A Phase 2a Double-blind, Placebo-controlled Study to Assess the Safety and Tolerability of a Single Intravenous Dose of an Investigational Monoclonal Antibody With Code Name VIS410 in Subjects With Uncomplicated Influenza A Infection
Phase: PHASE2
Conditions: Influenza
Sponsor: Visterra, Inc.

 
 
 
 
 
 
 
Official Title: 
Protocol VIS410-202, A Phase 2a Double-
blind, Placebo-controlled Study to Assess the 
Safety and Tolerability of a Single 
Intravenous Dose of VIS410 in Subjects with 
Uncomplicated Influenza A Infection 
 
NCT Number: 
NCT02989194 
 
Document Date: 14 March 2017 
 
 

 
 
 
 
Clinical Study Protocol 
 
A Phase 2a Double-blind, Placebo-controlled Study to Assess the Safety and Tolerability 
of a Single Intravenous Dose of VIS410 in Subjects with Uncomplicated Influenza A 
Infection 
 
Product VIS410 
Protocol Number VIS410-202 
EudraCT Number 2015-004546-26 
Clinical Phase 2a 
Clinical Indication Influenza infection 
Issue Date (Version) 14 March 2017 (Version 2.2) 
 
Sponsor Visterra, Inc. 
One Kendall Square, Suite B3301 
Cambridge, MA 02139 
United States of America 
Sponsor Representative  
  
 
 
 
Page 2 of 75

Visterra, Inc.
Version 2.2
SIGNATURES
Clnucer, SruovPnormor
vIS4l0-202
14 Mmch 2017
Signature of Sponsor Representative
Title A Phase 2a Double-blind, Placebo-controlled Study to Assess the Safety and
Tolerability of a Single Intravenous Dose of YIS410 in Subjects with Uncomplicated
Influenza A Infection
Name:
Jos6 Trevejo, MD, PhD
'This Clinical Study Protocol has been reviewed and approved by the Sponsor
in order to ensure compliance with Good Clinical Practice.'
"7fr\a-
vIS410-202
Visterra Confidential
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Visterra Inc.
VIS410-202 Clinical Study Report
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Signature of Investigator 
 
Title:  A Phase 2a Double-blind, Placebo-controlled Study to Assess the Safety and 
Tolerability of a Single Intravenous Dose of VIS410 in Subjects with Uncomplicated 
Influenza A Infection 
 
Name: 
 
Affiliation: 
 
Address: 
 
 
 
 
 
 
‘I have read and understood all sections of the protocol entitled, “A Phase 2a Double-blind, 
Placebo-controlled Study to Assess the Safety and Tolerability of a Single Intravenous Dose 
of VIS410 in Subjects with Uncomplicated Influenza A Infection.” 
 
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with the Final Protocol, the International Conference on Harmonisation tripartite 
guideline E6(R1): Good Clinical Practice and all applicable government regulations. I will 
not make changes to the protocol before consulting with Visterra, Inc., or implement protocol 
changes without independent ethics committee approval except to eliminate an immediate 
risk to subjects. I agree to administer study treatment only to subjects under my personal 
supervision or the supervision of a subinvestigator. 
 
I will not supply the investigational product to any person not authorized to receive it. 
Confidentiality will be protected. Subject identity will not be disclosed to third parties or 
appear in any study reports or publications. 
 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without authorization from Visterra, Inc.’ 
 
 
Signature: 
 
Date: 
 
 
Visterra Inc.
VIS410-202 Clinical Study Report
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PROTOCOL HISTORY 
Protocol History 
Visterra, Inc. – VIS410-202 
Document  
Issue Date 
Amendment Type 
Comments 
Initial Clinical Study Protocol 
6 January 2016 
- 
This document 
Revised Clinical Study Protocol 
14 September 2016 
 
 
Revised Clinical Study Protocol 
12 October 2016 
Country Specific-
South Africa 
Inclusion of HIV testing at 
baseline 
Revised Clinical Study Protocol 
14 March 2014 
Country Specific 
South Africa 
Modification of HIV 
exclusion criteria #12 
 
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TABLE OF CONTENTS 
Title Page ........................................................................................................................... 1 
Signatures .......................................................................................................................... 2 
Protocol History ................................................................................................................ 4 
Table of Contents .............................................................................................................. 5 
Synopsis .............................................................................................................................. 8 
Time and Events Schedule ............................................................................................. 15 
List of Abbreviations and Definitions of Terms ........................................................... 19 
1. 
Introduction ............................................................................................................. 21 
1.1 
Background Information ...................................................................................... 21 
1.2 
Nonclinical Studies .............................................................................................. 21 
1.3 
Clinical Studies .................................................................................................... 22 
1.4 
Overall Rationale for the Study ........................................................................... 27 
1.5 
Risk Benefit Analysis .......................................................................................... 27 
1.5.1 
Potential Risks ....................................................................................... 28 
1.5.2 
Potential Benefits ................................................................................... 29 
2. 
Study Objectives...................................................................................................... 29 
2.1 
Primary Objective ................................................................................................ 29 
2.2 
Secondary Objectives .......................................................................................... 29 
2.3 
Exploratory Objectives ........................................................................................ 29 
3. 
Study Endpoints ...................................................................................................... 30 
3.1 
Primary Endpoints ............................................................................................... 30 
3.2 
Secondary Endpoints ........................................................................................... 30 
3.3 
Exploratory Endpoints ......................................................................................... 30 
4. 
Study Design ............................................................................................................ 30 
4.1 
Overview of Study Design ................................................................................... 30 
4.2 
Discussion of Study Design ................................................................................. 31 
4.3 
Inclusion Criteria ................................................................................................. 32 
4.4 
Exclusion Criteria ................................................................................................ 33 
5. 
Treatment(s) ............................................................................................................ 34 
5.1 
Physical Description of the Study Drug .............................................................. 34 
5.2 
Other Medication Administered in the Study ...................................................... 34 
5.3 
Storage and Drug Accountability ........................................................................ 35 
5.3.1 
Study Drug ............................................................................................. 35 
5.4 
Dose and Administration ..................................................................................... 35 
5.5 
Treatment Compliance ......................................................................................... 36 
5.6 
Data Safety Monitoring Board ............................................................................. 36 
6. 
Prior and Concomitant Therapy ........................................................................... 37 
6.1 
Prior medications ................................................................................................. 37 
6.2 
Permitted Concomitant Therapies ....................................................................... 37 
6.3 
Excluded Concomitant Medications .................................................................... 37 
7. 
Assessments ............................................................................................................. 38 
7.1 
Timing of Assessments ........................................................................................ 38 
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7.1.1 
Screening Examination and Eligibility Screening Form ....................... 38 
7.1.2 
Contraception Requirements ................................................................. 38 
7.1.3 
Procedures for Enrollment of Eligible Subjects .................................... 39 
7.1.4 
Clinical Assessments and Procedures.................................................... 39 
7.1.5 
Virological Assessments ....................................................................... 40 
7.1.6 
Unscheduled Visits ................................................................................ 40 
7.2 
Pharmacokinetic Evaluations ............................................................................... 41 
7.2.1 
Sample Collection and Handling ........................................................... 41 
7.2.2 
Bioanalysis ............................................................................................ 41 
7.2.3 
Pharmacokinetic Parameters.................................................................. 41 
7.3 
Illness Evaluations ............................................................................................... 42 
7.3.1 
Viral Shedding ....................................................................................... 42 
7.3.2 
Signs and Symptoms of Influenza ......................................................... 42 
7.4 
Immunology ......................................................................................................... 42 
7.4.1 
ADA Response ...................................................................................... 42 
7.4.2 
Anti-Influenza Antibody Response ....................................................... 42 
7.5 
Resistance Analysis ............................................................................................. 43 
7.6 
Safety Evaluations ............................................................................................... 43 
7.6.1 
Adverse Events ...................................................................................... 43 
7.6.2 
Clinical Laboratory Tests ...................................................................... 43 
7.6.3 
Vital Signs ............................................................................................. 44 
7.6.4 
Electrocardiography............................................................................... 44 
7.6.5 
Physical Examination ............................................................................ 44 
7.7 
Total Volume of Blood Sampling........................................................................ 44 
7.8 
Appropriateness of Measurements ...................................................................... 44 
8. 
Study Termination/Completion ............................................................................. 45 
8.1 
Study Completion ................................................................................................ 45 
8.2 
Withdrawal of Subjects from Study .................................................................... 45 
8.3 
Stopping Rules or Discontinuation Criteria ......................................................... 45 
9. 
Statistical Methods .................................................................................................. 46 
9.1 
Determination of Sample Size ............................................................................. 46 
9.2 
Randomization and Blinding ............................................................................... 46 
9.3 
Statistical Analysis ............................................................................................... 47 
9.3.1 
Analysis Populations ............................................................................. 47 
9.3.2 
Initial Characteristics of the Subject Sample ......................................... 47 
9.3.3 
Pharmacokinetics ................................................................................... 47 
9.3.4 
Viral Shedding ....................................................................................... 48 
9.3.5 
Signs and Symptoms of Influenza ......................................................... 49 
9.3.6 
Immunology .......................................................................................... 49 
9.3.7 
Exploratory Pharmacokinetic/Pharmacodynamic Analyses .................. 49 
9.3.8 
Safety ..................................................................................................... 50 
9.4 
Interim Analysis ................................................................................................... 51 
10. Adverse Event Reporting ....................................................................................... 52 
10.1 
Definitions ........................................................................................................... 52 
10.2 
Intensity of Adverse Events ................................................................................. 53 
10.3 
Causality Assessment .......................................................................................... 54 
10.4 
Action Taken Regarding Investigational Product ................................................ 54 
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10.5 
Outcome ............................................................................................................... 54 
10.6 
Recording of Adverse Events .............................................................................. 54 
10.7 
Reporting of Serious Adverse Events .................................................................. 55 
10.8 
Pregnancy ............................................................................................................ 55 
10.9 
Reporting of SAEs to Competent Authorities/Ethics Committees ...................... 56 
11. Ethical Aspects ........................................................................................................ 57 
11.1 
Study-Specific Design Considerations ................................................................ 57 
11.2 
Regulatory Ethics Compliance ............................................................................ 57 
11.2.1 
Investigator Responsibilities ................................................................. 57 
11.2.2 
Independent Ethics Committee or Institutional Review Board ............. 57 
11.2.3 
Informed Consent .................................................................................. 59 
11.2.4 
Privacy of Personal Data ....................................................................... 59 
12. Administrative Requirements ................................................................................ 60 
12.1 
Protocol Amendments ......................................................................................... 60 
12.2 
Subject Identification, Enrollment, and Screening Logs ..................................... 60 
12.3 
Source Documentation ......................................................................................... 60 
12.4 
Case Report Form Completion ............................................................................ 61 
12.5 
Monitoring ........................................................................................................... 61 
12.6 
Data Management ................................................................................................ 61 
12.7 
Data Quality Assurance ....................................................................................... 62 
12.8 
On-Site Audits ..................................................................................................... 62 
12.9 
Study Termination ............................................................................................... 63 
12.10 
Record Retention ................................................................................................. 63 
12.11 
Use of Information and Publication ..................................................................... 63 
12.12 
Registration of Clinical Studies and Disclosure of Results ................................. 65 
12.13 
Confidentiality ..................................................................................................... 65 
13. References ................................................................................................................ 65 
Appendix 1: Laboratory Assessments ........................................................................... 66 
Appendix 2: DMID Adult Toxicity Table ..................................................................... 67 
 
List of Tables 
Table 1. 
Schedule of Assessments ................................................................................15 
Table 2. 
Study VIS-C001 ADA Data ............................................................................24 
Table 3. 
Distribution of Subjects ..................................................................................24 
Table 4. 
Viral Load and AUC Data ..............................................................................25 
 
List of Figures 
Figure 1. 
Schematic Overview of the Study ...................................................................31 
 
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SYNOPSIS 
Name of Company: 
Visterra, Inc. 
 
(for national authority only) 
Name of the Finished 
Product: 
Not applicable 
Name of the Active 
Substance: 
VIS410 
Study Title: 
A Phase 2a Double-blind, Placebo-controlled Study to Assess the Safety and 
Tolerability of a Single Intravenous Dose of VIS410 in Subjects with 
Uncomplicated Influenza A Infection 
Protocol Number 
VIS410-202 
EudraCT Number 
2015-004546-26 
Clinical Indication: 
Influenza infection 
Clinical Phase:  
2a 
Number of Clinical 
Sites: 
Approximately 50-75 sites worldwide 
Number of Subjects:  
Approximately 150 
Objectives: 
Primary Objective: 
• 
Assess the safety and tolerability of a single intravenous (IV) dose of VIS410 in patients with 
uncomplicated influenza infection 
Secondary Objectives: 
• 
Evaluate the efficacy of VIS410 compared with placebo on the time to alleviation of clinical 
symptoms of acute uncomplicated influenza  
• 
Evaluate the effect of VIS410 on severity of influenza infection 
• 
Assess the pharmacokinetics of VIS410 in serum 
• 
Assess the effects of VIS410 on viral shedding 
• 
Assess the immunogenicity of VIS410 
Exploratory Objectives: 
• 
Assess the pharmacokinetics of VIS410 from nasopharyngeal secretions 
• 
Assess viral isolates to determine the emergence of VIS410-resistant viruses 
• 
Assess correlations between virology, safety, pharmacokinetics, viral shedding, clinical symptoms, 
and other endpoints 
• 
Assess the anti-influenza immune response 
Study Design: 
This is a Phase 2a randomized, double-blind, placebo-controlled study to be conducted in approximately 
150 subjects with uncomplicated influenza. Subjects will be admitted to an infusion unit for drug administration 
and observation following infusion. The study is designed to compare an infusion of a single high or low IV 
dose of VIS410 against placebo. Subjects will be assigned randomly to receive VIS410 at a dose of 2000 mg 
(low dose) or 4000 mg (high dose) or placebo (0.9% sodium chloride) at a ratio of 1:1:1 using a permuted block 
randomization method. Eligible subjects will receive VIS410 2000 mg, VIS410 4000 mg, or placebo 
administered as a single IV infusion over 2 hours on Day 1. Subjects will receive a pretreatment regimen of 
diphenhydramine 50 mg PO and ibuprofen 400 mg PO or acetylsalicylic acid 325 mg PO 60 minutes before 
infusion. 
The subjects will be observed for at least 2 hours after the end of the infusion and will have a follow-up phone 
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Name of Company: 
Visterra, Inc. 
 
(for national authority only) 
call in the evening of the dosing day to ensure subjects’ safety and well-being. Subjects will return for follow-up 
visits on Days 3 (±1 day), 5 (±1 day), 7 (±1 day), 14 (±3 days), 28 (±3 days), 56 (±7 days) and 100 (±7 days). In 
addition, between clinic visits up to Day 7 (e.g., on Days 2, 4 and 6) subjects will receive a follow-up telephone 
call to ensure compliance with FluPRO Influenza Symptom Questionnaire and review any new or worsening 
signs or symptoms.  
The Schedule of Assessments is presented in Table 1. 
In case of clinical worsening of influenza-related symptoms recorded at baseline or development of two new 
symptoms after 48 hours of study drug administration, additional antiviral prescription medication may be used, 
at the discretion of the Investigator, for management of influenza-like symptoms per standard of care. The use of 
over-the-counter, symptom-modifying drugs such as non-steroidal anti-inflammatory drugs (NSAIDs), 
antihistamines, or pseudoephedrine are discouraged and paracetamol/acetaminophen should be encouraged as a 
replacement medication.  
In case of hospitalization due to worsening of influenza symptoms, subjects should be managed per standard of 
care and local guidelines, which may include use of neuraminidase inhibitors. An independent Data Safety 
Monitoring Board (DSMB) will be established to review all available safety data after 30 subjects have 
completed the Day 5 visit and again after 75 subjects have completed the Day 28 visit. In addition, following the 
first DSMB, the DSMB will convene if the overall relative gastrointestinal (GI) adverse event rate reaches 50% 
or the rate of moderate GI adverse events reaches 25%. Study enrollment and dosing will continue whilst the 
DSMB evaluates data.  
Based upon any safety assessments and after mutual agreement with the Investigator (or designee) and the 
Sponsor, the study may be temporarily or permanently halted. 
Dosing will temporarily pause whilst the DSMB meets if: 
• 
a drug-related or unexpected drug-related SAE occurs in at least 1 subject 
• 
25% or more subjects have GI symptoms of Grade 3 following the first DSMB. 
Doses may be adjusted downward at the discretion of the DSMB based on review of safety data including GI 
adverse events. 
Study Population: 
Approximately one hundred fifty (150) subjects will be enrolled in 3 equal arms: VIS410 2000 mg, 
VIS410 4000 mg, and placebo. The subjects will be carefully screened for eligibility. 
Inclusion Criteria: 
Subjects meeting all of the following criteria are eligible to participate in this study: 
1. Male and female subjects aged ≥18 years and ˂65 years 
2. Women should fulfill one of the following criteria:  
a. 
Post-menopausal; either amenorrhea ≥12 months or follicle stimulating hormone >40 mIU/mL as 
documented in their medical history.  
b. Surgically sterile; hysterectomy, bilateral oophorectomy, or tubal ligation.  
c. 
Women of childbearing potential participating in heterosexual sexual relations must be willing to 
use adequate contraception from screening until 60 days post-infusion, per Section 7.1.2.  
3. Non-vasectomized (or vasectomized less than 6 months prior to dosing) male subjects who have a 
female partner of childbearing potential must use an effective birth control method (see Section 7.1.2) 
when having heterosexual intercourse, from screening until 60 days post-infusion.  
4. Test positive for influenza A by Rapid Antigen Test performed with a commercially available test on 
an adequate nasopharyngeal specimen in accordance with the manufacturer's instructions 
5. Presence of at least one respiratory symptom (cough, sore throat, or nasal symptoms) of moderate to 
severe intensity, or presence of at least one constitutional symptom (myalgia [aches and pains], 
headache, feverishness, or fatigue) of moderate to severe intensity 
6. Onset of symptoms (time when the temperature was first measured as elevated [temperature of 
≥100.4°F or ≥38°C], OR the time when the subject experienced at least one respiratory symptom or at 
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Name of Company: 
Visterra, Inc. 
 
(for national authority only) 
least one constitutional symptom) no more than 72 hours before the start of infusion 
7. Subject is able and willing to comply with study procedures, as per protocol 
8. Subject is able and willing to give voluntary written informed consent 
Exclusion Criteria: 
Subjects meeting any of the following criteria are excluded from participation in this study: 
1. Use of NSAIDs or antihistamines within 6 hours of study drug dosing with the exception of those used 
as part of the pretreatment regimen. 
2. History of intolerance or allergic response to monoclonal antibodies and/or pretreatment medications 
diphenhydramine, ibuprofen and acetylsalicylic acid) 
3. History of receiving monoclonal antibody products within 3 months prior to enrollment in this study or 
planned administration during the study period 
4. Subjects in whom nasopharyngeal swabbing is not possible 
5. Subject weight less than (<) 45 kg 
6. Subjects with clinical history that would lead to increased risk of influenza complications including but 
not limited to clinically significant cardiac disease, moderate to severe asthma, or other moderate to 
severe chronic obstructive pulmonary disease, metabolic syndrome including moderate to severe 
diabetes or active tuberculosis. 
7. History of chronic GI disease, including bleeding, ulceration, Irritable Bowel Syndrome, systemic 
mastocytosis or chronic diarrhea 
8. Women who are pregnant, breast-feeding, or considering becoming pregnant.  
9. Patients with hypoxemia requiring oxygen support. 
10. Clinical evidence of worsening of any chronic medical condition (temporally associated with the onset 
of symptoms of influenza) which, in the Investigator's opinion, indicates that such finding(s) could 
represent complications of influenza 
11. Presence of immunocompromised status due to chronic illness, previous organ transplant, or use of 
immunosuppressive medical therapy including systemic steroids. 
12. Presence of known human immunodeficiency virus (HIV) infection PLUS any one of the following: 
a. 
A CD4 count ≤500 cells/mm3 (CD4 count obtained within the 3 months prior to screening)  
b. An Acquired Immune Deficiency Syndrome-defining illness. (HIV testing required at 
screening visit for all patients with no documented HIV status within 3 months prior to 
screening.) 
13. Presence of known chronic hepatitis B or hepatitis C. 
14. Receipt of any dose of antiviral therapy such as, but not limited to, rimantadine, amantadine, peramivir, 
zanamivir, laninamivir or oseltamivir in the 7 days prior to screening 
15. Enrollment in any other investigational drug or device study, any disease or vaccine study within 
30 days prior to Day 1 or within 5 half-lives of the investigational compound, whichever is longer 
16. Presence of any pre-existing illness that, in the opinion of the Investigator, would place the subject at 
an unreasonably increased risk through participation in this study 
17. Subjects unable to comply with study protocol procedures and study visit schedules for whatever 
reason 
18. Subjects unable to take oral predose medication 
19. Known or suspected alcohol or drug abuse, that is, abuse of a level that would compromise the safety 
or cooperation of the subject in the opinion of the Investigator 
20. Subjects on chronic medications where the dose has not been stable for at least 3 months 
Test Product, Dose, Mode of Administration: 
VIS410 (2000 mg or 4000 mg) will be administered IV over 2 hours as a single 200-mL infusion followed by a 
25 mL saline flush to ensure all product is administered.  
 
Reference Product, Dose, Mode of Administration: 
Placebo, normal saline solution (0.9%), will be administered IV over 2 hours as a single 200-mL infusion 
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Name of Company: 
Visterra, Inc. 
 
(for national authority only) 
followed by a 25 mL saline flush to ensure all product is administered.  
Study Drug Preparation: 
The required amount of VIS410 to be dosed (2000 mg or 4000 mg) will be diluted with normal saline up to a 
total volume of 200 mL; for placebo subjects, 200 mL of normal saline will be prepared. Length of IV line will 
be set for max volume of 25 mL so that the 25 mL saline flush following administration will ensure all study 
product has been administered.  
The study infusion will be administered IV using a 0.22 µm in-line filter and will be controlled by a volumetric 
pump. Standard, uniform-length infusion lines will be used and microfilters will be provided by the Sponsor. 
The infusion bag will be covered with an opaque sleeve in the pharmacy to maintain the study blind. The study 
drug will be administered IV at a rate of 100 mL/h, over 2 hours. After 200 mL of the diluted dose has been 
administered, the infusion will be stopped; followed by a 25-mL saline flush. The infusion time may be longer 
at the Investigator’s discretion based on local infusion site-related symptoms up to a maximum of 4 hours. 
VIS410 or placebo will be administered within 48 hours of being prepared by the study pharmacist. 
Pretreatment: Subjects will be given a pretreatment regimen of diphenhydramine 50 mg PO and ibuprofen 
400 mg PO or acetylsalicylic acid 325 mg PO 60 minutes before IV infusion. If the subject has any history of 
delayed gastric emptying, including premenstruation syndrome or menstruation, the subject may receive 
premedications 120 minutes prior to IV infusion.  
Following administration, subjects will be observed for at least 2 hours at the infusion center and discharged if 
considered safe by the investigator. Prior to discharge, all subjects will be counseled on the potential GI AEs 
and management of these events.  
Study Duration: 
The total study duration for each subject (screening through study exit) will be approximately 14 weeks 
(Day 100). 
Criteria for Evaluation: 
Primary Endpoints:  
• 
The proportion of subjects with adverse events (AEs) and serious adverse events (SAEs) following 
administration of VIS410 
• 
The proportion of subjects with treatment-emergent AEs (TEAEs) including hypersensitivity 
reaction, anaphylactic reaction, and AEs of special interest (AESIs) following dosing 
Secondary Endpoints: 
• 
The incidence, severity, and duration of signs and symptoms of influenza-like illness as assessed 
by the Influenza Patient Reported Outcomes questionnaire after a single IV dose of VIS410 
• 
Percentage of participants requiring hospitalization for influenza-related complications  
• 
Duration of hospitalization for influenza-related complications  
• 
Percentage of participants with complications of influenza  
• 
Percentage of participants with influenza A relapse/reinfection  
• 
VIS410 pharmacokinetic (PK) parameters (Cmax, tmax, AUC0-∞, AUC0-last, t1/2, Vd, CL) in serum 
• 
The difference between VIS410 and placebo treatment groups in viral AUC from nasopharyngeal 
swabs 
• 
The difference between VIS410 and placebo treatment groups in peak viral load and time to 
resolution of viral load from nasopharyngeal swabs 
• 
Titer of anti-VIS410 antibody-positive samples 
Exploratory Endpoints: 
• 
PK parameters (Cmax, tmax, AUC0-∞, AUC0-last, t1/2) of VIS410 from nasopharyngeal secretions 
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Name of Company: 
Visterra, Inc. 
 
(for national authority only) 
• 
Genotypic and phenotypic assessment to determine the emergence of VIS410-resistant viruses 
• 
Correlations between serum and/or nasopharyngeal PK with viral load, clinical symptoms, 
presence of anti-drug antibodies, and additional endpoints 
• 
Titer of anti-influenza A antibodies by hemagglutinin inhibition assay (HAI) in serum 
• 
Correlations between virology and safety parameters and/or additional parameters may be explored 
Statistical Methods: 
Sample size: 
Approximately one hundred fifty (150) subjects. No formal sample size calculations were done for this study. 
The sample size is consistent with Phase 2a studies to assess safety and tolerability. VIS410 endpoints will 
compare aggregated VIS410 data as well as different dose levels of VIS410 to the placebo arm. 
Descriptive analyses of data from subjects will be performed for demographic characteristics, AEs, concomitant 
medication use, and PK parameters in serum and nasopharyngeal secretions as described below. All calculations 
will use the actual times recorded in the electronic data capture (EDC) system for dosing and sampling. 
Individual and mean (± standard deviation [SD]) or median concentrations versus time profiles will be plotted 
by study period on both linear and logarithmic scales. Additional plots and PK parameters may be generated as 
appropriate. 
Serum Pharmacokinetics  
Serum concentrations and the computed PK parameters will be listed by subject for VIS410. Summary statistics 
of serum concentrations and PK parameters will be presented including means, geometric means, standard 
deviations, CV, medians and ranges, as appropriate. Additional analyses and summaries may be generated as 
appropriate. 
The following PK parameters will be determined for VIS410 in serum: 
• 
Cmax: maximum observed serum concentration 
• 
Tmax: time of Cmax 
• 
AUC0-∞: area under the serum concentration-time curve from time 0 extrapolated to infinity 
• 
AUC0-last: area under the serum concentration-time curve from time 0 to the last measurable 
concentration 
• 
t1/2: terminal elimination half-life 
• 
CL: total clearance 
• 
Vd: volume of distribution 
 
PK data from this study will be also analyzed by population PK modeling.  
Nasopharyngeal Secretion Pharmacokinetics 
Nasopharyngeal secretion concentrations and the computed PK parameters will be listed by subject for VIS410. 
Summary statistics of nasopharyngeal secretion concentrations and PK parameters will be presented including 
means, geometric means, standard deviations, CV, medians and ranges, as appropriate. Additional analyses and 
summaries may be generated as appropriate. 
The following PK parameters will be determined for VIS410 from nasopharyngeal secretions: 
• 
Cmax: maximum observed concentration from nasopharyngeal secretions 
• 
Tmax: time of Cmax 
• 
AUC0-∞: area under the nasopharyngeal secretion concentration-time curve from time 0 
extrapolated to infinity 
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Name of Company: 
Visterra, Inc. 
 
(for national authority only) 
• 
AUC0-last: area under the nasopharyngeal secretion concentration-time curve from time 0 to the last 
measurable concentration 
• 
t1/2: terminal elimination half-life 
• 
Ratio of nasal:serum AUC 
 
Additional PK parameters may be determined as appropriate. 
Adverse Events 
The original terms in the EDC system used by Investigators to identify AEs other than symptoms of influenza A 
will be fully described and coded according to the Medical Dictionary for Regulatory Activities (MedDRA 
current version 19). The reported AEs will be allocated to phases based on their start date. All AEs will be 
listed. All AEs with onset during the treatment phase (i.e., TEAEs) will be summarized. 
AEs will be summarized by treatment group and by MedDRA body organ system and preferred term, severity, 
relatedness, and seriousness.  
The difference in proportions of subjects with AEs, TEAEs, AESIs, and SAEs between treatment groups and 
their 95% CI will be calculated (primary safety endpoint). 
Special attention will be paid to those subjects who died, discontinued the study drug due to an AE, or 
experienced a severe or serious AE. Summaries, listings, and narratives may be provided, as appropriate. 
Injection Site Tolerability 
Injection site tolerability is defined as AEs demonstrating significant injection site irritation or tissue damage. 
Injection site tolerability will be reported by variable, treatment group, and time point. 
Complications of Influenza 
Complications of influenza are defined as pneumonia, myocarditis, worsening of chronic bronchitis, other 
chronic pulmonary diseases, sinus infection, otitis, and death. Complications of influenza will be reported by 
variable, treatment group, and time point. 
Clinical Laboratory Tests 
Actual values and changes from baseline of each continuous biochemistry, hematology and urinalysis test will 
be evaluated by means of descriptive statistics by assessment time point and by treatment group. For categorical 
urinalysis tests, frequency tables of actual values will be provided by assessment time point and by treatment 
group. 
Relative changes in clinical laboratory test values compared to values at baseline will be evaluated according to 
the DMID grading table or in accordance with the normal ranges of the clinical laboratory (below, within, or 
above normal range) for parameters for which no toxicity grades are defined. A shift from baseline table of the 
abnormalities will be provided by assessment time point and by treatment group. 
A listing of subjects with any clinical laboratory test result outside the reference ranges will be provided. 
Vital Signs 
Actual values and changes from baseline of heart rate, respiratory rate, temperature, systolic blood pressure 
(SBP), and diastolic blood pressure (DBP) measurements will be evaluated by means of descriptive statistics by 
assessment time point and by treatment group. 
A shift from baseline table of vital sign abnormalities will be provided by assessment time point and by 
treatment group. 
Electrocardiography 
The ECG variables that will be analyzed are heart rate, PR interval, QRS interval, and QT interval. Values for 
QT corrected for heart rate (QTc) will be derived. QTc corrected according to Fridericia (QTcF) [6] will be the 
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Name of Company: 
Visterra, Inc. 
 
(for national authority only) 
primary correction parameter.  
Actual values and changes from baseline of ECG variables will be evaluated by means of descriptive statistics 
by assessment time point and by treatment group. 
A shift from baseline table of ECG abnormalities will be provided by assessment time point and by treatment 
group. For absolute QTcF interval prolongation (>450, >480, >500 msec) and changes from baseline (increase 
>30 and >60 msec), a frequency table by assessment time point and by treatment group will be provided. 
Signs and Symptoms of Influenza 
• 
Frequency tabulation of the occurrence and severity of each of the subject-reported symptoms of 
influenza-like illness by assessment time point and by treatment group 
• 
Descriptive statistics of the duration of each of the subject-reported symptoms of influenza-like 
illness by treatment group 
Immunology 
Immunological assessments will be summarized by parameter, treatment group, and time point using descriptive 
statistics: 
• 
Anti-VIS410 antibody titers by ADA in serum 
• 
Anti-influenza A antibodies by HAI in serum 
• 
HAI levels to determine a proper immune response to the influenza infection 
Exploratory Pharmacokinetic/Pharmacodynamic Analyses 
Various techniques will be used to explore exposure–response relationships, and to compare the strength of the 
relationship between each independent variable (e.g., AUC, Cmax, and concentration at specific time point) and 
the dependent variables (e.g., viral AUC, peak viral load, and time to cessation of viral shedding, clinical 
symptoms, and additional endpoints). These techniques may include graphical and statistical methods, including 
the creation of boxplots, spaghetti plots, histograms, and a variety of linear, nonlinear, or logistic regression 
techniques and time-to-event methods. If appropriate, continuous independent variables will be evaluated as 
such, and as categorical variables (grouping subjects into exposure categories).  
Anti-Drug Antibodies 
Anti-VIS410 antibody titer will be summarized by treatment group and time point using descriptive statistics. 
Physical Examination 
Abnormal findings in physical examination will be listed. 
 
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TIME AND EVENTS SCHEDULE 
Table 1. 
Schedule of Assessments 
Study Time Point 
Screening 1 
Day 1 
Clinic Visit Day 
Baseline 1 
Predose  
0 hour 
End of  
Infusion 
≥2 Hours 
from End of 
Infusion 
3 (±1) 2 
5 (±1) 2 
7 (±1) 
14 (±3) 
28 (±3) 
56 (±7) 
100 (±7) 
FU/ET3 
Screening/Administrative Assessments 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Admission 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Discharge 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Nasopharyngeal swab for Rapid flu test 4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Onset of symptoms interview 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Safety Assessments 5  
Supine ECG 6 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
Vital signs 7 
X 
X 8 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
Body temperature 9 
X 
X 8 
 
 
X 
X 
X––––––––––––––––––––––X 
X 
X 
X 
Physical exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted physical exam 10 
 
X 8 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Urine pregnancy test 11 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Serology (HIV rapid test) 12 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry 13 
X 
 
 
 
 
 
 
X 
 
X 
 
 
X 
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Study Time Point 
Screening 1 
Day 1 
Clinic Visit Day 
Baseline 1 
Predose  
0 hour 
End of  
Infusion 
≥2 Hours 
from End of 
Infusion 
3 (±1) 2 
5 (±1) 2 
7 (±1) 
14 (±3) 
28 (±3) 
56 (±7) 
100 (±7) 
FU/ET3 
Hematology 13 
X 
 
 
 
 
 
 
X 
 
X 
 
 
X 
Urinalysis 13 
X 
 
 
 
 
 
 
X 
 
X 
 
 
X 
Instructions conmeds and FluPRO 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Observation in unit 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
FluPRO completion 14 
 
X 
 
 
 
 
X––––––––––––––––––––––X 
 
 
 
FluPRO compliance 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
FluPRO collection, review and reinstructions 
 
 
 
 
 
 
X 
X 
X 
 
 
 
 
AESIs 
 
X––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––X 
 
X 15 
Concomitant therapy, AEs 2 
 
X–––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––X 
Collection of SAEs 
 
X–––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––X 
Influenza complications 
 
X–––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––X 
Study Agent Administration/Virologic/PK, and Immunogenicity Assessments 
Pretreatment medications – 1 hour (±5 min) 
prior to start of infusion 16 
 
 
X 
 
 
 
 
 
 
 
 
 
 
VIS410/placebo infusion 17 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Serum PK  
 
 
X 18 
 
X 19 
 
X 
X 
X 
X 
X 
X 
X 
Nasopharyngeal swab 20  
 
 
X 18 
 
 
 
X 
X 
X 
X 21,22 
X 21,22 
X 21,22 
X 21,22 
Serum ADA 
 
 
X 
 
 
 
 
 
 
X 
 
X 
X 
Serum HAI sample  
 
 
X 
 
 
 
 
 
 
X 
X 
 
 
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1 Screening and baseline activities may be performed on the same day. 
2 Subjects will have a follow-up phone call in the evening of the dosing day to ensure subjects’ safety and well-being. In addition, between clinic visits up to Day 7 (e.g., 
Days 2, 4 and 6), subjects will receive a follow-up telephone call to ensure compliance with FluPRO Influenza Symptom Questionnaire and review any new or worsening 
signs or symptoms. 
3 Subjects who terminate the study early will return to the clinical site within 14 days after discontinuation for safety assessments. See Section 8.2 for discharge procedure in 
case of early termination. All other subjects will return for a final follow-up visit at Day 100 ±7 days. 
4 Single nasopharyngeal swab will be obtained from one nostril.  
5 Safety Assessments may be performed at another time, if considered needed at the Investigator’s discretion. In case unexpected symptoms are noticed in subjects, additional 
safety assessments might be performed. 
6 Single 12-lead ECG will be performed after a 5-min rest in supine position. Any significant elevation of QTc>500 msec/min should trigger repeat confirmation in triplicate. 
7 Vital signs should be measured after 5 minutes of rest in a supine position and include heart rate, respiratory rate and blood pressure. Vital signs will only be measured 
while the subject is in the clinic. 
8 Only if screening and baseline are not on the same day. 
9 Body temperature will be measured twice daily from Days 1 through 10 (inclusive) and then once at each follow-up visit. Self-measurement will be done by the subject 
when not in the clinic preferably at approximately the same times each day. 
10 A targeted physical exam may be performed at the Investigator’s or his/her designee’s discretion. 
11 A pregnancy test will be performed for all female subjects of childbearing potential. 
12 For patients with no documented HIV status within 3 months prior to the screening visit, a rapid HIV test will be conducted. Consent for this testing will be obtained prior 
to conducting any HIV testing. All positive rapid tests will be followed up according to local requirements. Patients with documented HIV positive status are assessed 
according to Exclusion 12 for eligibility. 
13 See Laboratory Assessments for list of tests in Appendix 1. 
14 FluPRO questionnaire will be completed at home between clinic visits through Day 10 (inclusive). 
15 Only for subjects who terminate early within 28 days after study drug infusion. 
16 If the subject has any history of delayed gastric emptying, including premenstruation syndrome or menstruation, the subject may receive premedications 120 minutes prior 
to IV infusion. 
17 Subjects will be observed during infusion and at least 2 hours after completing the infusion of VIS410 to allow monitoring for possible hypersensitivity reactions. VIS410 
will be administered over 2 hours. Infusion time can be extended at discretion of the Investigator up to 4 hours based on local infusion-related symptoms. If any serious 
systemic reactions occur, the infusion of VIS410 can be slowed or stopped at the discretion of the Investigator. 
18 Within 1 hour prior to VIS410 administration. 
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19 Sample collected within 30 minutes after completing the infusion of VIS410/placebo. 
20 Nasopharyngeal swabs will be obtained from both nostrils (1 swab per nostril). 
21 Will be done for the first 50 subjects enrolled only. 
22 If a subject presents with or reports influenza-like illness, additional swabs (1 swab per nostril) should be taken (see Section 7.1.5). 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AUC 
Area under the curve 
AUC0-∞ 
Area under the concentration-time curve extrapolated to infinity 
AUC0-last 
Area under the concentration-time curve from time 0 to the last measurable concentration 
CD-1 
Cluster of differentiation 1 
CL 
Clearance 
Cmax 
Maximum serum concentration 
CRO 
Contract Research Organization 
DBA 
Dilute Brown Non-Agouti 
DBP 
Diastolic blood pressure 
DMID 
Division of Microbiology and Infectious Diseases 
DSMB 
Data Safety Monitoring Board 
EC50 
Half-maximal effective concentration 
EDC 
Electronic data capture system 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GLP 
Good Laboratory Practice 
HA 
Hemagglutinin 
HAI 
Hemagglutination inhibition assay 
HIV 
Human immunodeficiency virus 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IgG1 
Immunoglobulin G1 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IV 
Intravenous 
LSLV 
Last Subject Last Visit 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified intent-to-treat 
NOAEL 
No-observed-adverse-effect level 
NSAID 
Non-steroidal anti-inflammatory drug 
PK 
Pharmacokinetic 
PO 
Oral (by mouth) 
qRT-PCR 
Quantitative reverse transcriptase polymerase chain reaction 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SUSAR 
Suspected unexpected serious adverse reaction 
t½ 
Elimination half-life  
TCID50 
Half-maximal tissue culture infective dose 
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Abbreviation 
Definition 
TEAE 
Treatment-emergent adverse event 
tmax 
Time corresponding to maximum serum concentration 
Vd 
Volume of distribution 
 
Definitions of Terms 
BMI 
Body Mass Index, Weight in kilogram divided by the square of height in meters 
Study drug 
VIS410 or placebo 
VIS410 
Investigational product 
 
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1. INTRODUCTION 
1.1 
BACKGROUND INFORMATION 
Severe influenza disease is a common occurrence each season, especially in high-risk groups 
such as young children, older adults, patients with pulmonary conditions, inflammatory 
conditions, malignancies, and pregnant women [1,2]. Despite available therapy with 
neuraminidase inhibitors, including oseltamivir (Tamiflu®; Roche; oral), zanamivir 
(Relenza®; GlaxoSmithKline; inhaled), and peramivir (Rapivab™; Biocryst; IV), 10%-44% 
of hospitalized patients require intensive care and 25%-50% of these patients die. In the 
United States, it is estimated that more than 200,000 patients are hospitalized with influenza 
each year, with up to 48,000 deaths per year [3]. 
The therapeutic use of passive polyclonal antibodies to prevent viral infections, including 
hepatitis B, varicella, cytomegalovirus, rabies, and respiratory syncytial virus has been well 
established. More recently, monoclonal antibodies for viral infections have been developed, 
including palivizumab (Synagis®), a Food and Drug Administration-licensed treatment for 
the prevention of respiratory syncytial virus infection. 
Visterra has developed a novel approach to antibody discovery whereby functionally 
conserved epitopes are identified based on atomic interaction networks and targeted with 
rationally engineered human antibodies. Using this approach, VIS410, a broad spectrum 
human immunoglobulin G1 (IgG1) monoclonal antibody with demonstrated efficacy against 
both Group 1 (including H1 and H5) and Group 2 (including H3 and H7) influenza strains, in 
both treatment and prevention models of influenza, was developed. Visterra intends to 
develop this product for treatment of influenza A, specifically in severely ill hospitalized 
patients. 
This study will provide the first indications of safety and tolerability of VIS410 in subjects 
infected with uncomplicated seasonal influenza A. Efficacy as measured by signs and 
symptoms will also be collected although the sample size does not support statistically 
significant determination of efficacy. 
1.2 
NONCLINICAL STUDIES 
Pharmacology, Pharmacokinetics, and Metabolism 
VIS410 is a human IgG1 monoclonal antibody with a high sequence homology to human 
germ line sequences. VIS410 broadly neutralizes influenza A strains in vitro, with 
half-maximal inhibitory concentration values of approximately 0.1-11 μg/mL. Mechanistic 
studies indicate that VIS410 inhibits hemagglutinin (HA)-mediated cell membrane fusion, 
thus preventing viral replication. 
In vivo studies have demonstrated that VIS410 administered to mice in prevention and 
treatment models of influenza, at doses between 1 and 20 mg/kg (either 24 hours 
pre-exposure or 24-72 hours post-exposure) can protect mice challenged with influenza A 
strains (influenza A/Puerto Rico/8/1934 [H1N1], influenza A/Victoria/3/1975 [H3N2], and 
influenza A/Vietnam/1203/2004 [H5N1]). Additionally, in vivo studies in ferrets have 
demonstrated that treatment with VIS410 can reduce the transmission of influenza pH1N1 via 
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respiratory droplets. The serum concentrations of VIS410 associated with prevention of 
infection in ferrets should be readily achievable in humans also. VIS410 also demonstrates 
protection against a newly emerging highly pathogenic H7N9 (A/Anhui/1/2013) strain of 
influenza in a severe Dilute Brown Non-Agouti (DBA) mouse model [4]. 
Toxicology 
In a cynomolgus monkey Good Laboratory Practice (GLP) toxicity/toxicokinetics study, 
4 IV doses of VIS410 were administered over a 28-day period at 5, 50, and 250 mg/kg with 
no clinically significant findings. Based on this GLP study, the no-observed-adverse-effect 
level (NOAEL) was considered to be 250 mg/kg and the half-life (t1/2) of VIS410 was 
determined to be 8–9 days. 
In the cynomolgus monkey toxicology study, VIS410 was administered as an IV infusion 
over 10 minutes and no infusion reactions were observed.  
In a mouse GLP toxicity/toxicokinetics study (VIS410 IV 4 doses at 5, 50 and 250 mg/kg, 
infused over 14 days to 384 mice), 14 mice (3.6%) died 1-2 hours after Day 14 dosing in the 
5 and 50 mg/kg dose groups. This was likely due to an expected immunogenic response in 
mice, as VIS410 is a human antibody, and not a toxic response. The NOAEL was considered 
to be 250 mg/kg. 
In vitro tissue cross-reactivity studies of VIS410 with normal human tissues, cynomolgus 
monkey tissues, and cluster of differentiation 1 (CD-1) mouse tissues showed VIS410 to be 
broadly cross-reactive. VIS410 staining of membrane was limited to cells within the 
surface/mucosal epithelium in colon, small intestine, and fallopian tube. Of note, staining was 
not observed in vivo, in tissues from toxicology studies in monkeys or mice when assessed by 
immunohistochemistry post-sacrifice. 
The lack of toxicity in the in vivo cynomolgus monkey and mouse toxicology studies 
suggests that the cross-reactivity findings were of little toxicological significance. 
An in vitro soluble cytokine release assay performed using human whole blood at VIS410 
concentrations that encompass the expected concentrations of VIS410 in human blood when 
administered as IV doses of 2 to 50 mg/kg, did not stimulate any acute or sustained release of 
any pro-inflammatory cytokines. 
1.3 
CLINICAL STUDIES 
Phase 1 (VIS-C001). In a Phase 1 study (VIS-C001), a total of 30 healthy volunteers 
received a single, 120-minute IV infusion of 2, 5, 15, 30, or 50 mg/kg of VIS410 (200 mL 
volume) (6 subjects per cohort) and 11 subjects received a single, 120-minute IV infusion of 
placebo (sodium chloride 0.9%; 200 mL volume). 
The PK and safety data are presented below. 
Pharmacokinetics 
PK profiles of the serum and nasopharyngeal samples demonstrated that VIS410 exposure 
was approximately proportional to the dose administered with a mean serum t1/2 of 12.9 days. 
This t1/2 is within the expected range for the IgG1 molecules. In addition, the 13-day t1/2 
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supports the single dosing of VIS410, as the circulating levels should be sufficiently high 
during the normal course of an influenza infection in hospitalized patients (5–14 days). The 
maximum concentration (Cmax) values in the serum for the 30 and 50 mg/kg cohorts were 
980 and 1316 µg/mL, respectively. 
Nasopharyngeal swabs were taken from the 15, 30, and 50 mg/kg cohorts for upper 
respiratory pharmacokinetics. The nasopharyngeal PK profiles were approximately dose 
proportional. Mean nasal Cmax values at the 30 and 50 mg/kg dose levels were 20.0 and 
25.3 µg/mL, respectively. 
Safety 
Overall, VIS410 was generally safe and well tolerated at all dose levels studied. 
Treatment-emergent adverse events (TEAEs) were reported for 20/30 (66.7%) subjects 
receiving VIS410 and 7/11 (63.6%) subjects receiving placebo. There were no drug-related 
serious adverse events (SAEs), no drug-related discontinuations, and no infusion-related 
reactions such as anaphylaxis or injection site reactions.  
Notable adverse events (AEs) included one unrelated SAE of leukopenia and esophagitis 
secondary to primary HSV-1 infection in one subject (VIS410, 30 mg/kg cohort). This SAE 
resolved and the subject is doing well. Another unrelated SAE of acute appendicitis was also 
reported (placebo cohort).  
The most common AEs observed were diarrhea (10/41, 24.4%) and headache (8/41, 19.5%). 
All diarrheal or loose stool AEs were observed in the VIS410-treated subjects and were 
usually mild to moderate, started ~2–4 hours after dosing, were transient and resolved 
spontaneously within 24 hours after dosing with no associated dehydration. The 
gastrointestinal (GI) events were dose proportional and the majority of the AEs were 
observed at the highest dose tested (50 mg/kg). None of the GI events were associated with a 
systemic allergic reaction or elevation in liver or biliary laboratory values. Mean hematology, 
serum chemistry, and urinalysis results were within the normal limits and the mean values 
and changes from baseline were similar across the treatment groups and placebo. Overall, 
mean vital sign measurements observed after dosing were similar to those observed at 
baseline. Mean changes from baseline were also similar across VIS410 dose levels, and no 
apparent treatment- or dose-related trends were observed.  
The anti-drug antibody (ADA) data demonstrated a low level of positive ADA in 4 out of 
30 subjects receiving VIS410 (Table 2). The subjects with positive ADA did not demonstrate 
any impact on their PK profile. 
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Table 2. 
Study VIS-C001 ADA Data 
Cohort Dose 
(mg/kg) 
No. of Confirmed 
ADA Positive 
Pre-Infusion 
Titer 
Confirmed 
Day 
Positive 
Titer 
2 
0/6 
None detected 
NA 
None detected 
5 
3/6 
None detected 
120 
titer 10 
None detected 
14 
titer 10 
120 
titer 40 
None detected 
120 
titer 40 
15 
1/6 
None detected 
120 
titer 40 
30 
0/6 
None detected 
NA 
None detected 
50 
0/6 
None detected 
NA 
None detected 
 
Phase 2a Challenge Study (VIS410-201). Study VIS410-201, “A Phase 2a Randomized, 
Double-blind, Placebo-controlled Study to Assess the Safety, Tolerability and Antiviral 
Activity of a Single Intravenous Dose of VIS410 in Healthy Subjects after a Viral Inoculation 
with Influenza A (H1N1),” was conducted at a single site in Antwerpen, Belgium by SGS 
Life Sciences. Briefly, 24 hours after inoculation with a 106 tissue culture infective dose 
(TCID) of naturally attenuated influenza A (H1N1) virus [7], subjects receive a single IV 
administration of VIS410 (2300 mg fixed dose, equivalent of 30 mg/kg) or placebo 
(7:5 randomization to VIS410:placebo). Subjects were quarantined 10 days post-inoculation 
and discharged thereafter. 
A total of 46 subjects were treated with VIS410 (n=33) or placebo (n=13) across 5 cohorts. 
Cohorts were performed sequentially and included different pretreatment regimens used to 
mitigate the GI events observed with VIS410. Preliminary findings from the first 31 subjects 
are presented below. 
Preliminary Efficacy Data 
A partially blinded pre-specified interim analysis of the first 3 cohorts was conducted to 
evaluate the safety and efficacy of the 2300 mg VIS410 dose and to determine whether dose 
escalation was appropriate. The distribution of subjects is presented in Table 3. 
Table 3. 
Distribution of Subjects 
Treatment 
No. Dosed 
Per Protocol* 
No. Infected** 
Placebo 
13 
9 
7 
VIS410 (2300 mg) 
18 
16 
13 
Total 
31 
25 
20 
HAI = hemagglutinin inhibition assay positive seroconversion at Day 14 or 28. 
*Subjects with HAI >10 at baseline excluded per inclusion/exclusion criteria. 
**Infected subjects who are either polymerase chain reaction positive or HAI positive. 
 
Based on the preliminary results, VIS410 2300 mg dose demonstrated a statistically 
significant antiviral effect with a 76% and 91% reduction in nasopharyngeal viral AUC by 
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quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and half-maximal 
tissue culture infective dose (TCID50) compared to placebo (Table 4).  
Table 4. 
Viral Load and AUC Data 
Viral Measure 
Placebo 
(N=7) 
VIS410 
(N=13) 
Reduction 
(%) 
p Value* 
Median Viral AUC TCID50 (log10 X hours) 
546 
45 
92 
0.019 
Median Viral AUC qPCR (log10 X hours) 
1031 
235 
77 
0.024 
Median Peak Viral Load TCID50 (log10) 
5.0 
2.7 
2.2 
0.009 
Median Peak Viral Load qPCR (log10) 
7.1 
5.6 
1.5 
0.043 
*Calculated with Mann-Whitney U Test. 
 
In addition, analysis of the symptoms data demonstrated a trend in respiratory symptom 
resolution that was consistent with the virology data. Although this study was not powered to 
detect a statistical difference in symptom relief, a 2-day reduction in resolution of upper 
respiratory symptoms and AUC was observed in the VIS410 2300 mg group vs. placebo. 
Preliminary Safety Data 
In the first cohort, 7 subjects received 2300 mg of VIS410 while 5 subjects received placebo. 
Moderate to severe cramping, loose stool and/or diarrhea were reported in 6 of the 7 subjects 
receiving VIS410 and none of the placebo subjects. Most symptoms were observed either 
during the infusion or within 30 minutes of the end of infusion and resolved within 
~12 hours. Given the association with infusion, these AEs were all considered possibly 
related to the study drug. In subsequent cohorts, the addition of a pretreatment regiment 
containing diphenhydramine mitigated the GI AEs and VIS410 was generally well tolerated 
with a reduction in frequency and the severity of GI events from moderate/severe to mild. 
As statistically significant efficacy was demonstrated with the 2300 mg dose in the first 
3 cohorts, the protocol was amended to optimize the tolerability of VIS410. This was done by 
testing different pretreatment regimens and escalating the dose of VIS410 to 4600 mg in the 
context of the virus challenge model. This portion of the study (designated as Part 2) was 
open label; however, virological data were collected to understand viral response and 
pharmacokinetics/pharmacodynamics. 
Eleven subjects were enrolled in Cohort 4 and were inoculated with H1N1 influenza virus 
and administered VIS410 2300 mg 24 hours later. Four subjects were pretreated with 
diphenhydramine 50 mg PO and montelukast 10 mg PO (Group1); 4 subjects were pretreated 
with diphenhydramine 50 mg PO and ibuprofen 600 mg PO (Group 2); and 3 subjects were 
pretreated with diphenhydramine 50 mg IV and montelukast 10 mg PO (Group 3).  
Three subjects in Groups 1 and 3 subjects in Group 3 experienced transient loose stool that 
resolved spontaneously. Only 1 of 4 subjects in Group 2 pretreated with diphenhydramine 
and ibuprofen experienced mild and transient loose stools. Based on these results it was 
determined that the regimen of diphenhydramine plus ibuprofen resulted in the best 
tolerability profile and this pretreatment regimen was further assessed in 4 subjects at the 
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4600 mg dose of VIS410 following viral challenge. Overall, 4600 mg VIS410 following 
pretreatment was generally well tolerated. None of the 4 subjects reported cramping or any 
other symptoms associated with severe infusion reactions. Mild and transient loose stools 
were observed in 3 of the subjects. A fourth subject had a transient episode of nausea and 
vomiting about 8.3 hours after the start of infusion. All events were considered resolved 
within 24 hours of onset. 
Phase 1 (VIS410-102) Study VIS410-102 is a Phase 1, randomized, placebo-controlled study 
to evaluated safety, tolerability, and PK of a single 2300 mg and 3800 mg dose of VIS410 
following administration of different pretreatment regimens. A total of 83 subjects received 
study drug (Placebo (n=12), VIS410 2300 mg (n=59), VIS410 3800 mg (n=12)). VIS410 
2300 mg was evaluated at a 2-hour infusion (n=12), 4-hour infusion (n=12), 2-hour infusion 
following a pretreatment regimen of diphenhydramine 50 mg PO and ibuprofen 400 mg PO 
60 minutes before infusion (n=12), 2-hour infusion following a pretreatment regimen of 
cetirizine 10 mg PO 60 minutes before infusion (n=12), and 2-hour infusion following a 
pretreatment regimen of diphenhydramine 50 mg PO and acetylsalicylic acid 325 mg PO 
60 minutes before a 2-hour infusion (n=11). The 3800 mg VIS410 dose was evaluated at a 
2-hour infusion following a pretreatment regimen of diphenhydramine 50 mg PO and 
ibuprofen 400 mg PO 60 minutes before infusion (n=12). The pretreatment regimens were 
selected in order to mitigate the GI AEs observed with VIS410. This study is currently 
ongoing and a preliminary summary of safety data to date is presented below.  
To date there have been no reports of SAEs. One subject at the 3800 mg dose discontinued 
study drug infusion due to AEs of nausea, vomiting, chills, and hot flashes. All events 
resolved after study drug discontinuation despite slow decrease in serum concentration of 
VIS410. VIS410 was not associated with any signs or symptoms that are consistent with 
systemic allergic reactions or anaphylaxis. Gastrointestinal events were observed at a higher 
frequency in the VIS410 treated subjects compared to Placebo. Based on the data from the 
2300 mg and 3800 mg dose groups, VIS410 was associated with GI events ranging from mild 
to severe; however, a 2300 mg dose of VIS410 with a single-dose pretreatment regimen of 
diphenhydramine and low dose ibuprofen or acetylsalicylic acid was associated with a low 
rate of GI events (16.7% and 9.1%, respectively). Overall, the most commonly reported 
events were loose stool, diarrhea, and abdominal cramping. Subjects who received no 
pretreatment regimen had the highest number of GI AEs ranging from mild to severe. The 
prolonged infusion of VIS410 (over 4 hours) resulted in a larger number of GI events than the 
2-hour infusion (41 events in 10 subjects vs. 18 events in 6 subjects, respectively), suggesting 
that GI events will not be mitigated by slowing the infusion rate. Pretreatment regimens of an 
antihistamine (cetirizine) or an antihistamine (diphenhydramine) plus a prostaglandin 
inhibitor (ibuprofen or acetylsalicylic acid) mitigated the GI events compared with the no 
pretreatment cohorts. The rate (13 GI events in 7 subjects) and severity of events (12/13 mild) 
were slightly lower in the cetirizine group than the no pretreatment groups. The lowest rate of 
GI events with VIS410 was observed in subjects who received the diphenhydramine plus 
acetylsalicylic acid pretreatment regimen, with only 1 subject reporting a mild episode of 
loose stool and abdominal pain approximately 22 hours after initiation of study drug 
administration that resolved spontaneously with no intervention. Another effective 
pretreatment regimen included diphenhydramine plus ibuprofen at both 2300 and 3800 mg 
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dose, with only 2 subjects in the 2300 mg dose group reporting a mild episode of loose stool 
7 to 9 hours after initiation of study drug administration that resolved spontaneously with no 
intervention and 1 report of mild nausea in the same subject. The same pretreatment with a 
higher dose of 3800 mg, showed a low rate of GI events with 1 subject reporting a mild 
episode of loose stool approximately 21 hours after start of infusion and another subject 
reporting mild nausea. Both events resolved spontaneously with no intervention. In addition, 
one (1) subject at the 3800 mg dose discontinued study drug infusion due to AEs of nausea, 
vomiting, chills, and hot flashes. 
To date, no clinically significant changes have been observed in hematology, chemistry, and 
urinalysis parameters. Specifically, no alterations in electrolytes were observed in the 
subjects with loose stool or diarrhea. 
In summary, the type and timing of GI AEs observed in this study are consistent with prior 
studies, are mostly mild in intensity, are self-limiting in nature, and resolve following the 
completion of infusion with no sequelae. These data suggest that a pretreatment regimen is 
necessary to mitigate the GI events associated with VIS410; however, an antihistamine alone 
may not be as effective in mitigating the AEs. Addition of a prostaglandin 
inhibitor/non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen or 
acetylsalicylic acid to an antihistamine was necessary to further reduce the frequency and 
severity of GI events. These data were consistent with previous safety data in an influenza 
virus challenge study where a regimen of diphenhydramine and ibuprofen mitigated the 
severity and or frequency of GI AEs in 8 subjects given 2300 mg (n=4) and 4600 mg of 
VIS410 (n=4). 
For more detailed information on VIS410, refer to the current Investigator Brochure [5]. 
1.4 
OVERALL RATIONALE FOR THE STUDY 
This study will be used to determine the safety and efficacy of VIS410 in subjects with 
seasonal influenza A and is an important study for progression of the program toward testing 
in hospitalized subjects with severe influenza. 
1.5 
RISK BENEFIT ANALYSIS 
In animal studies, single or multiple dose administrations of VIS410 were generally well 
tolerated at doses of up to 250 mg/kg. In the Phase 1 VIS-C001 study in 41 subjects (see 
Section 1.3), all doses studied were generally safe and well tolerated with only mild to 
moderate loose stool or diarrhea seen at the highest doses administered (30 and 50 mg/kg). 
The most common AE was a mild/Grade 1 loose stool or diarrhea that was self-limiting. In 
the Phase 2a challenge study (VIS410-201), administration of 2300 mg of VIS410 in the 
context of an influenza infection resulted in 6 of 7 subjects having moderate to severe 
cramping and loose stools that mostly resolved within 10 hours. Following this initial cohort 
study, a pretreatment regimen was implemented using antihistamines including 
diphenhydramine that resulted in 4 of 5 pretreated subjects in the VIS410 arm experiencing 
mild stomach discomfort. An additional open-label tolerability study tested several 
pretreatment regimens including diphenhydramine and ibuprofen in the influenza-infected 
volunteers. Following dosing of 2300 mg of VIS410 in the ibuprofen and diphenhydramine 
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pretreatment group, the subjects tolerated VIS410 well with only 1 of 4 subjects experiencing 
any GI AE and this was a mild transient loose stool without any associated cramping. At 
4600 mg of VIS410, pretreatment with ibuprofen and diphenhydramine was also generally 
well tolerated with no associated cramping. Transient and mild loose stools were reported in 
2 of the 4 subjects and 1 subject also had a transient episode of nausea and vomiting. The 
AEs observed to date with the projected therapeutic dose of 2300 mg were mostly GI events, 
were mild to moderate in intensity, resolved spontaneously with no additional intervention, 
and decreased in severity and frequency following pretreatment with ibuprofen and 
diphenhydramine. Considering the potential benefit of VIS410 in treatment of severe 
influenza A infection and the types and severity of AEs observed to date at the 2300 mg dose, 
the benefit outweighs the risk of further evaluation of VIS410 in patients with influenza A 
infection. 
1.5.1 
Potential Risks 
As described above, some subjects may experience cramping and/or a transient loose stool or 
diarrhea. Animals that received VIS410 as either treatment or prophylaxis experienced 
decreased weight loss compared with vehicle/placebo-treated animals following challenge 
with various strains of influenza virus. In mice treated with 4 doses of VIS410 over 14 days, 
14 of 384 animals had severe systemic hypersensitivity (anaphylaxis) with death within 
1-2 hours after the fourth dose; and ADAs were found in 8 animals at the end of the 28-day 
recovery period. This was not considered to be a VIS410 specific effect as the NOAEL was 
250 mg/kg but rather a consequence of immunological response in mice to a human antibody. 
Other human antibodies have elicited ADA in mice without clinical problems in humans. 
Administration of VIS410, IV once weekly for 4 weeks in a non-human primate model of 
cynomolgus monkeys was well tolerated. All animals survived and there were no abnormal 
clinical observations suggesting distress to the animals (hypersensitivity-related or other) 
throughout the duration of the study period (including the administration or recovery 
periods). 
ADAs were elicited in 3 of the 42 (7%) samples that had a reduction in titers that were most 
likely due to drug exposure. As with the mice, there were no findings suggesting VIS410 
toxicity in clinical, laboratory or pathology examinations. 
In an in vitro soluble cytokine release assay performed using human whole blood, VIS410 
did not stimulate any dramatic or pervasive release of any pro-inflammatory cytokine (see 
Section 1.2).  
Pharmacological class effects commonly associated with marketed monoclonal antibody 
products used for treatment in humans include serious infusion reactions including 
anaphylaxis (see Section 1.3). VIS410 is to be administered as a single infusion and is 
directed at an exogenous viral target. As a result, it is considered to be of low probability that 
other SAEs such as infection risks reported for approved monoclonal antibodies directed 
against endogenous human protein targets such as immune modulating cytokines and often 
administered as multiple doses over a long period will be observed with VIS410.  
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As described in Section 1.3, a single administration of VIS410 to healthy volunteers was safe 
and well tolerated. The potential exists for subjects to experience cramping or loose stools, 
but pretreatment with histamine antagonists (diphenhydramine) with an NSAID such as 
ibuprofen or acetylsalicylic acid ameliorated the GI effects. 
Given the potential for acute severe hypersensitivity and other adverse reactions observed 
with other monoclonal antibody therapies, subjects should be closely monitored for relevant 
signs and symptoms following administration of VIS410. VIS410 should only be 
administered when personnel and therapies are immediately available for the treatment of 
anaphylaxis and other hypersensitivity reactions.  
1.5.2 
Potential Benefits 
Animals that received VIS410 as either treatment or prophylaxis experienced prolonged 
survival compared with vehicle/placebo-treated animals following challenge with various 
strains of influenza A virus. The Phase 2a challenge study demonstrated a statistically 
significant reduction in viral AUC following treatment with VIS410 compared with placebo 
(Section 1.3). 
At this time, the actual benefits of VIS410 for the treatment of influenza patients are 
unknown. However, data from a recently conducted human challenge study in 31 healthy 
volunteers given influenza A demonstrated a statistically significant decrease in shedding of 
influenza virus with a shorter duration of symptoms (2 days) in the VIS410-treated group 
compared with the placebo group. 
 
2. STUDY OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
• Assess the safety and tolerability of a single intravenous (IV) dose of VIS410 in patients 
with uncomplicated influenza infection 
2.2 
SECONDARY OBJECTIVES 
• Evaluate the efficacy of VIS410 compared with placebo on the time to alleviation of 
clinical symptoms of acute uncomplicated influenza 
• Evaluate the effect of VIS410 on severity of influenza infection 
• Assess the pharmacokinetics of VIS410 in serum 
• Assess the effects of VIS410 on viral shedding 
• Assess the immunogenicity of VIS410 
2.3 
EXPLORATORY OBJECTIVES 
• Assess the pharmacokinetics of VIS410 from nasopharyngeal secretions 
• Assess viral isolates to determine the emergence of VIS410-resistant viruses 
• Assess correlations between virology, safety, pharmacokinetics, viral shedding, clinical 
symptoms, and other endpoints 
• Assess the anti-influenza immune response 
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3. STUDY ENDPOINTS 
3.1 
PRIMARY ENDPOINTS 
• The proportion of subjects with adverse events (AEs) and serious adverse events (SAEs) 
following administration of VIS410 
• The proportion of subjects with treatment-emergent AEs (TEAEs) including 
hypersensitivity reaction, anaphylactic reaction, and AEs of special interest (AESIs) 
following dosing 
3.2 
SECONDARY ENDPOINTS 
• The incidence, severity, and duration of signs and symptoms of influenza-like illness as 
assessed by the Influenza Patient Reported Outcomes questionnaire after a single IV dose 
of VIS410 
• Percentage of participants requiring hospitalization for influenza-related complications  
• Duration of hospitalization for influenza-related complications  
• Percentage of participants with complications of influenza  
• Percentage of participants with influenza A relapse/reinfection  
• VIS410 PK parameters (Cmax, tmax, AUC0-∞, AUC0-last, t1/2, Vd, CL) in serum 
• The difference between VIS410 and placebo treatment groups in viral AUC from 
nasopharyngeal swabs 
• The difference between VIS410 and placebo treatment groups in peak viral load and time 
to resolution of viral load from nasopharyngeal swabs 
• Titer of anti-VIS410 antibody-positive samples 
3.3 
EXPLORATORY ENDPOINTS 
• PK parameters (Cmax, tmax, AUC0-∞, AUC0-last, t1/2) of VIS410 from nasopharyngeal 
secretions 
• Genotypic and phenotypic assessment to determine the emergence of VIS410-resistant 
viruses 
• Correlations between serum and/or nasopharyngeal PK with viral load, clinical 
symptoms, presence of ADAs, and additional endpoints 
• Titer of anti-influenza A antibodies by hemagglutinin inhibition assay (HAI) in serum 
• Correlations between virology and safety parameters and/or additional parameters may be 
explored  
 
 
4. STUDY DESIGN 
4.1 
OVERVIEW OF STUDY DESIGN 
This is a Phase 2a randomized, double-blind, placebo-controlled study to be conducted in 
approximately 150 subjects with uncomplicated influenza. This study will include 
approximately 50–75 clinical sites worldwide.  
Subjects will be admitted to an infusion unit for drug administration and observation 
following infusion. The study is designed to compare an infusion of a single high or low IV 
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dose of VIS410 against placebo. Subjects will be assigned randomly to receive VIS410 at a 
dose of 2000 mg (low dose) or 4000 mg (high dose) or placebo (0.9% sodium chloride) at a 
ratio of 1:1:1 using a permuted block randomization method. Eligible subjects will receive 
VIS410 2000 mg, VIS410 4000 mg, or placebo administered as a single IV infusion over 
2 hours on Day 1. Subjects will receive a pretreatment regimen of diphenhydramine 50 mg 
PO and ibuprofen 400 mg PO or acetylsalicylic acid 325 mg PO 60 minutes before infusion. 
The subjects will be observed for at least 2 hours after the end of the infusion and will have a 
follow-up phone call in the evening of the dosing day to ensure subjects’ safety and 
well-being. Subjects will return for follow-up visits on Days 3 (±1 day), 5 (±1 day), 
7 (±1 day), 14 (±3 days), 28 (±3 days), 56 (±7 days) and 100 (±7 days). In addition, between 
clinic visits up to Day 7 (e.g., Days 2, 4 and 6) subjects will receive a follow-up telephone 
call to ensure compliance with FluPRO Influenza Symptom Questionnaire and review any 
new or worsening signs or symptoms. The Schedule of Assessments is presented in Table 1.  
An independent Data Safety Monitoring Board (DSMB) will be established to review all 
available safety data after 30 subjects have completed the Day 5 visit and again after 
75 subjects have completed the Day 28 visit. In addition, following the first DSMB, the 
DSMB will convene if the overall relative GI adverse event rate reaches 50% or the rate of 
moderate GI adverse events reaches 25%. 
A schematic overview of the study design is shown in Figure 1. The assessments performed 
are summarized per visit in the Time and Events Schedule. 
Figure 1. Schematic Overview of the Study 
Screening; Rapid Diagnostic Test for Influenza A 
 
 
If Rapid Diagnostic Test is Influenza A-positive: Start dosing:  
2000 mg VIS410 (low dose), 4000 mg VIS410 (high dose) or placebo 
 
 
In 30 subjects, DSMB review of data up to Day 5 
 
 
In 75 subjects, DSMB review of data up to Day 28 and 
optional interim analysis 
 
 
Optional interim analysis after all subjects completed Day 14 
 
4.2 
DISCUSSION OF STUDY DESIGN 
Dose Selection 
Various methods were utilized to determine the efficacious dose of VIS410 in humans for the 
treatment of influenza. These methods included evaluation of doses and exposures to provide 
VIS410 levels which exceed in vitro susceptibility measures, including neutralization EC50 
and binding affinity, bridging efficacious doses in preclinical species to humans based on a 
mg/kg dose and PK, and exploratory PK/PD analyses of serum and nasal exposure versus 
antiviral activity of VIS410 in a human influenza virus challenge study. VIS410 broadly 
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neutralizes influenza A strains in vitro with EC50 values ranging from 0.03 to 64.2 µg/mL 
(median of 3.15 µg/mL) and binds with high avidity (30 to 380 picomolar) to HA across 
Group 1 and Group 2 subtypes. VIS410 doses of approximately 2300 mg will result in Cmax 
serum level of 873 µg/mL, which is well above median EC50 of 3.15 µg/mL in serum and 
nasal cavity for the duration of viral shedding. Furthermore, in preclinical animal studies, 
VIS410 demonstrated efficacy at doses of 20 to 30 mg/kg or less against various Group 1 and 
Group 2 influenza A strains with EC50 values ranging from 0.57 to 2.4 µg/mL. Using a 
standard mg/kg conversion, these doses equate to 1500–2300 mg dose in humans (assuming a 
75-kg subject). In a human influenza virus challenge study a single dose of 2300 mg 
demonstrated significant reduction in viral load area under the curve (AUC) and peak viral 
load compared with placebo, suggesting that doses of approximately 2300 mg may be 
efficacious in naturally occurring influenza infection. For strains with higher EC50, doses 
greater than 2300 mg may be necessary to achieve adequate concentration at the primary site 
of infection. Based on these data, doses of 2000 and 4000 mg were selected for evaluation in 
this Phase 2a study. A dose of 4000 mg will ensure separation in VIS410 systemic exposures 
from the 2000 mg dose level to identify potential differences in safety and efficacy between 
the 2 doses. A dose level of 2000 mg provides a safety margin of approximately 9.4-fold to 
the nonclinical NOAEL (250 mg/kg), with the 4000 mg dose providing a safety margin of 
approximately 4.7-fold, assuming a 75-kg subject. In addition, in the Phase 1 pretreatment 
study (VIS410-102) doses of 2300 and 3800 mg were well tolerated following a pretreatment 
regimen of diphenhydramine plus ibuprofen.  
Selection of Study Population 
Approximately one hundred fifty (150) subjects will be enrolled in 3 equal arms: 
VIS410 2000 mg, VIS410 4000 mg, and placebo. The subjects will be carefully screened for 
eligibility. 
4.3 
INCLUSION CRITERIA 
Subjects meeting all of the following criteria are eligible to participate in this study: 
1) Male and female subjects aged ≥18 years and ˂65 years 
2) Women should fulfill one of the following criteria:  
a) Post-menopausal; either amenorrhea ≥12 months or follicle stimulating hormone 
>40 mIU/mL as documented in their medical history.  
b) Surgically sterile; hysterectomy, bilateral oophorectomy, or tubal ligation.  
c) Women of childbearing potential participating in heterosexual sexual relations must 
be willing to use adequate contraception from screening until 60 days post-infusion, 
per Section 7.1.2.  
3) Non-vasectomized (or vasectomized less than 6 months prior to dosing) male subjects 
who have a female partner of childbearing potential must use an effective birth control 
method (see Section 7.1.2) when having heterosexual intercourse, from screening until 
60 days post-infusion.  
4) Test positive for influenza A by Rapid Antigen Test performed with a commercially 
available test on an adequate nasopharyngeal specimen in accordance with the 
manufacturer's instructions 
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5) Presence of at least one respiratory symptom (cough, sore throat, or nasal symptoms) of 
moderate to severe intensity, or presence of at least one constitutional symptom (myalgia 
[aches and pains], headache, feverishness, or fatigue) of moderate to severe intensity 
6) Onset of symptoms (time when the temperature was first measured as elevated 
[temperature of ≥100.4°F or ≥38°C], OR the time when the subject experienced at least 
one respiratory symptom or at least one constitutional symptom) no more than 72 hours 
before the start of infusion 
7) Subject is able and willing to comply with study procedures, as per protocol 
8) Subject is able and willing to give voluntary written informed consent 
 
4.4 
EXCLUSION CRITERIA 
Subjects meeting any of the following criteria are excluded from participation in this study: 
1) Use of NSAIDs or antihistamines within 6 hours of study drug dosing with the exception 
of those used as part of the pretreatment regimen. 
2) History of intolerance or allergic response to monoclonal antibodies and/or pretreatment 
medications (diphenhydramine, ibuprofen and acetylsalicylic acid) 
3) History of receiving monoclonal antibody products within 3 months prior to enrollment in 
this study or planned administration during the study period 
4) Subjects in whom nasopharyngeal swabbing is not possible 
5) Subject weight less than (<) 45 kg 
6) Subjects with clinical history that would lead to increased risk of influenza complications 
including but not limited to clinically significant cardiac disease, moderate to severe 
asthma, or other moderate to severe chronic obstructive pulmonary disease, metabolic 
syndrome including moderate to severe diabetes or active tuberculosis. 
7) History of chronic GI disease, including bleeding, ulceration, Irritable Bowel Syndrome, 
systemic mastocytosis, or chronic diarrhea 
8) Women who are pregnant, breast-feeding, or considering becoming pregnant.  
9) Patients with hypoxemia requiring oxygen support. 
10) Clinical evidence of worsening of any chronic medical condition (temporally associated 
with the onset of symptoms of influenza) which, in the Investigator's opinion, indicates 
that such finding(s) could represent complications of influenza 
11) Presence of immunocompromised status due to chronic illness, previous organ transplant, 
or use of immunosuppressive medical therapy including systemic steroids. 
12) Presence of known human immunodeficiency virus (HIV) infection PLUS any one of the 
following: 
a) A CD4 count ≤500 cells/mm3 (CD4 count obtained within the 3 months prior to 
screening)  
b) An Acquired Immune Deficiency Syndrome-defining illness. (HIV testing required at 
screening visit for all patients with no documented HIV status within 3 months prior 
to screening.) 
13) Presence of known chronic hepatitis B or hepatitis C. 
14) Receipt of any dose of antiviral therapy such as, but not limited to, rimantadine, 
amantadine, peramivir, zanamivir, laninamivir or oseltamivir in the 7 days prior to 
screening 
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15) Enrollment in any other investigational drug or device study, any disease or vaccine study 
within 30 days prior to Day 1 or within 5 half-lives of the investigational compound, 
whichever is longer 
16) Presence of any pre-existing illness that, in the opinion of the Investigator, would place 
the subject at an unreasonably increased risk through participation in this study 
17) Subjects unable to comply with study protocol procedures and study visit schedules for 
whatever reason 
18) Subjects unable to take oral predose medication 
19) Known or suspected alcohol or drug abuse, that is, abuse of a level that would 
compromise the safety or cooperation of the subject in the opinion of the Investigator 
20) Subjects on chronic medications where the dose has not been stable for at least 3 months 
 
5. TREATMENT(S) 
Manufacturing, packaging, and labelling of the investigational product, VIS410, is done 
under the responsibility of the Sponsor. 
5.1 
PHYSICAL DESCRIPTION OF THE STUDY DRUG 
The investigational product is manufactured by KBI Biopharma and Lyophilization Services 
of New England in accordance with Good Manufacturing Practice as required by the current 
Good Clinical Practice (GCP). 
VIS410 is colorless to slightly yellow, clear to opalescent solution; essentially free of 
particles. VIS410 is formulated at a concentration of 25 mg/mL in 40 mM citrate-sodium 
phosphate, 150 mM sodium chloride, and 0.025% polysorbate 80. 
The investigational product will be provided by the Sponsor. VIS410 will be supplied in 
Type I 20-mL glass vials containing a nominal 20 mL solution. A copy of the certificate of 
analysis of the investigational product will accompany the study drug to the clinical center. 
The study drug will be labelled according to local law and regulatory requirements.  
Specific dilution procedures of the study drug will be described in detail in the dispensing 
protocol. 
Placebo will be a normal saline solution (0.9%) and will be prepared by the pharmacist. 
5.2 
OTHER MEDICATION ADMINISTERED IN THE STUDY 
Chronic medications not listed in excluded concomitant medications, are permitted where the 
dose has been stable for at least 3 months prior to screening. 
In case of hospitalization due to worsening of influenza symptoms, subjects should be 
managed per standard of care and local guidelines, which may include use of neuraminidase 
inhibitors. 
Subjects will receive a pretreatment regimen of diphenhydramine 50 mg PO and either 
ibuprofen 400 mg PO or acetylsalicylic acid 325 mg PO 60 minutes before infusion. If the 
subject has any history of delayed gastric emptying, including premenstruation syndrome or 
menstruation, the subject may receive premedications 120 minutes prior to IV infusion.  
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5.3 
STORAGE AND DRUG ACCOUNTABILITY 
5.3.1 
Study Drug 
The Investigator (or designee) is responsible for the safe storage of all study drugs assigned 
to the clinical site. The investigational product should be stored in a locked, secure storage 
facility with access limited to those individuals authorized to dispense the investigational 
product, and maintained within the appropriate ranges of temperature. All study drugs must 
be stored in the original packaging and as specified at delivery.  
The study investigational product be stored between 2°C and 8°C and should be protected 
from light during storage at the clinical site. 
Regular temperature recordings of the study drug storage refrigerator at the clinical site 
should be performed. In case a deviation in the storage conditions should occur, the site must 
not further dispense the affected study drug; instead, the Sponsor should be notified and will 
confirm whether or not the study drug may be further dispensed. 
The Investigator is responsible for ensuring that all study drugs received at the clinical site 
are inventoried and accounted for throughout the study.  
Study drugs should be dispensed under the supervision of the Investigator, a qualified 
member of the investigational staff, or by a hospital/clinic pharmacist. The Investigator must 
maintain accurate records demonstrating date and amount of drugs administered to whom and 
by whom. Study drugs will be supplied only to subjects participating in the study. 
The Monitor responsible for drug accountability will periodically check the supplies of study 
drugs held by the Investigator or pharmacist to ensure accountability and appropriate storage 
conditions for all the study drugs held at the site. 
Unused study drugs must be available for verification by the Sponsor’s Monitor responsible 
for drug accountability during on-site monitoring visits. Any discrepancies between returned 
and expected returned study drugs should be explained. 
After the last visit of the last subject in the study (LSLV), any used and unused 
investigational product will be returned to the Sponsor, or destroyed with the Sponsor’s 
written permission (in this case a certificate of destruction will be provided and filed in the 
Trial Master File). 
Hazardous materials such as used needles and syringes should be disposed of immediately in 
a safe manner and therefore will not be retained for drug accountability purposes. 
5.4 
DOSE AND ADMINISTRATION 
The site’s unblinded pharmacist or properly trained designee will prepare the VIS410 or 
placebo according to the instructions in the pharmacy manual. The required amount of 
VIS410 to be dosed (2000 mg or 4000 mg) will be diluted with normal saline up to a total 
volume of 200 mL. For placebo subjects, 200 mL of normal saline will be prepared. 
The study infusion will be administered IV using a 0.22 µm in-line filter and will be 
controlled by a volumetric pump. Standard, uniform-length infusion lines will be used and 
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microfilters will be provided by the Sponsor. Length of IV line will be set for maximum 
volume of 25 mL. The infusion bag will be covered with an opaque sleeve in the pharmacy to 
maintain the study blind. The product will be administered IV at a rate of 100 mL/h, over 
2 hours. After 200 mL of the diluted dose has been administered (the infusion bag is empty), 
the infusion line will be flushed with 25 mL of normal saline to ensure the total product dose 
is delivered. The infusion time may be longer at the Investigator’s discretion based on local 
infusion site-related symptoms up to a maximum of 4 hours. VIS410 or placebo will be 
administered within 48 hours of being prepared by the study pharmacist. All doses of study 
drug will be administered in the clinic under the direct supervision of the Investigator or 
designee. Following administration, subjects will be observed for at least 2 hours at the 
infusion center and discharged if considered safe by the investigator. Prior to discharge, all 
subjects will be counseled on the potential GI AEs and management of these events. 
Pretreatment: Subjects will be given a pretreatment regimen of diphenhydramine 50 mg PO 
with ibuprofen 400 mg PO or acetylsalicylic acid 325 mg PO 60 minutes before the IV 
infusion. If the subject has any history of delayed gastric emptying, including 
premenstruation syndrome or menstruation, they may receive premedications 120 minutes 
prior to IV infusion. In subjects with underlying renal impairment, caution should be taken 
with use of NSAIDs (ibuprofen or acetylsalicylic acid). Subjects with renal impairment must 
be adequately hydrated prior to administration of the pretreatment regimen and renal function 
should be monitored to ensure subject safety.  
5.5 
TREATMENT COMPLIANCE 
To ensure treatment compliance, all study drug infusions will be supervised by the 
Investigator or his/her designee.  
5.6 
DATA SAFETY MONITORING BOARD 
An independent DSMB will be established to review all available safety data after 30 subjects 
have completed the Day 5 visit and again after 75 subjects have completed the Day 28 visit. 
In addition, following the first DSMB, the DSMB will convene if the overall relative GI 
adverse event rate reaches 50% or the rate of moderate GI adverse events reaches 25%. Study 
enrollment and dosing will continue whilst the DSMB evaluates data.  
Assessment of subject safety will be determined from vital sign measurements ECGs, 
physical examinations, hematology, chemistry and urinalysis laboratory testing, use of 
concomitant medications, and review of AEs should they occur.  
If requested by the DSMB, additional meetings can be scheduled to follow up further safety 
data during the study. The DSMB will review the safety data in detail. If any safety concern 
is raised by the DSMB, treatment can be temporarily or permanently halted. 
Doses may be adjusted downward at the discretion of the DSMB based on review of safety 
data including GI adverse events. Further details will be described in a separate DSMB 
charter. 
 
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6. PRIOR AND CONCOMITANT THERAPY 
All therapies other than the study drug administered from signing of informed consent until 
the last study visit must be recorded in the electronic data capture (EDC) system (name of the 
drug and dates of administration). Intake of concomitant medication(s) will be monitored 
continuously from signing of Informed Consent Form (ICF) until the last study visit. 
6.1 
PRIOR MEDICATIONS 
All medications the subject has taken within 14 days of study drug administration will be 
documented in the EDC. Influenza vaccination within the prior 6 months will also be 
documented in the EDC. The use of over the counter, symptom-modifying drugs such as 
NSAIDS, antihistamines, or pseudoephedrine are prohibited in the 6 hours prior to dosing of 
study drug with the exception of the pretreatment medications. 
6.2 
PERMITTED CONCOMITANT THERAPIES 
The use of contraception and acetaminophen (paracetamol), as per license, is allowed during 
the study. As the impact of VIS410 on symptoms of influenza is a secondary objective of this 
study, the use of acetaminophen (paracetamol) should be minimized. 
Chronic medications not listed in excluded concomitant medications, are permitted where the 
dose has been stable for at least 3 months prior to screening. 
The use of symptom-modifying drugs such as NSAIDS, antihistamines, or pseudoephedrine 
are discouraged and in case a symptom modifying agent is needed, 
paracetamol/acetaminophen should be encouraged as the drug of choice.  
In case of clinical worsening of influenza-related symptoms recorded at baseline or 
development of two new influenza-related symptoms 48 hours after study drug 
administration, additional antiviral prescription medication may be used, at the discretion of 
the Investigator, for management of influenza-like symptoms per standard of care. 
Investigator can decide to initiate antiviral therapy sooner as needed for subject safety and 
well-being.  
6.3 
EXCLUDED CONCOMITANT MEDICATIONS 
Consistent with exclusion criteria, the use of antivirals should be excluded except as outlined 
in Section 6.2. Excluded antiviral medications include, but are not limited to: rimantadine, 
amantadine, peramivir, zanamivir, laninamivir or oseltamivir. 
Use of antibiotics is discouraged unless there is a documented or suspected bacterial 
infection. 
 
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7. 
ASSESSMENTS 
AEs and concomitant medications will be recorded from signing of the ICF to the subject’s 
last visit. 
7.1 
TIMING OF ASSESSMENTS 
If the following assessments are planned at the same time, the order of assessments should be 
as follows: 
1) Influenza Patient Reported Outcomes questionnaire  
2) Vital signs 
3) Nasopharyngeal swab 
4) Blood sampling 
7.1.1 
Screening Examination and Eligibility Screening Form 
All subjects must provide written informed consent before any study specific assessments or 
procedures are performed. 
Subjects will be assigned a unique screening number prior to Rapid Antigen Testing. 
Following confirmation of influenza A infection, subjects will be assessed for inclusion and 
exclusion criteria and those who fulfill all the inclusion and none of the exclusion criteria will 
be randomized into the study. 
A screen failure log must be maintained by the Investigator for all entry criteria failures. 
7.1.2 
Contraception Requirements 
All women of childbearing potential and all male subjects must practice effective 
contraception from screening until 60 days post-infusion. For the purposes of this study, 
women who do not meet one of the following criteria listed below are considered to be 
physiologically capable of becoming pregnant and are, therefore, defined as women of 
childbearing potential: 
o Non-childbearing potential: 
o Post-menopausal: ≥12 months of natural (spontaneous) amenorrhea or 
o 6 weeks after surgical bilateral oophorectomy with or without hysterectomy or  
o follicle stimulating hormone > 40 mIU/mL 
o hysterectomy 
o bilateral tubal ligation  
Women of childbearing potential and all male subjects participating in heterosexual sexual 
relations must be willing to practice effective contraception from screening until 60 days 
post-infusion. For the purposes of the study, highly effective contraception is defined as: 
o Combination of an established form of hormonal contraception (oral, injected, or 
implanted) or an intrauterine device or intrauterine system  
 
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and 
 
o A physical barrier method of contraception with use of a spermicide such as condom 
or occlusive cap (diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream suppository. The use of barrier contraceptives should always be 
supplemented with the use of a spermicide, unless not available in a country 
 
o Male vasectomy with negative semen analysis documentation. The use of 
contraception does not apply if the male partner has been vasectomized at least 
6 months prior to dosing  
 
o Complete abstinence can be considered an acceptable method of contraception at the 
discretion of the Investigator. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, or post-ovulation methods) and withdrawal are not considered 
acceptable methods of contraception 
 
The combination of 2 barrier methods, periodic abstinence (e.g., calendar, ovulation, 
symptothermal, or post-ovulation methods), and withdrawal are not considered acceptable 
methods of contraception.  
Pregnancy reporting is described in Section 10.8. 
7.1.3 
Procedures for Enrollment of Eligible Subjects 
Once a subject has fulfilled the entry criteria, he/she will be assigned a unique identifier. The 
site will randomize the subject using the Interactive Web Response System (IWRS).  
7.1.4 
Clinical Assessments and Procedures 
When required, subjects may be given a pre-screening informed consent in order to perform 
the Rapid Antigen Test for influenza. Flu-positive subjects will then be given a full 
explanation of the nature of the study and written informed consent (approved by the local 
ethics committee) will be obtained according to local requirements before any study-related 
assessment will be carried out.  
At screening, subjects will be requested to attend the clinical center to have assessments 
performed as described in the Time and Events Schedule.  
All results from the screening procedures required to evaluate eligibility must be available 
prior to drug infusion on Day 1. Any abnormal assessment at the screening visit will be 
assessed according to its clinical relevance, and if found relevant, the subject will not be 
included in the study.  
On Day 1, eligibility of the subjects will be confirmed and assessments will be performed as 
described in the Time and Events Schedule. 
Subjects will be admitted to the clinical center on Day 1 and will remain at the clinical center 
until at least 2 hours after study drug infusion on Day 1 and discharged if considered safe by 
the investigator. Prior to discharge, all subjects will be counseled on the potential GI AEs and 
management of these events. Subjects will have a follow-up phone call in the evening of the 
dosing day to ensure safety and well-being.  
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Follow-up Clinic Visits and Telephone Calls:  
All subjects will be asked to come back to the clinical center for follow-up visits on Day 3 
(±1 day), 5 (±1 day), 7 (±1 day), 14 (±3 days), 28 (±3 days), 56 (±7 days), and Day 100 
(±7 days). In order to provide some flexibility for the subjects regarding the site visits and to 
maintain the integrity of the study design, a time window is permitted for the follow-up visits 
in case of time conflict or unforeseen circumstances.  
In addition, between clinic visits up to Day 7 (e.g., Days 2, 4 and 6) subjects will receive a 
follow-up telephone call to ensure compliance with FluPRO Influenza Symptom 
Questionnaire and review any new or worsening signs or symptoms.  
Subjects who terminate the study before completion of the scheduled study procedures for 
any reason (AE, withdrawal of consent, etc.) should be asked to complete study assessments 
(including safety) prior to withdrawal if possible. Subjects who withdraw for safety reasons 
should come for a safety follow-up visit as soon as possible within 14 days after 
discontinuation. 
7.1.5 
Virological Assessments 
The virological laboratory assessments are: 
• At screening, a single nasopharyngeal swab will be obtained from one nostril for the 
rapid test.  
• A nasopharyngeal swab will be collected from each nostril as described in the 
schedule of assessments and laboratory manual. These swabs will be sent to a central 
virology laboratory for processing into appropriate aliquots for virology and analysis 
as detailed in Sections 7.2.1, 7.3.1, 7.4, and 7.5.  
• Further details on sample collection, processing, shipment, and storage will be 
described in the laboratory manual. 
• Virology samples taken from all subjects may be infectious and will be classified as 
“diagnostic specimens” for dispatch purposes. 
• The Investigator may also perform additional tests in the local laboratory consistent 
with standard of care for the illness being treated. 
7.1.6 
Unscheduled Visits 
Unscheduled visits can be planned at the discretion of the Investigator to obtain additional 
information to ensure the safety of the subject.  
Subjects will be instructed to contact the trial center if they exhibit worsening symptoms or 
new episode of influenza-like illness so that they may be monitored and asked to return to the 
site for additional assessments (safety, nasopharyngeal swabbing) at the Investigator’s 
discretion. Findings made during unscheduled visits should be reported in the EDC system 
and should be reported in the source documents. 
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7.2 
PHARMACOKINETIC EVALUATIONS 
7.2.1 
Sample Collection and Handling 
Throughout the study, 5 mL venous blood samples will be collected for analysis of VIS410 in 
serum, according to the time points defined in the Time and Events Schedule. The exact date 
and time of blood sampling and of administration of the study drug must be recorded in the 
EDC system. 
Blood samples will be collected by venipuncture or via indwelling cannula in the forearm 
into standard serum separator tubes and will be immediately chilled (ice bath). Further 
procedures for sample collection, shipment, processing, and storage will be described in the 
laboratory manual.  
Nasopharyngeal swabs for determination of VIS410 concentration from nasopharyngeal 
secretions will be taken at the time points defined in the Time and Events Schedule. Further 
details on sample collection, processing, shipment, and storage will be described in the 
laboratory manual. 
7.2.2 
Bioanalysis 
Serum samples and nasopharyngeal swabs for determination of the concentration of VIS410 
will be analyzed under the responsibility of the Sponsor. 
7.2.3 
Pharmacokinetic Parameters 
Standard non-compartmental approaches using Phoenix WinNonlin (Pharsight Corporation, 
Princeton, NJ, USA; Version 6.3 or higher) will be used to estimate PK parameters in serum 
and from nasopharyngeal secretions as described below.  
The following PK parameters will be determined for VIS410 in serum and/or from 
nasopharyngeal secretions: 
• Cmax: maximum observed concentration 
• Tmax: time of Cmax 
• AUC0-∞: area under the concentration-time curve from time 0 extrapolated to infinity 
• AUC0-last: area under the concentration-time curve from time 0 to the last measurable 
concentration 
• t1/2: terminal elimination half-life 
• CL: total clearance (serum only) 
• Vd: volume of distribution (serum only) 
• Ratio of nasal:serum AUC 
Additional PK parameters may be determined as appropriate. PK data from this study will be 
also analyzed by population PK modeling as appropriate. 
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7.3 
ILLNESS EVALUATIONS 
7.3.1 
Viral Shedding 
Nasopharyngeal swabs to determine viral shedding will be taken as indicated in the 
Time and Events Schedule. Further details on sample collection, processing, shipment, and 
storage will be described in the laboratory manual. 
7.3.2 
Signs and Symptoms of Influenza 
The FluPRO questionnaire will be completed by the subject at the time points indicated in the 
Time and Events Schedule. 
Unsolicited (i.e., not collected via the FluPRO questionnaire) signs and symptoms will be 
collected and scored via a targeted physical exam that will be performed by the Investigator 
or designee. Timing of this assessment is provided in the Time and Events Schedule and is to 
be performed at the discretion of the Investigator or designee.  
Body temperature will also be measured. Fever is defined as a body temperature ≥38°C. 
The solicited and unsolicited signs and symptoms of influenza will not be reported as AEs as 
these constitute an endpoint of the study and will be recorded as such, unless a situation 
arises whereby it is the opinion of the Investigator to do so. 
7.4 
IMMUNOLOGY 
Blood samples for immunology assessments will be collected at the time points indicated in 
the Time and Events Schedule according to the instructions provided in the laboratory 
manual.  
7.4.1 
ADA Response 
Throughout the study, 5 mL venous blood samples will be collected to determine 
anti-VIS410 antibody titers according to the time points defined in the 
Time and Events Schedule and according to the instructions provided in the laboratory 
manual. The exact date and time of blood sampling must be recorded in the EDC system. 
Anti-VIS410 antibody titers will be determined by Visterra or designee. These samples may 
be stored for further characterization of the effect of ADA on neutralization in accordance 
with local regulations. 
7.4.2 
Anti-Influenza Antibody Response 
Venous serum samples (5 mL) will be collected to determine anti-influenza antibody titers 
according to the time points defined in the Time and Events Schedule and according to the 
instructions provided in the laboratory manual. Anti-influenza antibody titers will be 
determined by Visterra or designee. 
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7.5 
RESISTANCE ANALYSIS 
Analysis of resistance will be performed by Visterra or designee on selected samples from 
nasopharyngeal swabs. Further procedures for sample collection, processing, shipment, and 
storage will be described in the laboratory manual. 
7.6 
SAFETY EVALUATIONS 
The safety assessment in this study will be based on AEs, clinical laboratory tests, vital signs, 
and physical examination, as described in the following sections. 
7.6.1 
Adverse Events 
AEs will be monitored continuously from signing of informed consent until the last 
study-related activity. At regular intervals during the study, subjects will be asked 
non-leading questions to determine the occurrence of any AEs. All AEs reported 
spontaneously during the course of the study will be recorded as well. 
Subjects will be observed during infusion and for at least 2 hours after completion of 
administration of study treatment to allow monitoring for possible hypersensitivity reactions, 
anaphylactic reactions, or other AEs that occur during this time period. 
All AEs will be recorded in the EDC system, except for the symptoms of influenza collected 
via the FluPRO questionnaire as discussed in Section 7.3.2.  
For detailed definitions and reporting procedures of AEs, see Section 10. 
7.6.2 
Clinical Laboratory Tests 
Blood samples will be collected by venipuncture or via indwelling cannula at the time points 
indicated in the Time and Events Schedule.  
Standard laboratory tests will be performed by a central or local laboratory. Appendix 1 lists 
the biochemistry, hematology, coagulation, and serology tests that will be performed on the 
safety blood samples.  
Creatine kinase-MB, creatinine kinase, and troponin are to be measured in the case where the 
subject has chest pain. 
A midstream urine sample will be collected for urinalysis by dipstick, flow cytometry, and 
microscopic examination. Appendix 1 lists the urinalysis parameters that will be assessed. 
Urine pregnancy tests will be performed at the time points indicated in the 
Time and Events Schedule. 
The Investigator must review the laboratory report, document this review, and record any 
change occurring during the study he/she considers to be clinically relevant in the EDC 
system. Laboratory values outside the normal range will be flagged and their clinical 
relevance will be assessed by the Investigator.  
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7.6.3 
Vital Signs 
Vital sign parameters will be assessed after 5 minutes in supine position at the time points 
indicated in the Time and Events Schedule. The vital sign parameters that will be assessed are 
supine systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate, respiratory 
rate and body temperature. 
Body temperature will be assessed using a thermometer preferably at approximately the same 
times of day for each measurement.  
Any change from baseline in vital sign values occurring during the study that is considered to 
be clinically relevant by the Investigator should be recorded in the EDC system. 
7.6.4 
Electrocardiography 
Single, 12-lead ECGs will be performed after a 5-minute rest at the time points indicated in 
the Time and Events Schedule. The ECG parameters assessed are heart rate, PR interval, 
QRS interval, QT interval. Values for QT corrected for heart rate (QTc) will be derived. QTc 
corrected according to Fridericia (QTcF) [6] will be the primary correction parameter. QTc 
parameters can be calculated subsequently if not immediately available at the site. If a subject 
has an elevated QTc >500 msec/min on assessment then repeat assessments in triplicate 
should be performed for confirmation. 
Any change from baseline in ECG values occurring during the study that is considered to be 
clinically relevant by the Investigator should be recorded in the EDC system. 
7.6.5 
Physical Examination 
A complete physical examination will be performed at the time points indicated in the Time 
and Events Schedule. A targeted physical exam may be performed at the Investigator’s or 
his/her designee’s discretion at the time points indicated in the Time and Events Schedule. 
Physical examination at screening will include height and weight. To obtain the actual body 
weight, subjects must be weighed lightly clothed at screening. The height should be measured 
barefoot. 
Any change in physical examination occurring during the study that is considered to be 
clinically relevant by the Investigator should be recorded in the EDC system. 
7.7 
TOTAL VOLUME OF BLOOD SAMPLING 
The total volume of blood that will be drawn from each subject will be approximately 
175 mL over the course of the study but no more than 25 mL per visit. In order to obtain 
additional information to ensure a subject’s safety (i.e., an AE), additional blood samples (up 
to 50 mL) and/or urine samples may be taken at the discretion of the Investigator per standard 
of care. 
7.8 
APPROPRIATENESS OF MEASUREMENTS 
The assessments that will be made in this study are standard, and are generally recognized as 
reliable, accurate, and relevant. 
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8. STUDY TERMINATION/COMPLETION 
8.1 
STUDY COMPLETION 
A subject will be considered to have completed the study if he or she has completed the last 
follow-up visit (Day 100). 
8.2 
WITHDRAWAL OF SUBJECTS FROM STUDY 
Subjects have the right to withdraw from the study at any time for any reason, including 
personal reasons. A subject can withdraw without giving a reason. The Investigator should, 
however, try to find out why a subject has withdrawn from the study and document the 
reason for withdrawal in the source documents and in the EDC system.  
Subjects may withdraw from the study, or be withdrawn at the request of the Investigator or 
Sponsor (or designee). Each subject withdrawn from the study after receipt of any amount of 
study drug is to be encouraged to undergo as many post-study drug administration 
assessments as possible at the time of withdrawal. The reason for a subject’s withdrawal 
should be recorded on the appropriate page(s) of the electronic Case Report Form. Reasons 
for withdrawal from the study may include, but are not limited to, the following: 
• Withdrawal of consent; 
• Significant subject noncompliance, defined as refusal or inability to adhere to the 
protocol requirements, e.g., subject restrictions and follow-up visit schedule;  
• The Investigator determines that it is in the best interest of the subject to withdraw 
from study participation 
If a subject is withdrawn from the study as a result of a product-related SAE (for details on 
AE reporting see Section 10), notify the Study Monitor and Sponsor within 24 hours. If a 
subject is withdrawn from the study due to an AE that is possibly related to study drug, notify 
the Sponsor within 2 days from the event.  
If there is a medical reason for withdrawal, the Investigator will monitor the subject until 
satisfactory health has returned. 
Subjects who terminate the study before completion of the scheduled study procedures for 
any reason (AE, withdrawal of consent, etc.) should be asked to complete study assessments 
(including safety) prior to withdrawal if possible. Subjects who withdraw for safety reasons 
should come for a safety follow-up visit within 14 days after discontinuation. 
Study drugs assigned to a withdrawn subject must not be assigned to another subject. 
8.3 
STOPPING RULES OR DISCONTINUATION CRITERIA 
The study will be overseen by a DSMB (see Section 5.6). Based upon any safety assessments 
and after mutual agreement with the Investigator (or designee) and the Sponsor, the study 
may be temporarily or permanently halted. Study enrollment and dosing will continue whilst 
the DSMB evaluates data. 
Dosing will temporarily pause whilst the DSMB meets if: 
• a drug-related or unexpected drug-related SAE occurs in at least 1 subject, 
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• 25% or more subjects have GI symptoms of Grade 3 following the first DSMB. 
 
Doses may be adjusted downward at the discretion of the DSMB based on review of safety 
data including GI adverse events. 
 
9. STATISTICAL METHODS 
9.1 
DETERMINATION OF SAMPLE SIZE 
The study will enroll approximately 150 subjects. No formal sample size calculations were 
done for this study. The sample size is consistent with Phase 2a studies to assess safety and 
tolerability. 
9.2 
RANDOMIZATION AND BLINDING 
This will be a double-blind study. The Contract Research Organization (CRO) and site study 
personnel and Visterra personnel will not be aware of which treatment (active study drug or 
placebo) the subjects have been given. Subjects will not be aware of which treatment they 
have been administered. 
Subjects will be randomized 1:1:1 to receive VIS410 2000 mg, VIS410 4000 mg, or placebo. 
A randomization list with randomization numbers will be created. The randomization 
numbers must be used sequentially to ensure an overall balance; no randomization number 
can be skipped. Allocation of each subject to a given treatment sequence will be described in 
a randomization list prepared by Visterra or designee. The randomization will be balanced 
using randomly permuted blocks across the treatment groups.  
The randomization list will not be available to the subjects, Investigators, (blinded) monitors, 
or employees of the clinical center involved in the management of the study before 
unblinding of the data, unless in case of emergency. The Sponsor’s clinical team will also be 
blinded during the study as they will not have direct access to the randomization list. The 
CRO performing data management and statistical activities will receive a copy of the 
randomization list during database lock. Other team members will not have access to any data 
that could lead to unblinding.  
Unblinding of the individual subject’s treatment by the Investigator should be limited to 
medical emergencies or urgent clinical situations in which knowledge of the subject's study 
treatment is necessary for clinical management. In such cases, the Investigator must first 
attempt to contact the Medical Monitor or appropriate back up (contact information as 
detailed in a separate document), to discuss and agree to the need for unblinding to occur. 
The Medical Monitor or designee will answer calls 24 hours a day, 7 days a week, 365 days 
of the year. In situations in which the Investigator has tried, but is unable to reach the 
Medical Monitor, they should use their best judgment, based on the nature and urgency of the 
clinical situation, and may proceed with unblinding without having successfully reached and 
discussed the situation with the Medical Monitor. 
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Once a subject's treatment assignment has been unblinded, the Medical Monitor and study 
coordinator should be notified within 24 hours of unblinding of the treatment. Information 
relating to unblinding (e.g., reason and date) shall be clearly recorded in the subject’s study 
file, as part of relevant standard operating procedures. In addition, the Investigator should 
consider whether the clinical event prompting unblinding should be considered an SAE, 
according to the regulatory definitions or criteria for SAEs, and if so, submit an SAE report to 
Visterra or designee. 
Visterra or designee will also unblind any SAE reports that are serious, unexpected, and 
considered to be related to the study drug, in accordance with safety reporting guidance and 
regulations. 
9.3 
STATISTICAL ANALYSIS 
VIS410 endpoints will compare aggregated VIS410 data as well as different dose levels of 
VIS410 to the placebo arm. Further details of the statistical methodology will be described in 
the statistical analysis plan (SAP). 
9.3.1 
Analysis Populations 
The following analysis populations will be defined for the study: 
Intent-to-Treat (ITT): All subjects randomized to treatment. 
Modified Intent-to-Treat (mITT): All subjects who receive IV study drug and are 
confirmed influenza A positive by a molecular test at the central virological laboratory. 
Safety Population: All ITT subjects who received IV study drug. 
PK Population (PK): All subjects who received IV study drug with at least 1 PK parameter 
that can be calculated. 
9.3.2 
Initial Characteristics of the Subject Sample 
Summary statistics will be provided per treatment group for demographic (e.g., age, height, 
weight, Body Mass Index, race, gender) and other initial subject characteristics (physical 
examination, medical history, concomitant diseases) will be provided per treatment group and 
for the total group. The ITT population will be used for the summaries. 
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary.  
9.3.3 
Pharmacokinetics 
Standard non-compartmental approaches using Phoenix WinNonlin (Pharsight Corporation, 
Princeton, NJ, USA; Version 6.3 or higher) will be used to estimate the PK parameters in 
serum and nasopharyngeal secretions (see Section 7.2.3) described below. All calculations 
will use the actual times recorded in the EDC system for dosing and sampling. Individual and 
mean (±SD) or median concentrations versus time profiles will be plotted by study period on 
both linear and logarithmic scales. Additional plots and PK parameters may be generated as 
appropriate. The PK population will be used for the summaries. 
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Serum Pharmacokinetics 
Serum concentrations and the computed PK parameters will be listed by subjects for VIS410. 
Summary statistics of serum concentrations and PK parameters will be presented including 
means, geometric means, standard deviations, CV, medians and ranges, as appropriate. 
Additional analyses and summaries may be generated as appropriate. 
The following PK parameters will be determined for VIS410 in serum: 
• Cmax: maximum observed serum concentration 
• Tmax: time of Cmax 
• AUC0-∞: area under the serum concentration-time curve from time 0 extrapolated to 
infinity 
• AUC0-last: area under the serum concentration-time curve from time 0 to the last 
measurable concentration 
• t1/2: terminal elimination half-life 
• CL: total clearance 
• Vd: volume of distribution 
PK data from this study will be also analyzed by population PK modeling. 
Nasopharyngeal Secretion Pharmacokinetics 
Nasopharyngeal secretion concentrations and the computed PK parameters will be listed by 
subject for VIS410. Summary statistics of nasopharyngeal secretion concentrations and PK 
parameters will be presented including means, geometric means, standard deviations, CV, 
medians and ranges, as appropriate. Additional analyses and summaries may be generated as 
appropriate. 
The following PK parameters will be determined for VIS410 from nasopharyngeal 
secretions: 
• Cmax: maximum concentration observed from nasopharyngeal secretions  
• Tmax: time of Cmax 
• AUC0-∞: area under the nasopharyngeal secretion concentration-time curve from 
time 0 extrapolated to infinity 
• AUC0-last: area under the nasopharyngeal secretion concentration-time curve from 
time 0 to the last measurable concentration 
• t1/2: terminal elimination half-life 
• Ratio of nasal:serum AUC 
Additional PK parameters may be determined as appropriate. 
9.3.4 
Viral Shedding 
Additional sensitivity analysis may be conducted excluding subjects that received 
concomitant antiviral therapy during the course of the study.  
• One-way analysis of variance (ANOVA) (with treatment group as the factor) or other 
appropriate statistics detailed in the SAP to assess the difference between VIS410 
treatment groups vs placebo in the area under the viral load-time curve (AUC) for 
influenza virus based on quantification of viral load from nasal swabs  
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• Descriptive statistics of the area under the viral load-time curve (AUC) for influenza 
virus based on quantification of viral load from nasopharyngeal swabs by treatment 
group. 
• Descriptive statistics of the time to resolution of viral load and of the peak viral load 
by treatment group. 
The mITT population will be used for the summaries.  
9.3.5 
Signs and Symptoms of Influenza 
The difference between VIS410 and placebo will be assessed as outlined below. 
• Frequency tabulation of the occurrence and severity of each of the subject-reported 
symptoms of influenza-like illness by assessment time point and by treatment group 
• Descriptive statistics of the duration of each of the subject-reported symptoms of 
influenza-like illness by treatment group 
Additional sensitivity analysis may be conducted excluding subjects that received 
concomitant antiviral therapy during the course of the study. The mITT population will be 
used for the summaries. Additional populations may be analyzed as described in the SAP.  
9.3.6 
Immunology 
Immunological assessments will be summarized by parameter, treatment group, and 
time point using descriptive statistics: 
• Anti-VIS410 antibody titers by ADA in serum 
• Anti-influenza A antibodies by HAI in serum 
• HAI levels to determine a proper immune response to the influenza infection 
The mITT population will be used for the summaries. Additional populations may be 
analyzed as described in the SAP. 
Anti-Drug Antibodies 
Anti-VIS410 antibody titer will be summarized by treatment group and by time point using 
descriptive statistics. 
9.3.7 
Exploratory Pharmacokinetic/Pharmacodynamic Analyses 
Various techniques will be used to explore exposure-response relationships, and to compare 
the strength of the relationship between each independent variable (e.g., AUC, Cmax, and 
concentration at specific time point) and the dependent variables (e.g., viral AUC, peak viral 
load, and time to cessation of viral shedding, clinical symptoms, and additional endpoints). 
These techniques may include graphical and statistical methods, including the creation of 
boxplots, spaghetti plots, histograms, and a variety of linear, nonlinear, or logistic regression 
techniques and time-to-event methods. If appropriate, continuous independent variables will 
be evaluated as such, and as categorical variables (grouping subjects into exposure 
categories). 
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9.3.8 
Safety 
The ITT, and safety populations will be used for the safety summaries. Additional 
populations may be analyzed and this will be documented in the SAP. 
Adverse Events 
The original terms in the EDC system by Investigators to identify AEs other than symptoms 
of influenza A will be fully described and coded according to the Medical Dictionary for 
Regulatory Activities (MedDRA current version 19). The reported AEs will be allocated to 
phases based on their start date. All AEs will be listed. All AEs with onset during the 
treatment phase (TEAEs) will be summarized.  
AEs will be summarized by treatment group and by MedDRA body organ system and 
preferred term, severity, relatedness, and seriousness. Classical symptoms of influenza 
including cough, sore throat, nasal congestion, fatigue, headache, myalgia or low-grade fever 
should not be reported as AEs unless there is a relationship between the event and study 
medication. 
The difference in proportions of subjects with AEs, TEAEs, AESIs, and SAEs between 
treatment groups and their 95% CI will be calculated (primary safety endpoint). 
Special attention will be paid to those subjects who died, discontinued the study drug due to 
an AE, or experienced a severe or serious AE. Summaries, listings, and narratives (also see 
Section 12.11) may be provided, as appropriate. 
Injection Site Tolerability 
Injection site tolerability is defined as AEs demonstrating significant injection site irritation 
or tissue damage. Injection site tolerability will be reported by variable, treatment group, and 
time point. 
Complications of Influenza 
Complications of influenza are defined as pneumonia, myocarditis, worsening of chronic 
bronchitis, other chronic pulmonary diseases, otitis, sinusitis, and death. Complications of 
influenza will be reported by variable, treatment group, and time point. 
Clinical Laboratory Tests 
Actual values and changes from baseline of each continuous biochemistry, hematology and 
urinalysis test will be evaluated using descriptive statistics by assessment time point and by 
treatment group. For categorical urinalysis tests, frequency tables of actual values will be 
provided by assessment time point and by treatment group. 
Relative changes in clinical laboratory test values compared with values at baseline will be 
evaluated in according to the Division of Microbiology and Infectious Diseases (DMID) 
grading table or in accordance with the normal ranges of the clinical laboratory (below, 
within, or above normal range) for parameters for which no toxicity grades are defined. A 
shift from baseline table of abnormalities in clinical laboratory test parameters will be 
provided by assessment time point and by treatment group. 
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A listing of subjects with any clinical laboratory test result outside the reference ranges will 
be provided. 
Vital Signs 
Actual values and changes from baseline of heart rate, respiratory rate, temperature, SBP, and 
DBP measurements will be evaluated by means of descriptive statistics by assessment time 
point and by treatment group. 
A shift from baseline table of vital sign abnormalities will be provided by assessment time 
point and by treatment group. 
Electrocardiography 
The ECG variables that will be analyzed are heart rate, PR interval, QRS interval, and 
QT interval. Values for QT corrected for heart rate (QTc) will be derived. QTc corrected 
according to Fridericia (QTcF) [6] will be the primary correction parameter.  
Actual values and changes from baseline of ECG variables will be evaluated by means of 
descriptive statistics by assessment time point and by treatment group. 
A shift from baseline table of ECG abnormalities will be provided by assessment time point 
and by treatment group. For absolute QTcF interval prolongation (>450, >480, >500 msec) 
and changes from baseline (increase >30 and >60 msec), a frequency table by assessment 
time point and by treatment group will be provided. 
Physical Examination 
Abnormal findings in physical examination will be listed. 
9.4 
INTERIM ANALYSIS 
The following optional safety and efficacy interim analyses may be performed at the 
following times: 
• After 75 subjects have completed the Day 28 visit  
• After all enrolled subjects have completed the Day 14 visit 
The optional interim analysis would review safety and efficacy results in a partially blinded 
fashion. If performed, the interim analyses will be included in the SAP and will be used to 
assist with the planning of future studies. The statistician performing the analysis and the 
PK/PD team at Visterra may be unblinded. 
 
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10. 
ADVERSE EVENT REPORTING 
10.1 
DEFINITIONS 
Type of Event 
Collection Period 
AESIs a  
28 days after drug administration  
TEAEs 
Entire study period b 
SAEs c and Pregnancies 
Entire study period b, d 
a If a subject was enrolled with a concurrent AESI, received investigational product, and then has worsening of 
an AESI (severity of symptoms), then this event should also be reported. 
b The entire study period is from the time a subject receives the study drug through the Day 100 Visit.  
c If the Investigator becomes aware of any related SAE after completion of the study, he or she is obligated to 
report this event.  
d If a subject or the female partner of a male subject, becomes pregnant during the study or within 100 days 
following study drug infusion, the Sponsor must be notified within 24 hours of the site’s knowledge of the 
pregnancy; the subject or partner will be followed until the end of the pregnancy; and the infant will be 
followed for 1 year after the birth, provided informed consent is obtained.  
 
Adverse Event 
An AE is any untoward medical occurrence in a patient administered a medicinal 
(investigational or non-investigational) product in a clinical study. An AE does not 
necessarily have a causal relationship with the treatment. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational or non-investigational) 
product, whether or not related to that medicinal (investigational or non-investigational) 
product. 
This includes any occurrence that is new in onset or aggravated in severity or frequency from 
the baseline condition, or abnormal results of diagnostic procedures, including clinical 
laboratory test abnormalities. 
New or worsening symptoms of influenza including cough, sore throat, nasal congestion, 
fatigue, headache, myalgia or low-grade fever should not be reported as AEs unless they 
result in an SAE (i.e., lead to hospitalization). 
Adverse Event of Special Interest 
An AESI (serious or non-serious) is one of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and rapid communication by 
the Investigator to the Sponsor will be warranted. Such an event might warrant further 
investigation in order to characterize and understand it. Depending on the nature of the event, 
rapid communication by the trial Sponsor to other parties (e.g., regulators) might also be 
warranted (based on CIOMS VI). 
For VIS410, the AESIs include the following: 
• Abdominal cramping 
• Diarrhea 
• Nausea and vomiting 
• Pruritus 
• Rash 
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• Hypotension 
• Throat tightening 
• Trouble breathing or wheezing 
 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose meets any of the following 
conditions: 
• results in death 
• is life-threatening, i.e., the patient was at risk of death at the time of the event (e.g., 
ventricular fibrillation and anaphylaxis). The term does not refer to an event which 
hypothetically might have caused death if it were more severe. 
• requires inpatient hospitalization or prolongation of existing inpatient hospitalization: 
Hospitalization refers to an overnight admission into hospital for the purpose of 
investigating and/or treating the AE. Hospitalization for an elective procedure, or 
routinely scheduled treatment for a pre-existing condition that has not worsened, is 
not an SAE. 
• results in persistent or significant disability/incapacity, i.e., causing substantial 
disruption of the patient’s ability to conduct normal life 
• is a congenital anomaly/birth defect 
• is medically significant, i.e., may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient’s health or may require 
intervention to prevent one of the above outcomes. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias, or convulsions that do not result in hospitalization or development 
of drug dependency or drug abuse. 
Unlisted (Unexpected) Adverse Event 
An AE is considered unlisted if the nature or severity is not consistent with the applicable 
product reference safety information (Investigator Brochure [5]). 
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are SAEs that are unexpected and 
judged by the Investigator or Sponsor to be related to the study treatment administered. 
The Sponsor or designee will report SUSARs and other applicable SAEs to the appropriate 
regulatory authorities, Central Institutional Review Board (IRBs)/Ethics Committees (ECs) 
and Investigators as required, according to local law. 
Treatment-Emergent Adverse Event 
A TEAE is defined as any event not present prior to the initiation of the treatments or any 
event already present that worsens in either intensity or frequency following exposure to the 
treatments. 
10.2 
INTENSITY OF ADVERSE EVENTS 
Each AE must be rated on a 3-point scale of increasing intensity according to DMID 
(Appendix 2): 
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Note: the semi-colon within the description of the grade indicates ‘or’. 
Grade 1 
Mild transient or mild discomfort (<48 hours); no medical intervention/therapy 
required 
Grade 2 
Moderate/mild to moderate limitation in activity—some assistance may be 
needed; no or minimal medical intervention/therapy required 
Grade 3 
Severe/marked limitation in activity, some assistance usually required; medical 
intervention/therapy required, hospitalizations possible  
 
10.3 
CAUSALITY ASSESSMENT 
The following binary choice will be used by the Investigator to describe the causality 
assessment with the test treatment: 
Reasonable Possibility 
There is evidence to suggest a causal relationship between the test treatment and the AE (e.g., 
AE is uncommon and known to be strongly associated with drug exposure or is uncommon in 
the study population, but not commonly associated with drug exposure). 
No Reasonable Possibility 
There is no evidence to suggest a causal relationship between the test treatment and the AE. 
10.4 
ACTION TAKEN REGARDING INVESTIGATIONAL PRODUCT 
The action taken towards the study drug must be described as follows: 
• Permanently discontinued 
• Stopped temporarily 
• Modified infusion rate 
• No action Taken 
• Not applicable  
10.5 
OUTCOME 
The outcome of each AE must be rated as follows: 
• Recovered/resolved 
• Recovering/resolving 
• Not recovered/not resolved 
• Recovered with sequelae/resolved with sequelae 
• Fatal 
• Unknown 
10.6 
RECORDING OF ADVERSE EVENTS 
All (S)AEs occurring during the clinical investigation must be documented in the EDC 
system. 
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Whenever possible, diagnoses should be given when signs and symptoms are due to a 
common etiology (e.g., skin erythema, induration, edema and warmth should be reported as 
“cellulitis”). Investigators must record their opinion concerning the relationship of the (S)AE 
to the study drug in the EDC system. All measures required for (S)AE management must be 
recorded in the source documents and reported according to Sponsor’s instructions. 
All (S)AEs occurring at any time during the study (including the follow-up period) will be 
followed by the Investigator until satisfactory resolution (e.g., value back to baseline value) 
or stabilization or until final database lock. If necessary, in order to obtain additional 
information to ensure safety to the subject, additional blood and urine samples may be taken 
at the discretion of the Investigator. Certain long-term AEs related to therapy cannot be 
followed until resolution within the setting of this study. In these cases follow up will be the 
responsibility of the treating physician. 
10.7 
REPORTING OF SERIOUS ADVERSE EVENTS 
All SAEs, irrespective of the circumstances or suspected cause, must be reported on a Serious 
Adverse Event Form by the Investigator to the Sponsor or designee within 24 hours of their 
knowledge of the event, preferably by email. Other means of transmission can be decided 
when email is not possible (fax).  
The Sponsor and Medical Monitor will be notified of SAEs within 24 hours. 
Contact details for reporting SAEs:  
 
 
Contact details for Pharm-Olam Medical Monitor: 
 
 
 
The SAE form should include a clearly written narrative describing signs, symptoms, and 
treatment of the event, diagnostic procedures, as well as any relevant laboratory data and any 
sequelae, in order to allow a complete medical assessment of the case and independent 
determination of the possible causality.  
Follow-up and outcomes should be reported for all subjects that experience an SAE. 
It is critical that the information provided on the Serious Adverse Event Form matches the 
information recorded in the EDC system for the same event. In addition, the same 
information is to be recorded in the source documents. 
Copies of additional reports and documents should be sent when requested and applicable. 
Follow-up reports relative to the subject’s subsequent course must be submitted to CRO until 
the event has subsided or, in case of permanent impairment, until the condition stabilizes. 
10.8 
PREGNANCY 
Subjects should not become pregnant during the study.  
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The Investigator must report any pregnancy which occurs in a female subject or the female 
partner of a male subject up to 60 days after dosing by faxing the pregnancy form to the 
Sponsor or designee within 24 hours of the study site staff becoming aware of the pregnancy. 
The Investigator or study site staff must report the outcome of the pregnancy to the Sponsor 
or designee.  
Contact details:  
 
 
 
 
 
 
Pregnancy is not an SAE, however congenital abnormalities and birth defects in the offspring 
of male or female subjects should be reported as an SAE if the subject was pregnant during 
the study treatment period or in the 60-day period after dosing of study drug. 
10.9 
REPORTING OF SAES TO COMPETENT AUTHORITIES/ETHICS 
COMMITTEES 
Visterra or designee is responsible for appropriate reporting of AEs to the regulatory 
authorities. Visterra or designee will also report to the Investigator all SAEs that are unlisted 
(unexpected) and associated with the use of the drug. The Investigator must report these 
events to the appropriate Independent Ethics Committee/Institutional Review Board 
(IEC/IRB) that approved the protocol, unless otherwise required and documented by the 
IEC/IRB. 
Visterra or designee, will be responsible for unblinding and submitting SUSARs involving 
the study drug to the applicable regulatory authorities according to International Conference 
on Harmonization (ICH) guidelines. In addition, Visterra or designee, will be responsible for 
the submission of safety letters to the central IRB/EC and to participating Investigators of all 
SUSARs involving VIS410 according to applicable regulations. For clinical sites that use a 
local IRB/EC, it is the responsibility of the Investigator to promptly notify the local IRB/EC 
of all unexpected serious adverse drug reactions involving risk to human subjects.  
After termination of the clinical study (determined as LSLV), any unexpected safety issue 
that changes the risk–benefit analysis and is likely to have an impact on the subjects who 
have participated in it, will be reported by the CRO as soon as possible to the competent 
authority(ies) concerned together with proposed actions. 
 
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11. 
ETHICAL ASPECTS 
11.1 
STUDY-SPECIFIC DESIGN CONSIDERATIONS 
Potential subjects will be fully informed of the risks and requirements of the study and during 
the study, subjects will be provided with any new information that may affect their decision 
to continue participation. Subjects will be informed that their consent to participate in the 
study is voluntary and may be withdrawn at any time without the need to provide a reason 
and without penalty or loss of benefits to which they would otherwise be entitled. Only 
subjects who are fully able to understand the risks, benefits, and potential AEs of the study, 
and provide their consent voluntarily will be enrolled. 
11.2 
REGULATORY ETHICS COMPLIANCE 
11.2.1 
Investigator Responsibilities 
The Investigator(s) should be qualified by education, training, and experience to assume 
responsibility for the proper conduct of the study, should meet all the qualifications specified 
by the applicable regulatory requirement(s), and should provide evidence of such 
qualifications through up-to-date curriculum vitae and/or other relevant documentation 
requested by the Sponsor, the IRB/IEC, and/or the regulatory authority(ies). 
The Investigator is responsible for ensuring that the clinical study is performed in accordance 
with the protocol, current ICH guidelines on GCP, and applicable regulatory and 
country-specific requirements. 
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects. 
Compliance with this standard provides public assurance that the rights, safety, and 
well-being of study subjects are protected, consistent with the principles that originated in the 
Declaration of Helsinki; and that the clinical study data are credible. 
11.2.2 
Independent Ethics Committee or Institutional Review Board 
An IRB/IEC should safeguard the rights, safety, and well-being of all study subjects. Special 
attention should be paid to studies that may include vulnerable subjects. 
Before the start of the study, the Investigator (or Sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents: 
• Final protocol and, if applicable, amendments 
• Sponsor-approved ICF (and any updates) and any other written materials to be 
provided to the subjects; 
• Sponsor-approved subject recruiting materials 
• Investigator Brochure (or equivalent information) and addenda 
• available safety information 
• information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable 
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• Investigator’s current curriculum vitae or other documentation evidencing 
qualifications (unless not required, as documented by IEC/IRB) 
• information regarding funding, name of the Sponsor, institutional affiliations, other 
potential conflicts of interest, and incentives for subjects; 
• any other documents that the IEC/IRB may require to fulfill its obligation 
This study will be undertaken only after the IEC/IRB has given full written approval of the 
final protocol and amendments (if any), the ICF(s) and updates (if any), applicable recruiting 
materials, and any other written information to be provided to the subjects, and the Sponsor 
has received a copy of this approval. This approval letter must be dated and must clearly 
identify the IEC/IRB and the documents being approved. 
During the study, the Investigator (or Sponsor where required) will send the following 
documents and updates to the IEC/IRB for their review and approval, where appropriate:  
• protocol amendments 
• revision(s) to ICF and any other written materials to be provided to subjects; 
• if applicable, new or revised subject recruiting materials approved by the Sponsor; 
• revisions to compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable 
• Investigator’s Brochure addenda or new edition(s) 
• summaries of the status of the study at intervals stipulated in guidelines of the 
IEC/IRB (at least annually) 
• reports of AEs that are serious, unlisted, and associated with the investigational drug 
• new information that may adversely affect the safety of the subjects or the conduct of 
the study 
• deviations from or changes to the protocol to eliminate immediate hazards to the 
subjects; 
• report of deaths of subjects under the Investigator’s care 
• notification if a new Investigator is responsible for the study at the site 
• Development Safety Update Report, Short Term Study Specific Safety Summary and 
Line Listings, where applicable 
• any other requirements of the IEC/IRB 
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF 
revisions must be submitted promptly to the IEC/IRB for review and approval before 
implementation of the change(s), except when necessary to eliminate immediate hazard to the 
study subjects. If a deviation from, or a change to the protocol was implemented to eliminate 
an immediate hazard to study subjects, then the implemented deviation or change, the reasons 
for it, and, if appropriate, the protocol amendment should be submitted to the IEC/IRB as 
soon as possible. 
The Investigator (or Sponsor where required) will notify the IEC/IRB about the study 
completion within 90 days after the end of the study (defined as LSLV). 
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11.2.3 
Informed Consent 
Each subject must give written consent according to local requirements after the nature of the 
study has been fully explained. The consent form must be signed before performance of any 
study-related activity. The consent form that is used must be approved by both the Sponsor 
and by the reviewing IEC/IRB. The informed consent should be in accordance with principles 
that originated in the Declaration of Helsinki, current ICH and GCP guidelines, applicable 
regulatory requirements, and Sponsor policy. 
Before enrollment in the study, the Investigator or an authorized member of the 
investigational staff must explain to potential subjects the aims, methods, reasonably 
anticipated benefits, and potential hazards of the study, and any discomfort participation in 
the study may entail. Subjects will be informed that their participation is voluntary and that 
they may refuse to participate or withdraw consent to participate at any time, without penalty 
or loss of benefits to which the subject was entitled. Finally, they will be told that the 
Investigator will maintain a subject identification register for the purposes of long-term 
follow up if needed and that their records may be accessed by health authorities and 
authorized Sponsor staff without violating the confidentiality of the subject, to the extent 
permitted by the applicable law(s) or regulations. By signing the ICF the subject is 
authorizing such access, and agrees to allow his or her study physician to re-contact the 
subject for the purpose of obtaining consent for additional safety evaluations, if needed. 
The language used in the oral and written information about the study, including the ICF, 
should be non-technical and practical and should be understandable to the subject or the 
subject’s legal representative. The subject will be given sufficient time to read the ICF and 
the opportunity to ask questions. After this explanation and before entry into the study, 
consent should be appropriately recorded by means of the subject's personally dated 
signature. After having obtained the consent, a copy of the ICF must be given to the subject. 
If the subject is unable to read or write, an impartial witness should be present for the entire 
informed consent process (which includes reading and explaining all written information) and 
should personally date and sign the ICF after the oral consent of the subject is obtained, if 
permitted by local law. 
11.2.4 
Privacy of Personal Data 
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to investigate the safety, quality, and utility of the 
investigational study drug(s) used in this study. 
These data must be collected and processed with adequate precautions to ensure 
confidentiality and compliance with applicable data privacy protection laws and regulations. 
Appropriate technical and organizational measures to protect the personal data against 
unauthorized disclosures or access, accidental or unlawful destruction, or accidental loss or 
alteration must be put in place. Sponsor personnel whose responsibilities require access to 
personal data agree to keep the identity of study subjects confidential. 
The informed consent obtained from the subject includes explicit consent for the processing 
of personal data and for the Investigator to allow direct access to his or her original medical 
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records for study-related monitoring, audit, IEC/IRB review, and regulatory inspection. This 
consent also addresses the transfer of the data to other entities and to other countries. 
 
12. 
ADMINISTRATIVE REQUIREMENTS 
12.1 
PROTOCOL AMENDMENTS 
Neither the Investigator nor the Sponsor will modify this protocol without a formal 
amendment. All protocol amendments must be issued by the Sponsor, and signed and dated 
by the Investigator. Protocol amendments must not be implemented without prior IEC/IRB 
approval, or when the relevant competent authority has raised any grounds for 
non-acceptance, except when necessary to eliminate immediate hazards to the subjects, in 
which case an amendment must be promptly submitted to the IEC/IRB and relevant 
competent authority. Documentation of amendment approval by the Investigator and 
IEC/IRB must be provided to the Sponsor or its designee. When the change(s) involves only 
logistic or administrative aspects of the study, the IRB (and IEC where required) only needs 
to be notified. 
12.2 
SUBJECT IDENTIFICATION, ENROLLMENT, AND SCREENING LOGS 
The Investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by 
the Sponsor site contact for completeness. 
The subject identification and enrollment log will be treated as confidential and will be filed 
by the Investigator in the study file. To ensure subject confidentiality, no copy will be made. 
All reports and communications relating to the study will identify subjects by initials and/or 
assigned number only. 
The Investigator must also complete a subject-screening log, which reports on all subjects 
who were seen to determine eligibility for inclusion in the study. 
12.3 
SOURCE DOCUMENTATION 
The EDC system is an electronic data capturing and information management system that 
will also serve as the data management system for this study. The system combines all 
aspects of source data capturing with process control and clinical study management. All 
clinical and laboratory data, except those which are paper-based, will be collected in the 
EDC. The responsible study Monitor will check data at the monitoring visits to the clinical 
study site. The Investigator will ensure that the data collected are accurate, complete, and 
legible. Data will be monitored within EDC by the study Monitor who has only reading 
rights. Any changes required following monitoring will be made by site personnel or the 
Investigator and will be documented with a full audit trail within EDC. 
At a minimum, source documentation must be available for the following: subject 
identification, eligibility, and study identification; date of informed consent, dates of visits, 
results of safety and efficacy parameters as required by the protocol, record of all AEs, 
follow up of AEs, concomitant medication, drug receipt/dispensing/return records, study drug 
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administration information, laboratory printouts (if not available digitally), date of study 
completion, and reason for early discontinuation of study drug or withdrawal from the study, 
if applicable. 
It is recommended that the author of an entry in the (e-)source documents be identifiable. 
Source data may be directly captured from devices, transferred from third parties 
(e.g., laboratory data), or entered manually into the EDC system in use at the clinical center. 
In such case, the majority of the source data will only be available electronically. The 
remainder of the data, captured initially on paper, may be entered retrospectively into the 
EDC system. 
Following the ICH/GCP guidelines, direct access to (e-)source documentation (medical 
records) must be allowed. 
12.4 
CASE REPORT FORM COMPLETION 
All source data, except those that are paper based, will be collected directly into the EDC 
system. Paper-based sources will be manually transcribed in the EDC system. All data 
captured in EDC will be transferred to the clinical database electronically. 
12.5 
MONITORING 
The monitoring of the study will be done under the responsibility of the Sponsor by the CRO. 
The Monitor will perform on-site or remote monitoring visits as frequently as necessary. The 
Monitor will record dates of the on-site visits in a study center visit log that will be kept at the 
site. The first post-initiation visit will be made as soon as possible after enrollment has begun. 
At these visits, the Monitor will compare the data captured in the EDC system for 
completeness and accuracy and perform source data verification to any data that has been 
captured as paper source or entered in the system later on. The nature and location of all 
source documents will be identified to ensure that all sources of original data required to 
complete the EDC system are known to the Sponsor and investigational staff and are 
accessible for verification by the Sponsor site contact(s). If electronic records are maintained 
at the investigational site, the method of verification must be discussed with the 
investigational staff. 
Direct access to (e-)source documentation (medical records) must be allowed at all times for 
the purpose of verifying that the data recorded EDC system are consistent with the original 
(e-)source data. Findings from this review of captured data will be discussed with the 
investigational staff. During on-site monitoring visits (notified and agreed upfront with the 
investigational staff), the relevant investigational staff will be available, the (e-)source 
documentation will be accessible, and a suitable environment will be provided for review of 
study-related documents. The Monitor will meet with the Investigator on a regular basis 
during the study to provide feedback on the study conduct. 
12.6 
DATA MANAGEMENT 
Data management of the study will be performed under the responsibility of the Sponsor by 
the CRO. 
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After the data are released by the Investigator and the Monitor has reviewed the data for 
completeness and accuracy, the data will be uploaded into the clinical database to perform 
cleaning activities. Only the data of randomized subjects will be captured in the clinical 
database. 
Computerized data cleaning checks will be used in addition to manual review including 
listings review, to check for discrepancies and to ensure consistency and completeness of the 
data. Queries emerging during data cleaning will be generated by the clinical data manager in 
the EDC system. The Investigator or his designee will answer the queries and update the 
source data, if needed. Any changes required are to be documented with a full audit trail 
within the EDC system. 
An interim lock of the database will occur at the time of the interim analysis (see 
Section 9.4).  
The final clinical database will be locked as soon as it is considered clean. Only authorized 
and well-documented updates to the study data are possible after final database lock. The 
locked final database is used in the final statistical analysis for study reporting. Measures will 
be undertaken to protect subject data handed over by the Investigator to the Data 
Management Department and during inspections against disclosure to unauthorized third 
parties. Subject confidentiality will be maintained at all times. 
12.7 
DATA QUALITY ASSURANCE 
The accuracy and reliability of the study data will be assured by the selection of qualified 
Investigators and appropriate study centers, review of protocol procedures with the 
Investigator and associated personnel prior to the study, and by periodic monitoring visits by 
the Sponsor or designee. 
Written instructions will be provided for the collection, preparation, and shipment of samples.  
The Sponsor or its designee will review the EDC system for accuracy and completeness 
during (on-site) monitoring visits and after transmission to the Sponsor; any discrepancies 
will be resolved with the Investigator or designee, as appropriate. After upload of the data 
into the clinical study database, they will be verified for accuracy. 
In accordance with Good Clinical Research Practice Guidelines and Recommendations, the 
Sponsor will be entitled to audit the facilities used in the clinical and laboratory parts of the 
study, as well as to access all the data files pertaining to the study. Similar procedures may 
also be conducted by agents of any regulatory body, either as part of a national GCP 
compliance program or to review the results of this study in support of a regulatory 
submission. The Investigator should immediately notify the Sponsor if they have been 
contacted by a regulatory agency concerning an upcoming inspection. 
12.8 
ON-SITE AUDITS 
Investigators and institutions involved in the study will permit study-related monitoring, 
audits, IRB review, and regulatory inspections by providing direct access to all study records. 
In the event of an audit, the Investigator agrees to allow the Sponsor, representatives of the 
Sponsor, government or a regulatory agency access to all study records. 
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The Investigator should promptly notify the Sponsor and CRO of any audits scheduled by 
any regulatory authorities and promptly forward copies of any audit reports received to the 
Sponsor. 
Similar procedures may also be conducted by agents of any regulatory body, either as part of 
a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The Investigator should immediately notify the Sponsor if they have 
been contacted by a regulatory agency concerning an upcoming inspection. 
12.9 
STUDY TERMINATION 
The Sponsor reserves the right to terminate the study at any time. In case of an early 
termination of the study for safety reasons, or temporary halt by the Sponsor, the IEC/IRB 
should be notified within 15 calendar days, including a detailed written explanation of the 
reasons for the termination/halt. 
The end-of-study declaration will be submitted to the regulatory authorities and IEC after the 
complete study has ended. This notification will also be submitted within 90 days of the end 
of the study. 
12.10 RECORD RETENTION 
In compliance with the ICH/GCP guidelines, the Investigator/institution will maintain an 
archived copy of the EDC data and all paper source documents that support the data collected 
from each subject, as well as all study documents as specified in ICH/GCP Section 8, 
Essential Documents for the Conduct of a Clinical Trial, and all study documents as specified 
by the applicable regulatory requirement(s). The Investigator/institution will take measures to 
prevent accidental or premature destruction of these documents. 
Essential documents must be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will 
be retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the Sponsor. It is the responsibility of the Sponsor to inform the 
Investigator/institution as to when these documents no longer need to be retained.  
If the responsible Investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The Sponsor must be notified in writing of the name and address of 
the new custodian. Under no circumstance shall the Investigator relocate or dispose of any 
study documents before having obtained written approval from the Sponsor. 
If it becomes necessary for the Sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the Investigator must permit access to such reports. 
12.11 USE OF INFORMATION AND PUBLICATION 
All information, including but not limited to information regarding VIS410 or the Sponsor’s 
operations (e.g., patent application, formulas, manufacturing processes, basic scientific data, 
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prior clinical data, formulation information) supplied by the Sponsor to the Investigator and 
not previously published, and any data generated as a result of this study are considered 
confidential and remain the sole property of the Sponsor. The Investigator agrees to maintain 
this information in confidence, to use this information only to accomplish this study, and not 
to use it for other purposes without the Sponsor’s prior written consent. 
The Investigator understands that the information developed in this clinical study will be used 
by the Sponsor in connection with the continued development of the study drug, and thus 
may be disclosed as required to other clinical Investigators or regulatory agencies. To permit 
the information derived from the clinical studies to be used, the Investigator is obligated to 
provide the Sponsor with all data obtained in the study. 
The results of the study will be reported in a Clinical Study Report written by the CRO under 
responsibility of the Sponsor and will contain EDC system data from all investigational sites 
that participated in the study. Recruitment performance or specific expertise related to the 
nature and the key assessment parameters of the study will be used to determine a 
coordinating Investigator. 
Clinical narratives will be written for the following events: 
• All deaths (irrespective of drug relationship) 
• All other SAEs during treatment with the study drug 
• All discontinuations of the study due to AEs related to the study drug 
• At the discretion of the team and after statistical analysis of the data, certain 
discontinuations not related to AEs or treatment failure, i.e., related to lost to 
follow up or withdrawal of consent (irrespective of treatment group) 
• Any events of special interest explicitly requested by the regulatory agencies 
A summary of this final version will be provided to the Investigators, to the applicable 
regulatory authorities, and IECs/IRBs, if required by the applicable regulatory requirements, 
within 1 year of the end of the study (Last Subject Last Visit). 
The Sponsor shall have the right to publish such data and information without approval from 
the Investigator. 
Individual site publications are not expected as individual sites may not recruit enough 
subjects to enable detailed publications; therefore, results of this study will be reported in 
total. 
If an Investigator wishes to publish information from the study, a copy of the manuscript 
must be provided to the Sponsor for review at least 60 days before submission for publication 
or presentation. Expedited reviews will be arranged for abstracts, poster presentations, or 
other materials. If requested by the Sponsor in writing, the Investigator will withhold such 
publication for up to an additional 60 days to allow for filing of a patent application. In the 
event that issues arise regarding scientific integrity or regulatory compliance, the Sponsor 
will review these issues with the Investigator. The Sponsor will not mandate modifications to 
scientific content and does not have the right to suppress information. Authorship of 
publications resulting from this study will be based on the guidelines on authorship, such as 
those described in the Uniform Requirements for Manuscripts Submitted to Biomedical 
Journals, which state that the named authors must have made a significant contribution to the 
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design of the study or analysis and interpretation of the data, provided critical review of the 
paper, and given final approval of the final version. 
12.12 REGISTRATION OF CLINICAL STUDIES AND DISCLOSURE OF RESULTS 
The Sponsor will register and/or disclose the existence of and the results of clinical studies as 
required by law. 
12.13 CONFIDENTIALITY 
All study documents are provided by the Sponsor in confidence to the Investigator and 
his/her appointed staff. None of this material may be disclosed to any party not directly 
involved in the study without Sponsor’s written permission. 
The Investigator must assure that subject’s anonymity will be maintained. The Investigator 
will keep a separate list with at least the initials, the subject’s study numbers, names, 
addresses, and telephone numbers. The Investigator will maintain this for the longest period 
of time allowed by his/her own institution and, in any case, until further communication from 
the Sponsor. 
 
13. 
REFERENCES 
1. Treanor JJ, Hayden FG, Vrooman PS, et al, Efficacy and safety of the oral 
neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized 
controlled trial. US Oral Neuraminidase Study Group. JAMA. 2000;283(8):1016–024. 
2. Schanzer DL, Langley JM, Tam TW. Co-morbidities associated with 
influenza-attributed mortality, 1994-2000, Canada. Vaccine. 2008;26(36):4697–703. 
3. CDC. Estimates of deaths associated with seasonal influenza US, 1976-2007. 
MMWR. 2012;59(33):1057–62. 
4. Babcock G, Szretter K, Sloan S, et al. VIS410, a broadly HA-targeting human 
antibody, neutralizes H5 and H7 isolates with pandemic potential. ICAAC, Denver, 
2013. 
5. Investigator Brochure of VIS410, version 4.0, 2015. 
6. Fridericia LS. The duration of systole in the electrocardiogram of normal subjects and 
of subjects with heart disease. Acta Medica Scandinavica. 1920;53:469–86. 
7. Watson JM, Francis JN, Mesens S, et al. Characterisation of a wild-type influenza 
(A/H1N1) virus strain as an experimental challenge agent in humans. Virol J. 
2015;12(1):13. 
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APPENDIX 1: LABORATORY ASSESSMENTS 
Urinalysis 
Hematology 
Chemistry 
Dipstick: 
Hemoglobin 
Albumin 
• 
Specific gravity 
Hematocrit 
Alkaline phosphate 
• 
pH 
Red blood cells (RBC) 
Alanine amino transferase 
• 
Glucose 
White blood cells (WBC) with 
differential 
Aspartate amino transferase 
• 
Protein 
Lymphocytes 
Bicarbonate 
• 
Blood 
Monocytes 
Total bilirubin 
• 
Ketones 
Neutrophils c 
Direct bilirubin b 
• 
Bilirubin 
Eosinophils 
Blood urea nitrogen (or urea) 
• 
Urobilinogen 
Basophils 
Calcium 
• 
Nitrite 
Platelets 
Chloride 
• 
Leukocyte esterase 
 
Creatinine 
  
 
Glucose a  
Urine sedimentation count: 
 
Lactate dehydrogenase 
• 
Erythrocytes (RBC) 
 
Phosphate, inorganic 
• 
Leukocytes (WBC) 
 
Potassium 
• 
Epithelial cells 
 
Total protein 
  
 
Sodium 
Microscopy 
 
Creatine kinase-MB d, 
creatinine kinase d, troponin d 
• 
Crystals 
 
• 
Casts 
 
 
• 
Bacteria 
 
 
Serology a  
Other Assessments 
Coagulation 
Antibody screening test 
(immunoassay), rapid HIV test 
Urine pregnancy test 
Partial thromboplastin time 
 
Activated partial thromboplastin 
time 
a Screening only 
b Assay if total bilirubin is above normal range.  
c If immature neutrophils are detected, the sample is to be flagged and a blood slide for microscopic analysis 
will be made. If Bands are detected in the microscopic analysis, then a result will be provided.  
d Only measure if subject has chest pain.  
 
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APPENDIX 2: DMID ADULT TOXICITY TABLE 
 
ABBREVIATIONS: Abbreviations utilized in the Table: 
ULN = Upper Limit of Normal 
LLN = Lower Limit of Normal  
Rx = Therapy 
Req = Required 
Mod = Moderate 
IV = Intravenous 
ADL = Activities of Daily Living 
Dec = Decreased 
 
ESTIMATING SEVERITY GRADE 
For abnormalities NOT found elsewhere in the Toxicity Tables use the scale below to 
estimate grade of severity: 
GRADE 1 
Mild Transient or mild discomfort (< 48 hours); no medical 
intervention/therapy required 
GRADE 2 
Moderate Mild to moderate limitation in activity - some assistance may be 
needed; no or minimal medical intervention/therapy required 
GRADE 3 
Severe Marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalizations possible 
GRADE 4 
Life-threatening Extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, hospitalization or 
hospice care probable 
 
SERIOUS OR LIFE-THREATENING AEs 
ANY clinical event deemed by the clinician to be serious or life-threatening should be 
considered a grade 4 event. Clinical events considered to be serious or life-threatening 
include, but are not limited to: seizures, coma, tetany, diabetic ketoacidosis, disseminated 
intravascular coagulation, diffuse petechiae, paralysis, acute psychosis, severe depression. 
COMMENTS REGARDING THE USE OF THESE TABLES 
• Standardized and commonly used toxicity tables (Division of AIDS, NCI’s Common 
Toxicity Criteria (CTC), and World Health Organization (WHO)) have been adapted 
for use by the DMID and modified to better meet the needs of participants in DMID 
trials. 
• For parameters not included in the following Toxicity Tables, sites should refer to the 
“Guide For Estimating Severity Grade” located above. 
• Criteria are generally grouped by body system. 
• Some protocols may have additional protocol specific grading criteria, which will 
supercede the use of these tables for specified criteria. 
 
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HEMATOLOGY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin 
9.5 - 10.5 g/dL 
8.0 - 9.4gm/dL 
6.5 - 7.9 g/dL 
< 6.5 g/dL 
Absolute Neutrophil Count 
1000-1500/ mm3 
750-999/ mm3 
500-749/ mm3 
<500/ mm3 
Platelets 
75,000- 
99,999/ mm3 
50,000- 
74,999/ mm3 
20,000-49,999/ mm3 
<20,000/ mm3 
WBCs 
11,000-13,000/mm3 13,000-15,000/mm3 15,000-30,000/ mm3 
>30,000 or 
<1,000/mm3 
% Polymorphonuclear 
Leucocytes + Band Cells 
> 80% 
90 – 95% 
>95% 
---------- 
Abnormal Fibrinogen 
Low: 
100-200 mg/dL 
 
High: 
400-600 mg/dL 
Low: 
<100 mg/dL 
 
High: 
>600 mg/dL 
Low: 
< 50 mg/dL 
 
---------- 
Fibrinogen 
associated with 
gross bleeding or 
with disseminated 
coagulation 
Fibrin Split Product 
20-40 mcg/ mL 
41-50 mcg/ mL 
51-60 mcg/ mL 
> 60 mcg/ mL 
Prothrombin Time (PT) 
1.01 - 1.25 x ULN 
1.26-1.5 x ULN 
1.51 -3.0 x ULN 
>3 x ULN 
Activated Partial 
Thromboplastin (APPT) 
1.01 -1.66 x ULN 
1.67 - 2.33 x ULN 
2.34 - 3 x ULN 
> 3 x ULN 
Methemoglobin 
5.0 - 9.9 % 
10.0 - 14.9 % 
15.0 - 19.9% 
> 20.0 % 
 
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CHEMISTRIES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hyponatremia 
130-135 mEq/ L 
123-129 mEq/ L 
116-122 mEq/ L 
< 116 mEq/ L or 
abnormal sodium with 
mental 
status changes or seizures 
Hypernatremia 
146-150 mEq/ L 
151-157 mEq/ L 
158-165 mEq/ L 
> 165 mEq/ L or 
abnormal sodium with 
mental 
status changes or seizures 
Hypokalemia 
3.0 - 3.4 mEq/ L 
2.5 - 2.9 mEq/ L 2.0 - 2.4 mEq/ L or 
intensive 
replacement therapy 
or hospitalization 
required 
< 2.0 mEq/ L or 
abnormal potassium with 
paresis, ileus or life-
threatening arrhythmia 
Hyperkalemia 
5.6 - 6.0 mEq/ L 
6.1 - 6.5 mEq/ L 
6.6 - 7.0 mEq/L 
> 7.0 mEq/ L or 
abnormal 
potassium with life-
threatening arrhythmia 
Hypoglycemia 
55-64 mg/dL 
40-54 mg/dL 
30-39 mg/dL 
<30 mg/dL or abnormal 
glucose with mental  
status changes or coma 
Hyperglycemia 
(nonfasting and no prior 
diabetes) 
116 - 160 mg/dL 
161- 250 mg/dL 
251 - 500 mg/dL 
> 500 mg/dL or abnormal 
glucose with ketoacidosis 
or seizures 
Hypocalcemia (corrected 
for albumin) 
8.4 - 7.8 mg/dL 
7.7 - 7.0 mg/dL 
6.9 - 6.1 mg/dL 
< 6.1 mg/dL or abnormal 
calcium with life 
threatening arrhythmia or 
tetany 
 
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CHEMISTRIES (continued) 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hypercalcemia (correct for 
albumin) 
10.6 - 11.5 mg/dL 
11.6-12.5 mg/dL 
12.6 - 13.5 mg/dL 
> 13.5 mg/dL or 
abnormal calcium 
with life threatening 
arrhythmia 
Hypomagnesemia 
1.4 - 1.2 mEq/ L 
1.1 - 0.9 mEq/ L 
0.8 - 0.6 mEq/ L 
< 0.6 mEq/ L or 
abnormal magnesium 
with life-threatening 
arrhythmia 
Hypophosphatemia 
2.0 - 2.4 mg/dL 
1.5 -1.9 mg/dL or 
replacement Rx 
required 
1.0 -1.4 mg/dL 
intensive therapy or 
hospitalization 
required 
< 1.0 mg/dL or 
abnormal phosphate 
with life-threatening 
arrhythmia 
Hyperbilirubinemia (when 
accompanied by any 
increase in other liver 
function test) 
1.1 - <1.25 x ULN 1.25 - <1.5 x ULN 1.5 – 1.75 x ULN 
> 1.75 x ULN 
Hyperbilirubinemia (when 
other liver function are in 
the normal range) 
1.1 - <1.5 x ULN 
1.5 - <2.0 x ULN 
2.0 – 3.0 x ULN 
> 3.0 x ULN 
BUN 
1.25 - 2.5 x ULN 
2.6 - 5 x ULN 
5.1 - 10 x ULN 
> 10 x ULN 
Hyperuricemia (uric acid) 
7.5 – 10.0 mg/dL 10.1 – 12.0 mg/dL 12.1 – 15.0 mg/dL 
>15.0 mg/dL 
Creatinine 
1.1 - 1.5 x ULN 
1.6 - 3.0 x ULN 
3.1 - 6 x ULN 
> 6 x ULN or 
dialysis required 
 
ENZYMES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
AST (SGOT) 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
ALT (SGPT) 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
GGT 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
Alkaline Phosphatase 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
Amylase 
1.1 - 1.5 x ULN 
1.6 - 2.0 x ULN 
2.1 - 5.0 x ULN 
> 5.1 x ULN 
Lipase 
1.1 - 1.5 x ULN 
1.6 - 2.0 x ULN 
2.1 - 5.0 x ULN 
> 5.1 x ULN 
 
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URINALYSIS 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Proteinuria 
1+ or 200 mg - 1 g 
loss/day 
2-3+ or 1- 2 g 
loss/day 
4+ or 2-3.5 g loss/day nephrotic syndrome or 
>3.5 g loss/day 
Hematuria 
microscopic only <10 
RBC/HPF 
gross, no clots >10 
RBC/HPF 
gross, with or without 
clots, OR red blood 
cell casts 
obstructive or 
required transfusion 
 
CARDIOVASCULAR 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cardiac Rhythm 
 
asymptomatic, 
transient signs, no Rx 
required 
recurrent/persistent; 
symptomatic Rx 
required 
unstable dysrythmia; 
hospitalization and 
treatment required 
Hypertension 
transient increase >20 
mm/ Hg; no treatment 
recurrent, chronic 
increase > 20mm/ Hg. 
/treatment required 
acute treatment 
required; outpatient 
treatment or 
hospitalization 
possible 
end organ damage or 
hospitalization 
required 
Hypotension 
transient orthostatic 
hypotension with heart 
rate increased by 
<20 beat/min or 
decreased by <10 mm 
Hg systolic BP, No 
treatment required 
symptoms due to 
orthostatic 
hypotension or BP 
decreased by <20 mm 
Hg systolic; 
correctable with oral 
flu id treatment 
requires IV fluids; no 
hospitalization 
required 
mean arterial pressure 
<60mm/ Hg or end 
organ damage or 
shock; requires 
hospitalization and 
vasopressor treatment 
Pericarditis 
minimal effusion 
mild/ moderate 
asymptomatic 
effusion, no treatment 
symptomatic 
effusion; pain; EKG 
changes 
tamponade; 
pericardiocentesis or 
surgery required 
Hemorrhage, Blood 
Loss 
microscopic/occult 
mild, no transfusion gross blood loss; 1-2 
units transfused 
massive blood loss; > 
3 units transfused 
 
RESPIRATORY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cough 
transient- no 
treatment 
persistent cough; 
treatment responsive 
Paroxysmal cough; 
uncontrolled with 
treatment 
-------------------- 
Bronchospasm, Acute 
transient; no 
treatment; 70% - 
80% FEV1 of peak 
flow 
Requires treatment; 
normalizes with 
bronchodilator; FEV1 
50%-70% (of peak 
flow) 
no normalization 
with bronchodilator; 
FEV1 25% - 50% of 
peak flow; or 
retractions present 
cyanosis: FEV1 
< 25% of peak 
flow or intubation 
necessary 
Dyspnea 
dyspnea on exertion dyspnea with normal 
activity 
dyspnea at rest 
dyspnea requiring 
Oxygen therapy 
 
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GASTROINTESTINAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Nausea 
mild or transient; 
maintains reasonable 
intake 
moderate discomfort; 
intake decreased 
significantly; some 
activity limited 
no significant 
intake; requires IV 
flu ids 
hospitalization 
required; 
Vomiting 
1 episode in 24 
hours 
2-5 episodes in 
24 hours 
>6 episodes in 
24 hours or needing 
IV fluids 
physiologic 
consequences 
requiring 
hospitalization or 
requiring 
parenteral nutrition 
Constipation 
requiring stool 
softener or dietary 
modification 
Requiring laxatives 
Obstipation 
requiring manual 
evacuation or enema 
obstruction or toxic 
megacolon 
Diarrhea 
mild or transient; 
3-4 loose stools/day 
or mild diarrhea last 
<1 week 
moderate or persistent; 
5-7 loose stools/day or 
diarrhea lasting >1 
week 
>7 loose stools/day 
or bloody diarrhea; 
or orthostatic 
hypotension or 
electrolyte 
imbalance or >2 L 
IV fluids required 
hypotensive shock 
or physiologic 
consequences 
requiring 
hospitalization 
Oral 
Discomfort/Dysphagia 
mild discomfort; no 
difficulty 
swallowing 
some limits on 
eating/drinking 
eating/talking very 
limited; unable to 
swallow solid foods 
unable to drink 
fluids; requires IV 
fluids 
 
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NEUROLOGICAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Neuro-Cerebellar 
slight incoordination 
dysdiadochokinesis 
intention tremor, 
dysmetria, slurred 
speech; nystagmus 
locomotor ataxia 
incapacitated 
Psychiatric 
mild anxiety or depression moderate anxiety 
or depression; 
therapy required; 
change in normal 
routine 
severe mood 
changes requiring 
therapy; or suicidal 
ideation; or 
aggressive ideation 
acute psychosis 
requiring 
hospitalization; or 
suicidal 
gesture/attempt or 
hallucinations 
Muscle Strength 
subjective weakness no 
objective symptoms/ signs 
mild objective 
signs/symptoms no 
decrease in 
function 
objective weakness 
function limited 
paralysis 
Paresthesia (burning, 
tingling, etc.) 
mild discomfort; no 
treatment required 
moderate 
discomfort; non-
narcotic analgesia 
required 
severe discomfort; or 
narcotic analgesia 
required with 
symptomatic 
improvement 
incapacitating; or 
not responsive to 
narcotic analgesia 
Neuro-sensory 
mild impairment in 
sensation (decreased 
sensation, e.g., vibratory, 
pinprick, hot/cold in great 
toes) in focal area or 
symmetrical distribution; 
or change in taste, smell, 
vision and/or hearing 
Moderate 
impairment (mod 
decreased 
sensation, e.g., 
vibratory, pinprick, 
hot/cold to ankles) 
and/or joint 
position or mild 
impairment that is 
not symmetrical 
severe impairment 
(decreased or loss of 
sensation to knees or 
wrists) or loss of 
sensation of at least 
mod degree in 
multiple different 
body areas (i.e., 
upper and lower 
extremities) 
sensory loss 
involves limbs and 
trunk; paralysis; or 
seizures 
 
MUSCULOSKELATEL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Arthralgia (joint pain) 
mild pain not 
interfering with 
function 
moderate pain, 
analgesics and/or pain 
interfering with function 
but not with activities of 
daily living 
severe pain; pain 
and/or analgesics 
interfering with 
activities of daily 
living 
disabling pain 
Arthritis 
mild pain with 
inflammation, 
erythema or joint 
swelling – but not 
interfering with 
function 
moderate pain with 
inflammation, erythema 
or joint swelling – 
interfering with function, 
but not with activities of 
daily living 
severe pain with 
inflammation, 
erythema or joint 
swelling –and 
interfering with 
activities of daily 
living 
permanent and/or 
disabling joint 
destruction 
Myalgia 
myalgia with no 
limitation of activity 
Muscle tenderness (at 
other than injection site) 
or with moderate 
impairment of activity 
severe muscle 
tenderness with 
marked impairment 
of activity 
Frank myonecrosis 
 
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SKIN 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Mucocutaneous 
erythema; pruritus 
diffuse, 
maculopapular 
rash, dry 
desquamation 
vesiculation or mist 
desquamation or 
ulceration 
Exfoliative dermatitis, 
mucous membrane 
involvement or erythema, 
mutiforme or suspected 
Stevens-Johnson or 
necrosis requiring surgery 
Induration 
< 15mm 
15-30 mm 
>30mm 
 
Erythema 
< 15mm 
15-30 mm 
>30mm 
 
Edema 
< 15mm 
15-30 mm 
>30mm 
 
Rash at Injection Site 
< 15mm 
15-30 mm 
>30mm 
 
Pruritus 
slight itching at 
injection site 
moderate itching 
at injection 
extremity 
itching over entire 
body 
 
 
SYSTEMIC 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Allergic Reaction 
pruritus without 
rash 
localized urticaria 
generalized 
urticaria; 
angioedema 
anaphylaxis 
Headache 
mild, no treatment 
required 
transient, 
moderate; 
treatment required 
severe; responds 
to initial narcotic 
therapy 
intractable; requires 
repeated narcotic therapy 
Fever: oral 
37.7 - 38.5 C or 
100.0 - 101.5 F 
38.6 - 39.5 C or 
101.6 - 102.9 F 
39.6 - 40.5 C or  
103 - 105 F 
> 40 C or 
> 105 F 
Fatigue 
normal activity 
reduced < 48 hours 
normal activity 
decreased 25-  
50% > 48 hours 
normal activity 
decreased > 50% 
can’t work 
unable to care for self 
 
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