports, 
and protocol and GCP compliance. Site monitors will have access to the clinical site, study site 
staff, and all study documentation according to the Sponsor-approved site monitoring plan. Study 
monitors will meet with the Investigator to discuss any problems and actions to be taken and will 
document clinical site visit findings and discussions. 


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PUBLICATION POLICY 
Following completion of the study, the Sponsor is expected to publish the results of this research 
in a scientific journal. All Investigators funded by the NIH must submit or have submitted for 
them to the National Library of Medicine’s PubMed Central (http://www.ncbi.nlm.nih.gov/pmc/) 
an electronic version of their final, peer-reviewed manuscripts upon acceptance for publication, 
to be made publicly available no later than 12 months after the official date of publication. The 
NIH Public Access Policy ensures the public has access to the published results of NIH funded 
research. It requires the 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 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 need to be submitted no later than 12 months following the primary completion 
date. A delay of up to 2 years is available for trials that meet certain criteria and have applied for 
certification of delayed posting. 
As part of the result posting a copy of this protocol (and its amendments) and a copy of the 
statistical analysis plan will be posted on ClincialTrials.gov. 
For this trial the responsible party is AbViro 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 
AbViro, LLC. AV-1. Investigator’s brochure, 1st ed. Bethesda (MD); 2019. 61 p. 
Bhatt S, Gething PW, Brady OJ, et al. The global distribution and burden of dengue. Nature. 
2013;496(7446):504-7. 
Brady OJ, Gething PW, Bhatt S, et al. Refining the global spatial limits of dengue virus 
transmission by evidence-based consensus. PLoS Negl Trop Dis. 2012:6(8):e1760. 
Dejnirattisai W, Jumnainsong A, Onsirisakul N, et al. Cross-reacting antibodies enhance dengue 
virus infection in humans. Science. 2010;328(5979):745-8. 
Department of Health and Human Services (DHHS), Food and Drug Administration, Center for 
Drug Evaluation and Research (US). Guidance for Industry: Estimating the maximum safe 
starting dose in initial clinical trials for therapeutics in adult healthy volunteers. July 2005 
[cited 2019 May 22] [30 screens]. Available from: 
http://www.fda.gov/downloads/Drugs/Guidances/UCM078932.pdf 
Department of Health and Human Services (DHHS), Food and Drug Administration, Center for 
Biologics Evaluation and Research (US). Guidance for Industry: Toxicity grading scale for 
healthy adult and adolescent volunteers enrolled in preventive vaccine clinical trials. 
September 2007. [cited 2019 May 24] Available from: 
https://www.fda.gov/media/73679/download 
Guzman MG, Halstead SB, Artsob H, et al. Dengue: a continuing global threat. Nat Rev 
Microbiol. 2010;8(12 Suppl):S7-16. 
Henchal EA, Putnak JR. The dengue viruses. Clin Microbiol Rev. 1990;3(4):376-96. 
International Conference on Harmonisation. General Considerations for Clinical Trials, E8; 
International Conference on Harmonisation; 1997 [cited 2019 October 22] 
https://www.fda.gov/media/71324/download. 
Schmidt AC. Response to dengue fever-the good, the bad, and the ugly? N Engl J Med. 
2010;363(5):484-7. 
Simmons CP, Farrar JJ, Nguyen VV, et al. Dengue. N Eng J Med. 2012;366(15):1423-32. 






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(n) Women of childbearing potential only. A serum pregnancy test will be performed at Screening and Check-in, and tests must be negative prior to enrollment 
and dosing, respectively. 
(o) After verification of eligibility, subjects will be randomly assigned before dosing on Day 1.  
(p) The start of the IP infusion will be called “0” hour and is denoted with grey shading. All doses of the IP will be administered intravenously over a period of 
60 minutes. Subjects will maintain an upright (ie, seated or standing) position for at least 4 hours after the end of infusion. 
(q) Blood samples for PK analysis of AV-1 in serum will be collected predose (within 15 minutes); at 0.5, 1 (end of infusion), 1.25, 1.5, 2, 3, 4, 6, 8, 12, 24, and 
48 hours after the start of infusion, Day 5 prior to discharge, and at the follow-up visits on Days 8, 15, 22, 29, 43, 57, 85, and 120 (or ET). 
(r) A blood sample will be drawn on Day –1 and tested only if a suspected hypersensitivity reaction occurs during or following infusion on Day 1 at the 
discretion of the Investigator in consultation with the Sponsor. At the discretion of the Investigator, an additional blood sample will be drawn as soon as 
possible after the event occurs (Day 1) and again the following day (Day 2). 
(s) During fasting periods, subjects should have nothing to eat or drink except water from 10 hours prior to start of the IP infusion until 4 hours after the end of 
infusion.  
(t) During non-fasting periods when subjects are at the clinical site, subjects should receive standardized meals per the clinic’s standard procedures that are 
scheduled at the same time in each treatment period during the study. 
(u) Solicited AEs will be assessed from the start of IP infusion until Day 8 and unsolicited AEs will be assessed from the start of IP infusion through the final 
follow-up visit on Day 120. All AEs should be followed until they are resolved, stable, or judged by the Investigator to be not clinically significant. 
 


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 Appendix B. 
Toxicity Tables 
Table 17-1 
Toxicity Grading Scales for Clinical Adverse Events and Reactions 
Cardiovascular 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Arrhythmia 
N/A 
Asymptomatic; transient 
signs; no medical 
intervention required 
Recurrent or persistent 
symptoms; medical 
intervention required 
Hemorrhage, Blood 
Loss* 
Estimated blood loss is 
<100 mL 
Estimated blood loss is 
≥100 mL; no transfusion 
required 
Transfusion required 
QTc (Fridericia’s 
correction)  
 
Asymptomatic, QT 
interval 450 to 
479 msec (male) and 
460 to 479 msec 
(female) OR increase 
in interval <30 msec 
above baseline 
Asymptomatic, QTc 
interval 480 to 499 msec 
OR increase in interval 
30 to 50 msec above 
baseline 
Asymptomatic, QTc interval 
≥500 msec OR increase in 
interval ≥60 msec above 
baseline 
PR Interval 
(prolonged) 
PR interval 0.21 to 
0.25 sec 
PR interval >0.25 sec 
Type II 2nd degree AV block 
OR ventricular pause >3 sec 
Respiratory 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Cough 
Transient; no treatment 
Persistent 
Interferes with daily activities 
Bronchospasm, Acute 
Transient; no 
treatment; forced 
expiratory volume 
71 to 80% of predicted 
peak flow 
Requires medical 
intervention; normalizes 
with bronchodilator; forced 
expiratory volume 60 to 
70% of predicted peak 
flow 
No normalization with 
bronchodilator; forced 
expiratory volume <60% of 
predicted peak flow 
Dyspnea 
Does not interfere with 
usual and social 
activities 
Interferes with usual and 
social activities; no 
treatment 
Prevents daily and usual social 
activity OR requires treatment 
Gastrointestinal 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Nausea 
No interference with 
activity 
Some interference with 
activity 
Prevents daily activity 
Vomiting 
No interference with 
activity OR 1 to 
2 episodes/24 hours 
Some interference with 
activity OR 
>2 episodes/24 hours 
Prevents daily activity OR 
requires IV hydration OR 
requires medical intervention 
Diarrhea 
2 to 3 loose or watery 
stools OR 
<400 grams/24 hours 
4 to 5 loose or watery 
stools OR 400 to 
800 grams/24 hours 
6 or more loose or watery 
stools OR >800 grams/24 hours 
OR requires IV hydration OR 
requires medical intervention 
Local Reactions 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Pain 
Does not interfere with 
activity 
Repeated use of 
non-narcotic pain reliever 
> 24 hours OR interferes 
with activity 
Any use of narcotic pain 
reliever OR prevents daily 
activity 
Tenderness 
Discomfort only to 
touch 
Discomfort with movement 
or mild discomfort at rest 
Significant discomfort at rest 
Erythema/Redness** 
2.5 to 5 cm 
5.1 to 10 cm 
>10 cm 


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Induration/Swelling*** 
2.5 to 5 cm AND does 
not interfere with 
activity 
5.1 to 10 cm OR interferes 
with activity 
>10 cm OR prevents daily 
activity 
Systemic Reactions 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Allergic Reaction 
Pruritus without rash 
Localized urticaria OR 
requires oral therapy 
Generalized urticaria; 
angioedema OR anaphylaxis 
OR requires epinephrine 
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 OR requires triptans 
Fatigue 
No interference with 
activity 
Some interference with 
activity 
Significant; prevents daily 
activity 
Myalgia 
No interference with 
activity 
Some interference with 
activity 
Significant; prevents daily 
activity 
Systemic Illness 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Illness or clinical 
adverse event (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 
*Does not include blood loss from study. 
**The local reaction should be measured at the greatest single diameter and recorded as a continuous variable in 
addition to grading. 
***Induration/swelling should be evaluated and graded using the functional scale as well as the actual measurement. 
 
 


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Table 17-2 
Vital Signs Toxicity Grading 
Vital Signs*  
Mild (Grade 1)  
Moderate (Grade 2)  
Severe (Grade 3)  
Fever (°C) ** 
(°F) **  
38.0 to 38.4 
100.4 to 101.1 
38.5 to 38.9 
101.2 to 102.0 
39.0 to 40 
102.1 to 104 
Tachycardia - beats per 
minute  
101 to 115 
116 to 130 
>130 
Bradycardia - beats per 
minute***  
50 to 54 
45 to 49 
<45 
Hypertension (systolic) - 
mm Hg  
141 to 150 
151 to 155 
>155 
Hypertension (diastolic) - 
mm Hg  
91 to 95 
96 to 100 
>100 
Hypotension (systolic) – 
mm Hg  
85 to 89 
80 to 84 
<80 
Respiratory rate – breaths 
per minute  
17 to 20 
21 to 25 
>25 
*Subject should be at rest for all vital sign measurements.  
**Oral temperature; no recent hot or cold beverages or smoking.  
***When resting heart rate is between 60 to 100 beats per minute. Use clinical judgement when characterizing 
bradycardia among some healthy subject populations, for example, conditioned athletes. 
 
 


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Table 17-3 
Laboratory Toxicity Grading 
Laboratory Tests 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Liver Function Tests – ALT 
increase by factor 
1.1 – 2.5 × ULN 
2.6 – 5.0 × ULN 
>5.0 × ULN 
Liver Function Tests – AST 
increase by factor 
1.1 – 2.5 × ULN 
2.6 – 5.0 × ULN 
>5.0 × ULN 
Albumin – Hypoalbuminemia 
g/dL  
2.8 – 3.1 
2.5 – 2.7 
<2.5 
Alkaline Phosphatase – ALP 
increase by factor 
1.1 – 2.0 × ULN 
>2.0 – 3.0 × ULN 
>3.0 × ULN 
Anion Gap* – mEq/L 
N/A 
N/A 
N/A 
Bilirubin (total) – mg/dL 
1.1 – <1.6 × ULN 
1.6 – < 2.6 × ULN 
≥ 2.6 × ULN 
Blood Urea Nitrogen mg/dL 
27 – 30 
31 – 35 
> 35 
Calcium – 
Hypocalcemia mg/dL 
8.0 – 8.4 
7.5 – 7.9 
7.0 – 7.4 
Calcium – 
Hypercalcemia mg/dL 
10.5 – 11.0 
11.1 – 11.5 
11.6 – 12.0 
Creatinine – mg/dL  
1.2 – 1.3 × ULN 
>1.3 – 1.8 × ULN  
>1.8 × ULN 
Glucose (fasted) – 
Hypoglycemia mg/dL 
50 – 54 
40 – 49 
30 – 39 
Glucose (fasted) – 
Hyperglycemia 
Fasting – mg/dL 
117 – 127 
128 – 142 
>143 
Potassium – Hypokalemia 
mEq/L 
3.3 – 3.4 
3.1 – 3.2 
2.9 – 3.0 
Potassium – Hyperkalemia 
mEq/L 
5.1 – 5.2 
5.3 – 5.4 
5.5 – 5.6 
Sodium – Hyponatremia mEq/L 
129 – 131 
127 – 128 
122 – 126 
Sodium – Hypernatremia 
mEq/L  
146 – 147 
148 – 149 
150 – 152 
Hematology 
WBC increase - cell/mm3 
9,800 – 14,000 
14,001 – 19,000 
19,001 – 24,000 
WBC decrease - cell/mm3 
2,000 – 3,099 
1,000 – 1,999 
500 – 999 
Absolute Neutrophil Count - 
cell/mm3 
1,000 – 1.499 
500 – 999 
0 – 499 
Hemoglobin Decrease (female) 
- gm/dL  
9.7 – 10.7 
8.2 – 9.6 
6.7 – 8.1 
Hemoglobin Decrease (male) - 
gm/dL  
11.7 – 12.7 
9.76 – 11.6 
7.6 – 9.6 
Platelets Decrease - cell/mm3 
125,000 – 139,000 
100,000 – 124,000 
<100,000 
Coagulation 
Prothrombin Time – increase by 
factor  
>1.0 – 1.2 × ULN 
1.2 – 1.4 × ULN 
>1.4 × ULN 
Activated Partial 
thromboplastin time – increase 
by factor  
>1.0 – 1.2 × ULN 
1.2 – 1.4 × ULN 
>1.4 × ULN 


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Laboratory Tests 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Urine 
Blood** 
1+ 
2+ 
>2+ 
Glucose  
1+ 
2+ 
>2+ 
Protein 
1+ 
2+ 
>2+ 
Abbreviations: ALP, alkaline phosphatase; ALT, alanine transferase; AST, aspartate aminotransferase; ULN, upper 
limit of the normal range, WBC, white blood cell. 
*Only values above the ULN and below the LLN are considered abnormal. 
**For females: In case of menstruation, screening urinalysis must be postponed, but a result should be available 
prior to Day 1. Hematuria is acceptable for females in menses for the purposes of evaluating study halting criteria 
and dose escalation. 
Source: DHHS 2007. 
Table 17-4 
Infusion-related Reactions and Toxicity Grading 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Mild transient 
reaction; infusion 
interruption not 
indicated; intervention 
not indicated. 
Therapy or infusion interruption indicated 
but responds promptly to symptomatic 
treatment (eg, antihistamines, nonsteroidal 
anti-inflammatory drugs, narcotics [opioids], 
intravenous fluids); prophylactic medication 
indicated for less than or equal to 24 hours. 
Prolonged (eg, not rapidly responsive 
to symptomatic medication and/or brief 
interruption of infusion); recurrence of 
symptoms following initial 
improvement; hospitalization indicated 
for other clinical sequelae. 
Source: Adapted from the National Cancer Institute Common Terminology Criteria for Adverse Events (Version 5.0) 
for infusion-related reactions.  

SAP_001.pdf: 


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Statistical Analysis Plan, Version 1.0 
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Date Issued: 08MAR2021 
 
  
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ........................................................................................... IV 
1. 
INTRODUCTION ....................................................................................................1 
2. 
OBJECTIVES ...........................................................................................................1 
2.1. PRIMARY OBJECTIVE .................................................................................................... 1 
2.2. SECONDARY OBJECTIVES ............................................................................................. 1 
3. 
INVESTIGATIONAL PLAN ..................................................................................1 
3.1. OVERALL STUDY DESIGN AND PLAN ........................................................................... 1 
3.2. STUDY ENDPOINTS ....................................................................................................... 3 
3.2.1. 
Safety Endpoints ................................................................................................ 3 
3.2.2. 
Pharmacokinetic Endpoints .............................................................................. 3 
3.2.3. 
Immunogenicity Endpoints ................................................................................ 3 
4. 
GENERAL STATISTICAL CONSIDERATIONS ...............................................3 
4.1. SAMPLE SIZE ................................................................................................................ 4 
4.2. ANALYSIS POPULATIONS .............................................................................................. 4 
5. 
SUBJECT DISPOSITION, PROTOCOL DEVIATIONS, AND FOLLOW-UP
 ....................................................................................................................................4 
5.1. DISPOSITION ................................................................................................................. 4 
5.2. PROTOCOL DEVIATIONS ............................................................................................... 5 
6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ............................5 
6.1. DEMOGRAPHICS ........................................................................................................... 5 
6.1.1. 
Medical History ................................................................................................. 6 
7. 
TREATMENTS, MEDICATIONS, AND MEALS ...............................................6 
7.1. PRIOR AND CONCOMITANT MEDICATIONS ................................................................... 6 
7.2. MEDICAL AND SURGICAL TREATMENT PROCEDURES ................................................... 6 
7.3. STUDY DRUG ADMINISTRATION ................................................................................... 6 
8. 
PHARMACOKINETIC ANALYSIS .....................................................................7 
8.1. DATA HANDLING ......................................................................................................... 7 
8.2. SERUM CONCENTRATIONS ........................................................................................... 7 
8.3. SERUM PHARMACOKINETIC PARAMETERS ................................................................... 7 
8.4. PHARMACOKINETIC STATISTICAL ANALYSIS ............................................................... 9 
9. 
ANTI-AV-1 ANTIBODY ANALYSIS ....................................................................9 
10. 
SAFETY ANALYSIS .............................................................................................10 
10.1. ADVERSE EVENTS .................................................................................................... 10 
10.1.1. 
Incidence of Adverse Events ........................................................................ 10 


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10.1.2. 
Relationship of Adverse Events to Study Drug ............................................ 11 
10.1.3. 
Severity of Adverse Event ............................................................................. 11 
10.1.4. 
Serious Adverse Events ................................................................................ 12 
10.1.5. 
Adverse Events Leading to Study Drug Discontinuation ............................. 12 
10.2. CLINICAL LABORATORY EVALUATIONS ................................................................... 12 
10.3. VITAL SIGN MEASUREMENTS AND WEIGHT ............................................................. 13 
10.4. ELECTROCARDIOGRAMS ........................................................................................... 13 
10.5. PHYSICAL EXAMINATION ......................................................................................... 14 
11. 
CHANGES FROM THE PLANNED ANALYSIS ..............................................14 
12. 
INTERIM ANALYSIS ...........................................................................................14 
13. 
REFERENCES .......................................................................................................14 
14. 
APPENDICES ........................................................................................................15 
APPENDIX 1 SCHEDULE OF EVENTS .................................................................................. 15 
APPENDIX 2 CLINICAL LABORATORY ASSESSMENTS ........................................................ 18 
APPENDIX 3 TOXICITY TABLES ......................................................................................... 19 


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iv 
List of Abbreviations 
λz 
apparent terminal elimination rate constant 
AE 
adverse event 
AUC0-tlast   
area under the curve from time 0 to the last quantifiable 
concentration, calculated using the linear trapezoidal method 
AUC0-48 
area under the serum concentration-time curve from time 0 to 48 
hours postdose, calculated using the linear trapezoidal method 
AUC0-∞ 
extrapolation of the area under the curve from time 0 to infinity 
% AUCextrap 
percentage of the area extrapolated for calculation of AUC0-∞ 
BLQ 
below the limit of quantification 
CI 
confidence interval 
CL 
total serum clearance 
Cmax 
maximum (peak) serum drug concentration 
CSR 
clinical study report 
ECG 
electrocardiogram 
ECL 
electrochemiluminescence 
eCRF 
electronic case report form 
ELISA 
enzyme-linked immunosorbent assay 
EOS 
end of study 
ET 
early termination 
IP 
investigational product 
IV 
intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
PK 
pharmacokinetic(s) 
PT 
preferred term 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
SAE 
serious adverse event 
SD 
standard deviation 
SOC 
system organ class 
t1/2 
apparent terminal half life 
TEAE 
treatment-emergent adverse event 
Tmax 
time to reach maximum observed serum concentration 
ULN 
upper limit of normal 
Vz 
volume of distribution during the terminal phase 
 


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1. Introduction 
 
This document outlines the statistical methods to be implemented during the analysis of 
data collected within the scope of AbViro, Protocol AV1-PPD-0005 (A Phase 1a, Double-
Blind, Placebo-Controlled, Single Ascending Dose Study to Determine the Safety and 
Pharmacokinetics of AV-1 in Healthy Male and Female Adult Subjects), Protocol 
Amendment 2, 07 May 2020.  
 
This is a Phase 1a, first-in-human study with AV-1 and is designed to provide initial 
safety, pharmacokinetics (PK), and incidence of anti-AV-1 antibody responses data 
regarding AV-1 to help guide further development of AV-1 as a potential treatment against 
dengue.  
 
The purpose of this statistical analysis plan is to define the planned statistical analysis of 
the study data consistent with the study objectives. 
2. Objectives 
2.1. Primary Objective 
 
The primary objective of this study is to determine the safety of a single intravenous (IV) 
dose of AV-1 in healthy adult subjects. 
2.2. Secondary Objectives 
 
The secondary objectives of this study are as follows: 
 
• To characterize the PK of AV-1 following a single IV dose. 
• To evaluate if subjects develop anti-AV-1 antibodies following a single IV dose of 
AV-1. 
3. Investigational Plan 
3.1. Overall Study Design and Plan 
 
This is a Phase 1a, first-in-human, single-center, double-blind, randomized, 
placebo-controlled, sequential-group, single ascending dose study to determine the safety 
of AV-1 in healthy male and female adult subjects when administered as a single IV 
infusion. Additionally, the PK and the incidence of anti-AV-1 antibody responses will be 
studied.  
 


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Five sequential cohorts of 8 subjects (6 active and 2 placebo) each (Cohorts 1 to 5) are 
planned for this study. The starting dose of AV-1 will be 30 mg:  
 
The study will consist of a screening period, check-in, a treatment period, and 8 follow-up 
visits for each cohort. 
 
Potential subjects will be screened to assess their eligibility to enter the study within 
35 days prior to investigational product (IP) administration. Eligible subjects will check in 
to the clinical site on Day -1 (the day before dosing). In each cohort, subjects will fast 
overnight (nothing to eat or drink except water) for at least 10 hours before the start of the 
IP infusion. Subjects will remain fasted for 4 hours after dosing with the IP. Subjects will 
be randomly assigned to receive AV-1 or placebo as follows: 
 
• Cohort 1: AV-1 30 mg (n = 6) or placebo (n = 2) administered as an IV dose 
• Cohort 2: AV-1 90 mg (n = 6) or placebo (n = 2) administered as an IV dose 
• Cohort 3: AV-1 250 mg (n = 6) or placebo (n = 2) administered as an IV dose 
• Cohort 4: AV-1 500 mg (n = 6) or placebo (n = 2) administered as an IV dose 
• Cohort 5: AV-1 1000 mg (n = 6) or placebo (n = 2) administered as an IV dose 
 
Sentinel dosing will be used in each cohort as discussed in Protocol Section 8.2.3. In each 
cohort, the Investigator will review safety data for the sentinel subjects and notify the 
Sponsor of intent to proceed with dosing the rest of the cohort with a minimum of 72 hours 
between dosing of the sentinel subjects and dosing the rest of the cohort. Safety data 
through Day 8 will be reviewed in a blinded fashion by the Safety Review Committee for 
each dose cohort before escalating to the next dose cohort. Based on the review of safety 
data, the Sponsor and the Investigator may choose to repeat a dose level, administer a dose 
less than the previous dose, escalate to a dose lower than the next planned dose, or prolong 
the duration of the infusion. 
 
Subjects will be confined to the clinical unit from Day -1 until discharge on Day 5. On Day 
5, subjects will be discharged after all protocol-specified assessments have been 
completed. Subjects will return for 8 follow-up visits on Days 8 (+2), 15 (±2), 22 (±2), 
29 (±2), 43 (±3), 57 (±3), 85 (±5), and 120 (±5). Subjects will be asked to attend an early 
termination (ET) visit if they withdraw or are withdrawn from the study prior to the final 
follow-up visit on Day 120 (±5).  
 
The planned duration for each cohort (screening to final follow-up visit) is approximately 
22 weeks. 
 


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Safety, PK, and anti-AV-1 antibody endpoints will be evaluated in the study. Clinical 
laboratory evaluations, physical examination findings, vital sign measurements, safety 
12-lead electrocardiograms (ECGs), incidence and severity of adverse events (AEs), and 
incidence of serious AEs (SAEs) will be monitored to assess safety as specified in protocol 
Sections 7 and 8. 
3.2. Study Endpoints 
3.2.1. Safety Endpoints 
 
The primary safety endpoints are clinical laboratory evaluations (hematology, chemistry, 
urinalysis), physical examination findings, vital sign measurements, safety 12-lead ECG 
parameters, incidence and severity of AEs, and incidence of SAEs. 
3.2.2. Pharmacokinetic Endpoints 
 
The secondary PK samples will be assessed for AV-1 concentrations. The following PK 
parameters for AV-1 will be calculated as endpoints: 
• Cmax: Maximum observed serum drug concentration 
• Tmax: Time to reach maximum serum concentration following drug administration 
• AUC0-tlast: Area under the serum concentration versus time curve from time 0 to the 
last quantifiable concentration in serum 
• AUC0-48: Area under the serum concentration versus time curve from time 0 to 48 
hours postdose 
• AUC0-∞: Extrapolation of the area under the curve from time 0 to infinity 
• t1/2: Terminal half-life 
• CL: Total serum clearance 
• Vz: Volume of distribution during the terminal phase 
3.2.3. Immunogenicity Endpoints 
 
Incidence of anti-AV-1 antibodies as measured by the proportion of subjects with 
detectable anti-AV-1 antibody signal in serum, including treatment-emergent 
anti-AV-antibodies, using an electrochemiluminescence (ECL) enzyme-linked 
immunosorbent assay (ELISA). 
4. General Statistical Considerations 
 
All data collected will be presented in data listings. Data from subjects excluded from an 
analysis population will be presented in the data listings but not included in the calculation 
of summary statistics. 
 


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For categorical variables, frequencies and percentages will be presented. Continuous 
variables will be summarized using descriptive statistics (number of subjects, mean, 
median, standard deviation [SD], minimum, and maximum). 
 
Unless specified otherwise, baseline will be defined as the last non-missing assessment 
prior to the study drug administration. Unscheduled visits will be used in determining 
baseline. 
 
Unless otherwise indicated, outputs which are summarized by treatment will be 
summarized for each dose level for subjects on active study drug; subjects who receive 
placebo will be pooled into a single group. 
 
The study day of dosing will be considered as Day 1. Study day will be calculated relative 
to the first dose date as follows: 
• If assessment date is on or after the first dose of study drug administration, then 
Study Day = Assessment Date – Dose Date + 1 
• Otherwise, Study Day = Assessment Date – Dose Date 
4.1. Sample Size 
 
This study will enroll a total of 40 subjects in 5 cohorts of 8 subjects each and up to 8 
subjects for replacements as necessary. Each cohort will consist of 6 AV-1 treated and 2 
placebo treated subjects. The sample size (N = 40) for this study is based on clinical and 
practical considerations and not on a formal statistical power calculation. The sample size 
is considered sufficient to evaluate the objectives of the study. 
4.2. Analysis Populations 
 
The Safety population will include all subjects who receive any amount of the IP. The 
safety population will also be used for anti-AV-1 antibody assessment. 
 
The PK population will include subjects who receive the full dose of AV-1 and have at 
minimum all samples from predose through 1.5 hours from the start of infusion to have 
sufficient concentration data to support accurate estimation of at least 1 PK parameter. 
5. Subject Disposition, Protocol Deviations, and Follow-up 
5.1. Disposition 
 
Subject disposition will be summarized by treatment and total for all randomized subjects. 
 


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The number of subjects who are randomized in the study and the number and percentage of 
subjects who complete the study will be presented. Frequency and percentage of subjects 
who withdraw or discontinue from the study, and the reason for withdrawal or 
discontinuation, will also be summarized. 
 
Subject disposition data, analysis populations, and randomization data will be presented in 
data listings. 
5.2. Protocol Deviations 
 
A protocol deviation is any change, divergence, or departure from the study design or 
procedures defined in the protocol. An important deviation (sometimes referred to as a 
major or significant deviation) is a subset of protocol deviations that leads to a subject 
being discontinued from the study, or significantly affects the subject’s rights, safety, or 
well-being or the completeness, accuracy, and reliability of the study data. An important 
deviation can include nonadherence to inclusion or exclusion criteria or nonadherence to 
Food and Drug Administration regulations or International Council for Harmonisation 
(ICH) E6(R2) guidelines. 
 
Protocol deviations will be documented by the clinical monitor throughout the course of 
monitoring visits. The Investigator will be notified in writing by the monitor of deviations. 
The Institutional Review Board should be notified of all protocol deviations, if appropriate, 
in a timely manner. 
 
Important protocol deviations will be summarized for all randomized subjects. 
 
All protocol deviations will be presented in a data listing, including the categorization of 
the deviation as important or not. Details of admission criteria deviations will be presented 
in a separate data listing. 
6. Demographics and Baseline Characteristics 
6.1. Demographics 
 
Demographic and baseline characteristics will be summarized by treatment and total for 
Safety population.  
 
The demographic characteristics consist of age (years), sex, race, and ethnicity. The 
baseline characteristics consist of baseline weight (kg), height (cm), and body mass index 
(kg/m2). Percentages will be based on the total number of subjects in the Safety population. 
 
Subject demographic and baseline characteristics will be presented in a data listing. 


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6.1.1. Medical History 
 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA, version to be delineated in the Clinical Study Report [CSR]). 
 
Medical history will be presented in a data listing for safety population. 
7. Treatments, Medications, and Meals 
7.1. Prior and Concomitant Medications 
 
Information regarding prior medications taken by the subject within the 30 days before 
signing the informed consent form will be recorded in the subject’s electronic case report 
form (eCRF). 
 
Any concomitant medication deemed necessary for the welfare of the subject during the 
study may be given at the discretion of the investigator. If a concomitant medication is 
taken, except for those specified in the protocol, a joint decision will be made by the 
investigator and the Sponsor to continue or discontinue the subject based on the time the 
medication was administered, its pharmacology and PK, and whether the use of the 
medication will compromise the safety of the subject or the interpretation of the data. The 
investigator is responsible for ensuring that details regarding the medication are adequately 
recorded in the eCRF. 
 
Prior and concomitant medications and therapies will be coded using the latest version of 
the World Health Organization Drug Dictionary. 
 
All prior and concomitant medications will be presented in a data listing for the safety 
population. 
7.2. Medical and Surgical Treatment Procedures 
 
All medical and surgical treatment procedures will be coded using MedDRA (version to be 
delineated in the CSR). All medical and surgical treatment procedures will be presented in 
a data listing for safety population. 
7.3. Study Drug Administration 
 
All doses of study drug will be administered at the study site under direct observation of 
site personnel and recorded in the eCRF. Study site personnel will confirm that the subject 
has received the dose of study drug. The start and stop date/time, and amount of study drug 
dosing will be recorded on the appropriate page of the eCRF. If a subject does not receive 
study drug, the reason for the missed dose will be recorded. 


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All study drug administration data will be presented in a data listing. 
8. Pharmacokinetic Analysis 
8.1. Data Handling 
Serum concentrations that are below the limit of quantification (BLQ) will be treated as 
zero for calculation of descriptive statistics. Mean BLQ concentrations will be presented as 
BLQ, and the SD and CV will be reported as not applicable.  
 
For PK analysis, BLQ values will be treated as zero with the exception that a BLQ value 
between 2 quantifiable concentrations will be set as missing. If consecutive BLQ 
concentrations are followed by quantifiable concentrations in the terminal phase, those 
concentrations after BLQ concentrations will be treated as missing. 
 
Missing concentrations will be excluded from all calculations and PK analyses. 
8.2. Serum Concentrations  
 
Blood samples for the determination of serum concentrations of AV-1 will be collected on 
Day 1 at the following time points: predose (within 15 minutes), and at 0.5, 1 (end of 
infusion), 1.25, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours after the start of the infusion and on 
Day 5 prior to discharge, and at the follow-up visits on Days 8 (+2), 15 (±2), 22 (±2), 29 
(±2),85 (±5), and 120 (±5) (or ET).  AV-1 serum concentrations will be determined using a 
validated ECL ELISA method based on the MesoScale Discovery platform. 
 
AV-1 serum concentration data will be summarized using descriptive statistics (N, n 
[non-missing values within the population], arithmetic mean, SD, CV%, median, minimum, 
and maximum) by dose group and scheduled sampling time.  Individual and mean AV-1 
serum concentration versus time data will be plotted by dose group. For ease of presentation, 
mean serum concentrations of AV-1 will be plotted by nominal time by dose group on both 
linear and semi-logarithmic scales.  
 
Serum PK concentrations of AV-1 will be reported to the precision of the raw data in listing 
presentations; summary statistics for arithmetic mean, median, minimum, maximum, and 
SD will be reported to 3 significant figures; and CV% will be reported to 1 decimal place. 
8.3. Serum Pharmacokinetic Parameters 
 
The serum concentration-time data for AV-1 will be analyzed by non-compartmental 
analysis using Phoenix® WinNonlin® (Certara USA, Inc., Princeton, NJ) Version 8.0 or 
higher. Actual sampling times will be used for the estimation of all serum PK parameters. 
 


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PK parameters of AV-1 will be summarized using descriptive statistics by dose group.  
If data allow, the following PK parameters will be calculated: 
 
Parameter 
Description 
Cmax 
Maximum observed serum drug concentration 
Tmax 
Time to reach maximum observed serum concentration 
AUC0-48   
Area under the serum concentration-time curve from time 0 to 48 hours 
postdose, calculated using the linear trapezoidal method 
AUC0-tlast   
Area under the curve from time 0 to the last quantifiable concentration, 
calculated using the linear trapezoidal method 
AUC0-∞   
Area under the serum concentration-time curve from time 0 extrapolated 
to infinity, calculated as [AUC0-tlast + (Ct/λz)] where Ct is the last 
observed serum drug concentration. %AUCexp must be <0.20 to retain 
AUC0-∞ and associated parameters in the summary and statistical tables 
t1/2   
Apparent terminal half-life, calculated as:ln(2)/ λz 
CL 
Total serum clearance, calculated as Dose/AUC0-∞ 
Vz 
Volume of distribution during the terminal phase, calculated as 
Dose/AUC0-∞* λz 
 
In addition to the above PK parameters, which will be listed and summarized, the following 
parameters will also be listed to document the selection of data points used to estimate t1/2 
using non-compartmental procedures: 
 
Parameter 
Description 
%AUCexp 
Percentage of the area extrapolated for calculation of AUC0-∞. 
λz 
Apparent terminal elimination rate constant, where λz is the 
magnitude of the slope of the linear regression of the log 
concentration versus time profile during the terminal phase. 
Number of points Number of data points used to estimate λz; a minimum of 3 data 
points must be used, and Cmax must not be included. 
λz lower 
Lower bound used for the estimation of λz. 
λz upper 
Upper bound used for the estimation of λz. 
Rsq 
r2, the coefficient of determination (goodness of fit statistic); visual 
inspection of the terminal slope will be performed. In general, λz 
may only be retained if r2 ≥ 0.80 
 


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Serum PK parameters for AV-1 will be presented in data listings and summarized using 
descriptive statistics (n, arithmetic mean, SD, CV%, median, minimum, and maximum) by 
dose group. Geometric means and geometric CV will be reported for AUC0-tlast, AUC0-∞, and 
Cmax. Tmax will be summarized using the descriptive statistics median, minimum, and 
maximum only. 
 
Serum PK parameters of AV-1 will be displayed to 3 significant figures in all data listings 
and summary tables, with exception of time variables (Tmax, λz lower, and λz upper) which 
will be displayed to 2 decimal places. 
8.4. Pharmacokinetic Statistical Analysis 
 
Dose-proportionality for AV-1 will be evaluated for Cmax, AUC0-tlast, and AUC0-∞. A power 
model will be fitted to describe the relationship between Y (Cmax, AUC0-tlast and AUC0-∞) 
and X (dose) using the least-squares linear regression model [ln(Y) = ln(β0) + β1 ln(X)].  
 
From each model, the intercept of regression line [ln(β0)] and the slope of the regression 
line β1 will be presented along with the 90% confidence interval (CI) of the slope. 
Dose-proportionality will be concluded if the 90% CI of the slope β1 lies entirely within 
[1+ln(0.8)/ln(r), 1+ln(1.25)/ln(r)], where r is a ratio that describes the dose range and is 
defined as the ratio of highest dose/lowest dose. If dose proportionality is not observed, 
then the lowest dose followed by the highest dose in succession will be removed, and the 
model will be fit again after the removal of a dose until dose proportionality is achieved or 
less than 3 dose groups remain. 
 
The statistical analyses will be based on the PK population. 
9. Anti-AV-1 Antibody Analysis 
 
Blood samples for immunogenicity analysis will be collected at Check-in (Day –1) and on 
Days 29 (±2), 85 (±5), and 120 (±5) (or ET). A validated ECL ELISA method will be used 
for detection and confirmation of preexisting and treatment-emergent anti-AV-1 antibodies 
in serum samples based on the MesoScale Discovery platform that utilizes labeled AV-1 
for detection of anti-AV-1 antibodies and treatment emergent antibodies.  
 
Frequency and percentage of subjects who show detectable anti-AV-1 antibody signal in 
serum, including treatment-emergent anti-AV- antibodies, will be summarized for the 
safety population. Pharmacokinetic parameters may be displayed based on anti-AV-1 
antibody status as applicable. 
 
Anti-AV-1 antibody data will be presented in a data listing for the safety population. 


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10. Safety Analysis 
 
All safety summaries and analyses will be conducted for the safety population. 
10.1. Adverse Events 
 
An AE is defined by ICH E6(R2) 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 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 AEs, including solicited local (infusion site) 
and systemic (subjective and quantitative) reactions, will be captured on the appropriate 
data collection form and in the eCRF. 
 
A treatment-emergent AE (TEAE) is defined as any event that does not present before 
exposure to study drug or any event already present that worsens in intensity or frequency 
after exposure. 
 
Only TEAEs will be included in summary tables. 
 
Adverse events will be coded by preferred term (PT) and system organ class (SOC) using 
MedDRA (version to be delineated in the CSR).  
 
A subject may have more than 1 AE for an SOC or PT. A subject with 2 or more AEs 
within the same level of summarization will be counted only once in that summarization 
level. In addition to the summarization of subjects with AE at each level, the frequencies of 
AE occurrences will also be summarized at each level. Percentages will be based upon the 
number of subjects in the safety population for each treatment group.  
 
All AEs will be presented in a data listing.  
10.1.1. Incidence of Adverse Events 
 
An overview of AEs will be presented by treatment and total, including number and 
percentage of subjects with any: 
 
• Treatment-emergent AE 
• Treatment-related TEAE 
• Moderate TEAE 


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• Treatment-related moderate TEAE 
• Severe TEAE 
• Treatment-related severe TEAE 
• Serious TEAE 
• Treatment-related Serious TEAE 
• Treatment-emergent AE leading to early discontinuation 
• Death 
 
All TEAEs will be presented in a summary table by treatment and total for each SOC and 
PT. Percentages will be calculated out of the number of subjects in the safety population.  
10.1.2. Relationship of Adverse Events to Study Drug 
 
The relationship or association of the study drug in causing or contributing to the AE will 
be characterized by the investigator as “Related” or “Not Related”. 
 
All TEAEs will be presented in a summary table for each treatment group and total by 
relationship to study drug. If a subject has 2 or more TEAEs in the same SOC (or with the 
same PT) with a different relationship to study drug, then a “Related” event will be used 
for that subject. If the relationship information is missing, the AE will be considered 
related in the summary but will be presented as missing in the data listings. 
10.1.3. Severity of Adverse Event 
 
All AEs (laboratory and clinical symptoms) will be graded for severity. The severity will 
be classified as mild, moderate, or severe using the following criteria: 
 
• Mild (Grade 1): Events that are transient and may require only minimal or no 
treatment or therapeutic intervention and do not interfere with the subject’s usual 
activities of daily living. 
• Moderate (Grade 2): Events that are alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the subject. 
• Severe (Grade 3): Events interrupt usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. Severe 
events are usually incapacitating. 
 
All TEAEs will be summarized for each treatment group and total by maximum severity. If 
the severity information is missing, the AE will be considered severe in the summary but 
will be presented as missing in the data listings. 


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10.1.4. Serious Adverse Events 
 
An AE or suspected adverse reaction is considered an SAE/suspected unexpected serious 
adverse reaction if, in the view of either the investigator or sponsor, it results in any of the 
following outcomes: 
 
• Death 
• Life-threatening AE 
• 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 or birth defect 
 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
 
All SAEs will be presented in a data listing. 
10.1.5. Adverse Events Leading to Study Drug Discontinuation 
 
An AE where the answer to “What action was taken with study treatment?” is “Drug 
Withdrawn” will be considered an AE leading to study drug discontinuation. 
 
All AEs leading to study drug discontinuation will be presented in a data listing. 
10.2. Clinical Laboratory Evaluations 
 
Clinical laboratory testing will occur at Screening, Check-in, predose (within 60 minutes) 
and 48 hours after the start of the IP infusion on Day 1; and on Days 8, 15, 22, 43, 85, and 
120. A complete list of assessments is provided in Appendix 2.  
 
Actual results and changes from baseline values for hematology, coagulation, serum 
chemistry, and urinalysis tests will be summarized by visit and treatment for subjects in the 
safety population. The key parameters will be evaluated based on toxicity grading scale in 
Appendix 3, and the toxicity grades will be summarized in tables for subjects in safety 
population. 
 


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Shift from baseline in hematology, coagulation, serum chemistry, and urinalysis test results  
relative to the reference range will be summarized by visit and treatment using the 
frequency count and percentage of subjects in each category. 
 
Serology, urine drug screen, Flavivirus screening, and pregnancy test data will not be 
summarized. 
 
All laboratory data will be presented in data listings. 
10.3. Vital Sign Measurements and Weight 
 
Vital signs will be measured at Screening and Check-in; within 60 minutes prior to start of 
the IP infusion; at 0.5, 1 (±10 minutes), 2, 4, 8, 24, and 48 hours after the start of the IP 
infusion; and on Days 5, 8, 15, 22, 43, 85, and 120 (or ET). Vital signs will include systolic 
and diastolic blood pressure, heart rate, and oral body temperature. The subject will have 
rested comfortably in a seated or supine position for at least 5 minutes before all 
measurements are taken. 
 
Actual values and changes from baseline for vital sign data will be summarized by visit 
and treatment for subjects in the safety population. Changes from baseline to each 
scheduled post-baseline visit will be presented. Only systolic and diastolic blood pressure, 
heart rate, respiratory rate and temperature will be included in the summary tables. These 
key parameters will also be graded based on toxicity grading scale in Appendix 3, and the 
grades will be summarized in a table by visit and treatment for subjects in the safety 
population. 
 
All vital sign, height, and weight measurements will be presented in a data listing. 
10.4. Electrocardiograms 
 
Single 12-lead ECG recordings will be made at Screening, within 60 minutes prior to the 
start of the IP infusion; at 1 (±10 minutes), 2, 4, 8, and 24 hours after the start of the IP 
infusion; and on Days 8, 43, 85, and 120 (or ET). Electrocardiograms will be recorded 
after the subject has been in the supine position for at least 10 minutes. A single repeat 
measurement is permitted at Screening for eligibility determination. Measurements of the 
following intervals will be reported: RR interval, PR interval, QRS width, QT interval, and 
QTcF. Assessments should include comments on whether the tracings are normal or 
abnormal; rhythm; presence of arrhythmia or conduction defects; morphology; any 
evidence of myocardial infarction; or ST-segment, T-wave, and U-wave abnormalities. 
 
Actual values and changes from baseline for numeric ECG data will be summarized by 
visit and treatment for subjects in the safety population. Key parameters including QTcF 
and PR interval will be graded based on toxicity grading scale in Appendix 3, and the 


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toxicity grades will be summarized in a table by visit and treatment for subjects in the 
safety population. 
 
Shift from baseline in interpretation of ECG results will be summarized by visit and 
treatment using the frequency count and percentage of subjects in each category. 
 
All ECG data will be presented in a data listing. 
10.5. Physical Examination 
 
A full physical examination will be performed at Screening (skin, head, ears, eyes, nose, 
throat, neck, thyroid, lungs, heart, cardiovascular, abdomen, lymph nodes, and 
musculoskeletal system/extremities). Focused examination (lungs, cardiovascular, 
abdomen, and skin) will be performed on Days 5, 8, and 15. Targeted, symptom-directed 
physical examinations will be performed at all other follow-up visits. 
Physical examination results will be presented in a data listing for the safety population. 
11. Changes from the Planned Analysis 
 
Different from the Protocol, the safety population is defined as all subjects who receive 
any amount of IP in this SAP.  
12. Interim Analysis 
 
No formal interim analysis is anticipated for this study. The blinded safety data will be 
reviewed by the investigators, Medical Monitor and Sponsor’s representative to ensure that 
it is safe to proceed with the planned dose escalation of IP. 
13. References 
 
International Council for Harmonisation (ICH) E6 (R2) GCP: Integrated Addendum to 
ICH E6 (R1) Guidance for Industry, published in the Federal Register (83 Federal Register 
8882 [2018]) 
https://www.fda.gov/media/93884/download. 
 
 
Protocol AV1-PPD-0005: A Phase 1a, Double-Blind, Placebo-Controlled, Single 
Ascending Dose Study to Determine the Safety and Pharmacokinetics of AV-1 in Healthy 
Male and Female Adult Subjects, Protocol Amendment 2, 07 May 2020.






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(l) Clinical laboratory testing will occur at Screening, Check-in, predose (within 60 minutes) and 48 hours after the start of the IP infusion on Day 1; 
and on Days 8, 15, 22, 43, 85, and 120. A complete list of assessments is provided in protocol Section 7.2 Blood and urine samples will be 
collected under fasted conditions and prepared per the clinic’s standard procedures. 
(m) Urine drug screen will occur at Screening and Check-in and on Days 22, 43, and 85 per the clinic’s standard procedures and per Section 7.2. 
(n) Women of childbearing potential only. A serum pregnancy test will be performed at Screening and Check-in, and tests must be negative prior to 
enrollment and dosing, respectively. 
(o) After verification of eligibility, subjects will be randomly assigned before dosing on Day 1.  
(p) The start of the IP infusion will be called “0” hour and is denoted with grey shading. All doses of the IP will be administered intravenously over a 
period of 60 minutes. Subjects will maintain an upright (ie, seated or standing) position for at least 4 hours after the end of infusion. 
(q) Blood samples for PK analysis of AV-1 in serum will be collected predose (within 15 minutes); at 0.5, 1 (end of infusion), 1.25, 1.5, 2, 3, 4, 6, 8, 
12, 24, and 48 hours after the start of infusion, Day 5 prior to discharge, and at the follow-up visits on Days 8, 15, 22, 29, 85, and 120 (or ET). 
(r) A blood sample will be drawn on Day –1 and tested only if a suspected hypersensitivity reaction occurs during or following infusion on Day 1 at 
the discretion of the Investigator in consultation with the Sponsor. At the discretion of the Investigator, an additional blood sample will be drawn as 
soon as possible after the event occurs (Day 1) and again the following day (Day 2). 
(s) During fasting periods, subjects should have nothing to eat or drink except water from 10 hours prior to start of the IP infusion until 4 hours after 
the end of infusion. Water is permitted as desired except for the period of 1 hour prior to the start of the IP infusion until 1 hour after the end of the 
infusion. 
(t) During non-fasting periods when subjects are at the clinical site, subjects should receive standardized meals per the clinic’s standard procedures 
that are scheduled at the same time in each treatment period during the study. 
(u) Solicited AEs will be assessed from the start of IP infusion until Day 8 and unsolicited AEs will be assessed from the start of IP infusion through 
the final follow-up visit on Day 120. All AEs should be followed until they are resolved, stable, or judged by the Investigator to be not clinically 
significant. 
 


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Appendix 2 Clinical Laboratory Assessments 
 
The following clinical laboratory assessments will be performed: 
 
Hematology 
Absolute neutrophil count, hemoglobin, platelet count, and 
white blood cell count 
Coagulation(a) 
Prothrombin time and activated partial thromboplastin time 
Serum Chemistry 
Alanine aminotransferase, albumin(a), alkaline phosphatase, 
aspartate aminotransferase, bicarbonate(b), blood urea 
nitrogen, calcium(a), chloride(b), creatinine(c), glucose 
(fasted), potassium, sodium, and total bilirubin 
Urinalysis 
Blood, glucose(a), and protein 
Serology (IgG)(a) 
Hepatitis B surface antigen, hepatitis C virus antibody, and 
human immunodeficiency virus antibody types 1 and 2 
Flavivirus Screening (IgM 
and IgG)(a) 
DENV antibody, Zika virus antibody (IgM only), and West 
Nile virus antibody 
Urine Drug Screen(d) 
Amphetamines (includes methamphetamines and 
ecstasy/methylenedioxymethamphetamine), barbiturates, 
benzodiazepines, cannabinoids, cocaine metabolites, 
cotinine, ethyl alcohol, methadone, methamphetamines, 
opiates (including heroin, codeine, and 
oxycodone/oxymorphone) 
Pregnancy Test 
(female subjects only)(e) 
Follicle-stimulating hormone, serum pregnancy test (human 
chorionic gonadotropin) 
 
Abbreviations: IgG, immunoglobulin G; IgM, immunoglobulin M. 
Note: Results of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, blood urea 
nitrogen creatinine, and total bilirubin that are below the reference ranges are acceptable and will not exclude 
participation. 
(a) Clinical laboratory assessments will be performed at Screening and Check-in on Day  -1 only, except 
serology and flavivirus screening will occur only at Screening. 
(b) Bicarbonate and chloride will only be used for calculation of anion gap ([sodium + potassium] - [chloride 
+ bicarbonate)]. Volunteers with an anion gap greater than the upper limit of normal at Screening and Check-
in on Day -1 will be excluded from participation in the study. 
(c) Volunteers with an estimated creatinine clearance (calculated using CKD-EPI method) <90 mL/min/1.73 
cm2 at Screening will be excluded from participation in the study. 
(d) Urine drug screening will be performed at Screening, Check-in on Day –1, on Day 22 (±2), and on Day 43 
(±3), except cotinine screening will occur only on Day –1. 
(e) For females in menses, screening urinalysis may be postponed or repeated, but a result should be available 
prior to Day 1. 
 
 
 


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Appendix 3 Toxicity Tables 
 
Table 17-1 
Toxicity Grading Scales for Clinical Adverse Events and Reactions 
Cardiovascular 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Arrhythmia 
N/A 
Asymptomatic; transient 
signs; no medical 
intervention required 
Recurrent or persistent 
symptoms; medical 
intervention required 
Hemorrhage, Blood 
Loss* 
Estimated blood loss 
is <100 mL 
Estimated blood loss is 
≥100 mL; no transfusion 
required 
Transfusion required 
QTc (Fridericia’s 
correction)  
 
Asymptomatic, QT 
interval 450 to 
479 msec (male) and 
460 to 479 msec 
(female) OR increase 
in interval <30 msec 
above baseline 
Asymptomatic, QTc 
interval 480 to 499 msec 
OR increase in interval 
30 to 50 msec above 
baseline 
Asymptomatic, QTc interval 
≥500 msec OR increase in 
interval ≥60 msec above 
baseline 
PR Interval 
(prolonged) 
PR interval 0.21 to 
0.25 sec 
PR interval >0.25 sec 
Type II 2nd degree AV block 
OR ventricular pause >3 sec 
Respiratory 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Cough 
Transient; no 
treatment 
Persistent 
Interferes with daily 
activities 
Bronchospasm, Acute 
Transient; no 
treatment; forced 
expiratory volume 
71 to 80% of 
predicted peak flow 
Requires medical 
intervention; normalizes 
with bronchodilator; 
forced expiratory 
volume 60 to 70% of 
predicted peak flow 
No normalization with 
bronchodilator; forced 
expiratory volume <60% of 
predicted peak flow 
Dyspnea 
Does not interfere 
with usual and social 
activities 
Interferes with usual and 
social activities; no 
treatment 
Prevents daily and usual 
social activity OR requires 
treatment 
Gastrointestinal 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Nausea 
No interference with 
activity 
Some interference with 
activity 
Prevents daily activity 
Vomiting 
No interference with 
activity OR 1 to 
2 episodes/24 hours 
Some interference with 
activity OR 
>2 episodes/24 hours 
Prevents daily activity OR 
requires IV hydration OR 
requires medical intervention 
Diarrhea 
2 to 3 loose or 
watery stools OR 
<400 grams/24 hours 
4 to 5 loose or watery 
stools OR 400 to 
800 grams/24 hours 
6 or more loose or watery 
stools OR 
>800 grams/24 hours OR 
requires IV hydration OR 
requires medical intervention 
Local Reactions 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Pain 
Does not interfere 
with activity 
Repeated use of 
non-narcotic pain 
reliever > 24 hours OR 
interferes with activity 
Any use of narcotic pain 
reliever OR prevents daily 
activity 


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Tenderness 
Discomfort only to 
touch 
Discomfort with 
movement or mild 
discomfort at rest 
Significant discomfort at rest 
Erythema/Redness** 
2.5 to 5 cm 
5.1 to 10 cm 
>10 cm 
Induration/Swelling*** 
2.5 to 5 cm AND 
does not interfere 
with activity 
5.1 to 10 cm OR 
interferes with activity 
>10 cm OR prevents daily 
activity 
Systemic Reactions 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Allergic Reaction 
Pruritus without rash 
Localized urticaria OR 
requires oral therapy 
Generalized urticaria; 
angioedema OR anaphylaxis 
OR requires epinephrine 
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 OR 
requires triptans 
Fatigue 
No interference with 
activity 
Some interference with 
activity 
Significant; prevents daily 
activity 
Myalgia 
No interference with 
activity 
Some interference with 
activity 
Significant; prevents daily 
activity 
Systemic Illness 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Illness or clinical 
adverse event (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 
*Does not include blood loss from study. 
**The local reaction should be measured at the greatest single diameter and recorded as a continuous variable 
in addition to grading. 
***Induration/swelling should be evaluated and graded using the functional scale as well as the actual 
measurement. 
 
 


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Table 17-2 
Vital Signs Toxicity Grading 
Vital Signs*  
Mild (Grade 1)  
Moderate (Grade 2)  
Severe (Grade 3)  
Fever (°C) ** 
(°F) **  
38.0 to 38.4 
100.4 to 101.1 
38.5 to 38.9 
101.2 to 102.0 
39.0 to 40 
102.1 to 104 
Tachycardia - beats per 
minute  
101 to 115 
116 to 130 
>130 
Bradycardia - beats per 
minute***  
50 to 54 
45 to 49 
<45 
Hypertension (systolic) - 
mm Hg  
141 to 150 
151 to 155 
>155 
Hypertension (diastolic) - 
mm Hg  
91 to 95 
96 to 100 
>100 
Hypotension (systolic) – 
mm Hg  
85 to 89 
80 to 84 
<80 
Respiratory rate – breaths 
per minute  
17 to 20 
21 to 25 
>25 
*Subject should be at rest for all vital sign measurements.  
**Oral temperature; no recent hot or cold beverages or smoking.  
***When resting heart rate is between 60 to 100 beats per minute. Use clinical judgement when 
characterizing bradycardia among some healthy subject populations, for example, conditioned athletes. 
 
 


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Statistical Analysis Plan, Version 1.0 
AV1-PPD-0005 
 
Date Issued: 08MAR2021 
 
  
22 
Table 17-3 
Laboratory Toxicity Grading 
Laboratory Tests 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Liver Function Tests – ALT 
increase by factor 
1.1 – 2.5 × ULN 
2.6 – 5.0 × ULN 
>5.0 × ULN 
Liver Function Tests – AST 
increase by factor 
1.1 – 2.5 × ULN 
2.6 – 5.0 × ULN 
>5.0 × ULN 
Albumin – Hypoalbuminemia 
g/dL  
2.8 – 3.1 
2.5 – 2.7 
<2.5 
Alkaline Phosphatase – ALP 
increase by factor 
1.1 – 2.0 × ULN 
>2.0 – 3.0 × ULN 
>3.0 × ULN 
Anion Gap* – mEq/L 
N/A 
N/A 
N/A 
Bilirubin (total) – mg/dL 
1.1 – <1.6 × ULN 
1.6 – < 2.6 × ULN 
≥ 2.6 × ULN 
Blood Urea Nitrogen mg/dL 
27 – 30 
31 – 35 
> 35 
Calcium – 
Hypocalcemia mg/dL 
8.0 – 8.4 
7.5 – 7.9 
7.0 – 7.4 
Calcium – 
Hypercalcemia mg/dL 
10.5 – 11.0 
11.1 – 11.5 
11.6 – 12.0 
Creatinine – mg/dL  
1.2 – 1.3 × ULN 
>1.3 – 1.8 × ULN  
>1.8 × ULN 
Glucose (fasted) – 
Hypoglycemia mg/dL 
50 – 54 
40 – 49 
30 – 39 
Glucose (fasted) – 
Hyperglycemia 
Fasting – mg/dL 
117 – 127 
128 – 142 
>143 
Potassium – Hypokalemia 
mEq/L 
3.3 – 3.4 
3.1 – 3.2 
2.9 – 3.0 
Potassium – Hyperkalemia 
mEq/L 
5.1 – 5.2 
5.3 – 5.4 
5.5 – 5.6 
Sodium – Hyponatremia 
mEq/L 
129 – 131 
127 – 128 
122 – 126 
Sodium – Hypernatremia 
mEq/L  
146 – 147 
148 – 149 
150 – 152 
Hematology 
WBC increase - cell/mm3 
9,800 – 14,000 
14,001 – 19,000 
19,001 – 24,000 
WBC decrease - cell/mm3 
2,000 – 3,099 
1,000 – 1,999 
500 – 999 
Absolute Neutrophil Count - 
cell/mm3 
1,000 – 1.499 
500 – 999 
0 – 499 
Hemoglobin Decrease 
(female) - gm/dL  
9.7 – 10.7 
8.2 – 9.6 
6.7 – 8.1 
Hemoglobin Decrease (male) 
- gm/dL  
11.7 – 12.7 
9.76 – 11.6 
7.6 – 9.6 
Platelets Decrease - cell/mm3 
125,000 – 139,000 
100,000 – 124,000 
<100,000 
Coagulation 
Prothrombin Time – increase 
by factor  
>1.0 – 1.2 × ULN 
1.2 – 1.4 × ULN 
>1.4 × ULN 
Activated Partial 
thromboplastin time – 
increase by factor  
>1.0 – 1.2 × ULN 
1.2 – 1.4 × ULN 
>1.4 × ULN 


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Statistical Analysis Plan, Version 1.0 
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Date Issued: 08MAR2021 
 
  
23 
Laboratory Tests 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Urine 
Blood** 
1+ 
2+ 
>2+ 
Glucose  
1+ 
2+ 
>2+ 
Protein 
1+ 
2+ 
>2+ 
Abbreviations: ALP, alkaline phosphatase; ALT, alanine transferase; AST, aspartate aminotransferase; ULN, 
upper limit of the normal range, WBC, white blood cell. 
*Only values above the ULN and below the LLN are considered abnormal. 
**For females: In case of menstruation, screening urinalysis must be postponed, but a result should be 
available prior to Day 1. Hematuria is acceptable for females in menses for the purposes of evaluating 
study halting criteria and dose escalation. 
Source: DHHS 2007. 
Table 17-4 
Infusion-related Reactions and Toxicity Grading 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Mild transient 
reaction; infusion 
interruption not 
indicated; 
intervention not 
indicated. 
Therapy or infusion interruption indicated 
but responds promptly to symptomatic 
treatment (eg, antihistamines, nonsteroidal 
anti-inflammatory drugs, narcotics 
[opioids], intravenous fluids); 
prophylactic medication indicated for less 
than or equal to 24 hours. 
Prolonged (eg, not rapidly 
responsive to symptomatic 
medication and/or brief interruption 
of infusion); recurrence of symptoms 
following initial improvement; 
hospitalization indicated for other 
clinical sequelae. 
Source: Adapted from the National Cancer Institute Common Terminology Criteria for Adverse Events 
(Version 5.0) for infusion-related reactions.