Phase 2b, Multicenter, Randomized, Double-blind Study to Evaluate the Efficacy and Safety of IV VIS410 in Addition to Oseltamivir Compared With Oseltamivir Alone in Hospitalized Adults With Influenza A Infection Requiring Oxygen Support
Phase: PHASE2
Conditions: Influenza A
Sponsor: Visterra, Inc.

 
 
 
 
 
 
 
Official Title: 
Protocol VIS410-203, Phase 2b, Multicenter, 
Randomized, Double-blind, Controlled Study 
to Evaluate the Efficacy and Safety of 
Intravenous VIS410 in Addition to 
Oseltamivir (Tamiflu®) Compared with 
Oseltamivir Alone in Hospitalized Adults 
with Influenza A Infection Requiring Oxygen 
Support 
 
NCT Number: 
NCT03040141 
 
Document Date: 19 April 2018 
 
 

CONFIDENTIALITY STATEMENT 
The information in this document contains trade secrets and commercial information that are privileged or 
confidential and may not be disclosed unless such disclosure is required by applicable law or regulations. 
In any event, persons to whom the information is disclosed must be informed that the information is 
privileged or confidential and may not be further disclosed without written authorization of Visterra, Inc. 
This study will be conducted in compliance with this protocol,  
the ICH Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95),  
and with the applicable regulatory requirement(s). 
VIS410-203 
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`
 
 
 
 
Clinical Study Protocol 
Title: Phase 2b, Multicenter, Randomized, Double-blind, Controlled Study to Evaluate the 
Efficacy and Safety of Intravenous VIS410 in Addition to Oseltamivir (Tamiflu®) 
Compared with Oseltamivir Alone in Hospitalized Adults with Influenza A Infection 
Requiring Oxygen Support 
Product VIS410 
Protocol Number VIS410-203 
EudraCT Number 2016-004009-15 
Clinical Phase 2b 
Clinical Indication Influenza A infection 
Issue Date (Version) 19 April 2018 (Version 3.0) 
 
Sponsor Visterra, Inc. 
275 Second Avenue, 4th Floor 
Waltham, MA 02451 
United States of America 
Sponsor Representative  
 
 
 
 
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SIGNATURES 
Signature of Sponsor Representative 
 
Title: Phase 2b, Multicenter, Randomized, Double-blind, Controlled Study to Evaluate the 
Efficacy and Safety of Intravenous VIS410 in Addition to Oseltamivir (Tamiflu®) 
Compared with Oseltamivir Alone in Hospitalized Adults with Influenza A Infection 
Requiring Oxygen Support 
 
Name: 
 
 
 
This Clinical Study Protocol has been reviewed and approved by the Sponsor 
in order to ensure compliance with Good Clinical Practice. 
 
 
Signature: 
Date: 
 
 
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Signature of Investigator 
 
Title:  Phase 2b, Multicenter, Randomized, Double-blind, Controlled Study to Evaluate the 
Efficacy and Safety of Intravenous VIS410 in Addition to Oseltamivir (Tamiflu®) 
Compared with Oseltamivir Alone in Hospitalized Adults with Influenza A Infection 
Requiring Oxygen Support 
 
Name: 
 
Affiliation: 
 
Address: 
 
 
 
 
 
I have read and understood all sections of the protocol entitled, “Phase 2b, Multicenter, 
Randomized, Double-blind, Controlled Study to Evaluate the Efficacy and Safety of Intravenous 
VIS410 in Addition to Oseltamivir (Tamiflu®) Compared with Oseltamivir Alone in 
Hospitalized Adults with Influenza A Infection Requiring Oxygen Support.” 
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: Good Clinical Practice E6 (R1) 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 sub-Investigator. 
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: 
 
 
 
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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: 
Phase 2b, Multicenter, Randomized, Double-blind, Controlled Study to Evaluate the 
Efficacy and Safety of Intravenous VIS410 in Addition to Oseltamivir (Tamiflu®) 
Compared with Oseltamivir Alone in Hospitalized Adults with Influenza A Infection 
Requiring Oxygen Support 
Protocol Number: 
VIS410-203 
EudraCT Number: 
2016-004009-15 
Clinical Indication: 
Influenza A infection 
Clinical Phase:  
2b 
Number of Clinical Sites: 
Approximately 140 sites worldwide 
Number of Subjects:  
Approximately 120 
Study Objectives 
Primary Efficacy Objective 
 
Evaluation of the effect of 2 dose levels of VIS410 + oseltamivir on clinical outcome as assessed by 
comparison of clinical status ordinal scale Day 7 scores between treatment groups, and between all VIS410 
recipients versus placebo.   
Primary Safety Objective 
 
Safety and tolerability of 2 dose levels of a single intravenous (IV) dose of VIS410 when administered in 
combination with oseltamivir in hospitalized subjects with influenza A infection. 
Secondary Objectives 
 
Among patients requiring supplemental oxygen therapy at the time of enrollment with baseline room air 
oxygen saturation of ≤92%, time to cessation of oxygen (O2) support resulting in stable oxygen saturation 
(SpO2) by pulse oximetry. Stable SpO2 is defined as two consecutive SpO2 values of > 92% on room air 
that are at least 8 hours apart. 
 
For any patient requiring supplemental oxygen therapy at the time of enrollment (regardless of oxygen 
saturation), time to cessation of oxygen support.  
 
Evaluate the effect of 2 dose levels of VIS410 + oseltamivir vs oseltamivir alone on the following 
parameters: 
 
Viral load in upper respiratory samples 
 
Time to clinical response 
 
Time to cessation of ventilator support 
 
Time to resumption of normal activities 
 
All-cause and attributable 14-, 28-, and 56-day mortality 
 
Clinical status ordinal scale mean area under the curve for Days 1-7 and Days 1-14 using linear 
numeric scores for the ordinal categories. 
 
Comparison of clinical status ordinal scale scores for selected individual days (ie, Days 3, 4, 5, and 6)  
 
Comparison of clinical status ordinal scale scores using modified ordinal scale criteria (ie, pooling of 
selected severity criteria scores) 
 
Comparison of discrete ordinal scale parameters, including days of ventilator support, days in intensive 
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care, and duration of hospitalization 
 
Healthcare resource utilization 
 
Analysis of time to alleviation of signs and symptoms of influenza in the subset of subjects able to 
complete the Influenza Patient Reported Outcomes (FluPRO) Questionnaire at baseline and post-dose 
by Kaplan Meier analysis 
 
Proportion of subjects with new documented bacterial pneumonia/superinfection 
 
Proportion of subjects with influenza-related complications 
 
Pharmacokinetics of VIS410 in serum 
 
Immunogenicity of VIS410 
 
Emergence of resistance to VIS410 and oseltamivir 
Exploratory Objectives 
 
Evaluate the pharmacokinetics of VIS410 from nasopharyngeal secretions and tracheal aspirate (ventilated 
subjects only) 
 
Assess the effects of VIS410 on viral load in tracheal aspirate (ventilated subjects only) 
 
Assess correlations between virology, safety, VIS410 dose, pharmacokinetics, viral shedding, immunology, 
signs and symptoms of influenza, and other endpoints 
 
Assess the anti-influenza immune response 
Study Design 
This is a Phase 2b, multicenter, randomized, double-blind, controlled study comparing the efficacy and safety of 
2 dose levels of VIS410 (2000 and 4000 mg) in combination with oseltamivir vs oseltamivir alone in hospitalized 
subjects with influenza A infection requiring oxygen support. Subjects will be randomly assigned at a ratio of 1:1:1 
using a permuted block randomization method to receive VIS410 at a dose of 2000 mg (low dose) or 4000 mg (high 
dose) or placebo (0.9% sodium chloride), administered as a single IV infusion over 2 hours. Randomization will be 
stratified by presence or absence of positive pressure ventilation (PPV) at baseline to ensure an even distribution 
across treatment arms. All subjects will receive oseltamivir 75 mg twice daily (BID) for 5 days (total of 10 doses) as 
part of standard of care (SOC). Treatment with oseltamivir may be extended for up to 5 additional days (up to 20 
doses of total therapy) if clinical symptoms warrant further treatment as assessed by the Investigator.  
Note: based on SOC, subjects may have started oseltamivir therapy prior to randomization.  
All subjects will also receive a pretreatment regimen of diphenhydramine 50 mg PO or IV plus either ibuprofen 
400 mg PO or acetylsalicylic acid 320-325 mg PO approximately 60 minutes before infusion. Approximately 
120 evaluable subjects (40/arm) with confirmed influenza A infection will be treated. 
Subjects admitted to the hospital within 5 days of onset of initial symptoms who require supplemental oxygen will 
undergo a rapid influenza test or a local polymerase chain reaction (PCR) test, fluorescent immunoassay (FIA) test, 
or enzyme-linked immunosorbent assay (ELISA) test to confirm influenza A infection. Subjects diagnosed with 
influenza A will undergo the screening procedures to confirm eligibility. Study assessments are outlined in Table 1 
(Schedule of Assessments). 
 
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Eligible subjects will be randomized to receive either oseltamivir + VIS410 2000 mg, oseltamivir + VIS410 
4000 mg, or oseltamivir + placebo (0.9% sodium chloride) at a ratio of 1:1:1 using a permuted block randomization 
method according to the table below: 
Sample Size 
Treatment 
VIS410 Dose a 
Oseltamivir Dose b 
Infusion 
n = 40 
VIS410 + oseltamivir 
2000 mg IV 
75 mg administered BID 
for a minimum of 5 days  
Infused over 
120 minutes 
n = 40 
VIS410 + oseltamivir 
4000 mg IV 
n = 40 
Placebo c + oseltamivir 
0 mg IV 
a  Dose administered in 200 mL 
b Dosage and administration should follow local prescribing information for oseltamivir based on renal 
function. 
c  0.9% sodium chloride (200 mL). 
 
Oseltamivir (Tamiflu®) will be provided by the Sponsor. Treatment with oseltamivir may be extended for up to 
5 additional days (up to 20 doses of total therapy) if clinical symptoms \warrant further treatment as assessed by the 
Investigator. Note: based on SOC, subjects may have started oseltamivir therapy prior to randomization. 
Study assessments are outlined in Table 1. Subjects discharged from the hospital prior to Day 14 will attend the 
applicable outpatient follow-up visit(s) (eg, Day 3, Day 5, Day 7, Day 14) per Table 1. 
An independent data safety monitoring board (DSMB) will be established to review all available safety data after 
30 subjects and again after approximately 70 subjects have completed Day 14 assessments. The assessment of safety 
will be determined from vital sign measurements, physical examinations, hematology, chemistry and urinalysis 
laboratory testing, 12-lead electrocardiograms (ECGs), use of concomitant medications, and review of adverse 
events (AEs). Based on the safety data provided, the DSMB will determine if it is acceptable to continue the study 
or reduce the dose as appropriate. Dosing will temporarily pause while the DSMB meets if there are 4 treatment-
related serious adverse events (SAEs) or 4 severe gastrointestinal (GI) treatment–emergent adverse events (TEAEs) 
that require intervention, which is defined as requiring IV fluid and medication to decrease the frequency of diarrhea 
(ie, loperamide). 
Additional DSMB reviews can occur throughout the trial as deemed necessary by the DSMB or Sponsor to ensure 
subject safety and well-being. Study enrollment and dosing will continue while the DSMB evaluates data. 
Study Population 
Number of Subjects 
Approximately 120 evaluable subjects will be enrolled in 3 equal arms: VIS410 2000 mg, VIS410 4000 mg, and 
placebo. 
Inclusion Criteria 
Subjects meeting all of the following criteria are eligible to participate in this study: 
1. Male and female subjects aged ≥ 18 years. For a country where the legal age of consent is >18 years old, the 
country requirements should be followed. 
2. Test positive for influenza A by rapid antigen test or with another commercially available test on an adequate 
nasopharyngeal specimen in accordance with the manufacturer's instructions, or an acceptable local test, 
including PCR, FIA, or ELISA. 
3. Onset of influenza symptoms no more than 5 days before VIS410/placebo infusion; symptoms may include 
cough, dyspnea, sore throat, fever, myalgias, headache, nasal symptoms (rhinorrhea, congestion), fatigue, 
diarrhea, anorexia, nausea, and vomiting. 
4. Requirement for oxygen support including any positive pressure ventilation (PPV). 
5. Women of childbearing potential must have a negative pregnancy test within 2 days prior to VIS410/placebo 
infusion. 
6. 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 
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c. 
Women of childbearing potential participating in heterosexual sexual relations must be willing to use 
adequate contraception from screening until 60 days post-VIS410/placebo infusion (see Section 6.2). 
7. 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 6.2) when having 
heterosexual intercourse, from screening until 60 days post-VIS410/placebo infusion. 
8. Subject is able and willing to comply with study procedures, as per protocol. 
9. Subject, or a legally acceptable representative, is able to understand the purpose and risks of the study 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. Known or suspected intolerance or hypersensitivity to VIS410, oseltamivir, pretreatment medications 
(diphenhydramine, or to both ibuprofen and acetylsalicylic acid [ASA]), or closely related compounds (eg, 
other monoclonal antibodies). 
2. Subjects who have received VIS410 in the past.  
3. Subjects who have a history of receiving monoclonal antibody products within 3 months prior to 
VIS410/placebo dosing or planned administration of another monoclonal antibody during the study period. 
4. Subjects who have taken more than 6 doses of an approved antiviral therapy for influenza within the prior 
96 hours (eg, oral oseltamivir, inhaled zanamivir, IV peramivir, or oral ribavirin) between onset of symptoms 
and VIS410/placebo dosing. 
5. Subjects with known co-infection with influenza B or other viral respiratory infections (eg, respiratory syncytial 
virus [RSV], parainfluenza viruses, respiratory adenoviruses). 
6. Subjects with lung transplant or history of severe chronic lung disease, including cystic fibrosis or any condition 
requiring home oxygen therapy. 
7. Subjects on extracorporeal membrane oxygenation at time of randomization. 
8. Subjects with end-stage renal disease (ESRD) who are not undergoing hemodialysis. 
9. Subjects with active graft-vs-host disease, hematopoietic stem cell transplant within the previous 90 days, or 
human immunodeficiency virus infection with a CD4 cell count of less than 200 per cubic millimeter. 
10. High probability of mortality within 48 hours of randomization as determined by the Investigator. 
11. Women who are pregnant, breast-feeding, or considering to become pregnant. 
12. Subjects in whom nasopharyngeal swabbing is not possible. 
13. Subjects weighing less than 45 kg. 
14. 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. 
15. Presence of any preexisting illness that, in the opinion of the Investigator, would place the subject at an 
unreasonably increased risk through participation in this study. 
16. Subjects unable to comply with study protocol procedures and study visit schedules for whatever reason. 
17. 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. 
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 (or volume equivalent to IV line volume if greater than 25 mL) saline flush to ensure all product is 
administered, in addition to oseltamivir (Tamiflu) 75 mg BID for total of 5 days (10 doses). For patients with renal 
insufficiency, refer to prescribing information for administration of oseltamivir. For patients unable to swallow, 
oseltamivir capsules can be opened and mixed with liquid for ease of administration. 
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, followed 
by a 25-mL (or volume equivalent IV line volume if greater than 25 mL) saline flush to ensure all product is 
administered, in addition to oseltamivir (Tamiflu) 75 mg BID for total of 5 days (10 doses). For patients with renal 
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insufficiency, refer to prescribing information for administration of oseltamivir. 
VIS410 and Placebo Preparation 
The required amount of VIS410 to be dosed (2000 mg or 4000 mg) will be diluted with normal saline up to a 
maximum total volume of 200 mL; for placebo subjects, 200 mL of normal saline will be prepared. Length of IV 
line will ideally be set for maximum volume of 25 mL, so that the 25-mL (or increased volume as noted above) 
saline flush following administration will ensure all VIS410/placebo has been administered. In the event that the 
infusion line volume is greater than 25 mL the post-administration saline flush should be increased to match the 
volume of the infusion line kit.   
The VIS410/placebo 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 whenever possible, 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 
VIS410/placebo will be administered IV at a rate of 100 mL/h, over 2 hours. After the dose has been administered, 
the infusion will be followed by an appropriate volume saline flush as described above. The infusion time may be 
extended up to 4 hours at the Investigator’s discretion based on local infusion site–related symptoms.  
All subjects will be given a pretreatment regimen of PO or IV diphenhydramine 50 mg plus either ibuprofen 400 mg 
PO or acetylsalicylic acid 320-325 mg PO or crushed and given through the nasogastric tube approximately 
60 minutes before IV infusion of VIS410/placebo. 
Study Duration 
The total study duration for each subject (screening through study exit) will be approximately 8 weeks (Day 56). 
Study Endpoints 
Primary Efficacy Endpoint 
 
The primary efficacy outcome analysis compares Day 7 clinical status ordinal scale scores between treatment 
groups, and between all VIS410 recipients versus placebo. Clinical status is measured daily for 14 days using 
the below seven-level ordinal scale, with the classifications presented from the worst clinical outcome to the 
best clinical outcome in descending order; for each day, subject status will be classified by the worst clinical 
outcome for which they qualify.  
 
Death 
 
ICU stay with mechanical ventilation 
 
ICU stay without mechanical ventilation 
 
Non-ICU hospitalization with supplemental oxygen 
 
Non-ICU hospitalization without supplemental oxygen 
 
Discharge with partial resumption of normal activities 
 
Discharge with full resumption of normal activities 
Primary Safety Endpoint 
 
The proportion of subjects with AEs and SAEs following administration of VIS410 
Secondary Endpoints 
The difference between VIS410 + oseltamivir and oseltamivir alone treatment groups in the following endpoints:  
 
Among patients requiring supplemental oxygen therapy at the time of enrollment with baseline room air oxygen 
saturation of ≤92%, time to cessation of oxygen (O2) support resulting in stable oxygen saturation (SpO2) by 
pulse oximetry. Stable SpO2 is defined as two consecutive SpO2 values of > 92% on room air that are at least 8 
hours apart. 
 
For any patient requiring supplemental oxygen therapy at the time of enrollment (regardless of oxygen 
saturation), time to cessation of oxygen support 
 
Peak viral load, viral area under the concentration–time curve (AUC), duration of viral shedding, and time to 
resolution of viral load from nasopharyngeal swabs by TCID50 and qRT-PCR 
 
Time to clinical response defined as resolution of at least 4 of 5 vital signs: 
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 
Afebrile with core temperature ≤ 37.8°C, without use of antipyretics (oral ≤ 37.2°C) 
 
Oxygen saturation ≥ 95% on room air without support or a return to pre-infection status, if pre-infection 
status was < 95% 
 
Pulse rate ≤ 100/min 
 
Systolic blood pressure (SBP) ≥ 90 mm/Hg, without vasopressor use 
 
Respiratory rate ≤24 beats per minute 
 
Clinical status ordinal scale mean area under the curve for Days 1-7 and Days 1-14 using linear numeric scores 
for the ordinal categories. 
 
Comparison of clinical status ordinal scale scores for selected individual days (ie, Days 3, 4, 5, and 6)  
 
Comparison of clinical status ordinal scale scores using modified ordinal scale criteria (ie, pooling of selected 
severity criteria scores) 
 
Comparison of discrete ordinal scale parameters, including days of ventilator support, days in intensive care, 
and duration of hospitalization 
 
Number of days to resumption of normal activities 
 
All-cause and attributable mortality rates at Day 14, 28, and 56 
 
Total number of days in hospital and/or intensive care unit (ICU) from admission to discharge and rate of 
rehospitalization due to influenza A relapse/complication 
 
The incidence, severity, and duration of signs and symptoms of influenza-like illness as assessed by the FluPRO 
Questionnaire (see Appendix 14.1) 
 
Analysis of time to alleviation of signs and symptoms of influenza in the subset of subjects able to complete the 
Influenza Patient Reported Outcomes (FluPRO) Questionnaire at baseline and post-dose by Kaplan Meier 
analysis 
 
The percentage of subjects with new bacterial pneumonia/superinfection 
 
The percentage of subjects with influenza-related complications 
 
VIS410 population pharmacokinetic (PK) parameters in serum 
 
Titer of anti-VIS410 antibody positive samples 
 
Genotypic and/or phenotypic assessment to determine the emergence of VIS410 and oseltamivir-resistant 
viruses 
Exploratory Endpoints 
 
Population PK parameters of VIS410 from nasopharyngeal secretions 
 
VIS410 concentration in tracheal aspirates 
 
The difference in viral load between VIS410 + oseltamivir and oseltamivir alone treatment groups in tracheal 
aspirate of subjects on mechanical ventilation 
 
Titer of anti-influenza A antibodies by hemagglutinin inhibition assay (HAI) in serum 
 
Correlations between serum and/or nasopharyngeal PK with viral load, clinical symptoms, presence of antidrug 
antibodies (ADAs), safety, and additional endpoints 
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Statistical Methods 
Sample Size 
Approximately 120 evaluable subjects will be enrolled. The study is exploratory in nature, and is not powered to 
demonstrate significant differences between treatment groups in primary or secondary outcome measures. The 
protocol intent is to collect sufficient information to identify the most appropriate candidate endpoints for 
subsequent Phase 3 study evaluation from among the primary and secondary endpoints described below. Statistical 
significance testing will therefore be used to assess the relative strength of evidence of the primary and secondary 
endpoints, to provide reasonable assurance that the endpoints chosen for a confirmatory Phase 3 trial will elucidate 
treatment differences between VIS410 plus oseltamivir versus oseltamivir alone.  
Efficacy 
Efficacy analysis will have two complementary purposes in this Phase 2 study, both designed to aid in the optimal 
design of a confirmatory Phase 3 trial. First, primary and secondary endpoints will be analyzed for treatment group 
differences, to determine which endpoints might be most sensitive demonstration of treatment group differences 
using p-values as an indicator. Second, the relative contribution of the various efficacy endpoints to patient well-
being and benefit will be assessed, as well as potential correlations of endpoints such as the influence of peak viral 
load or number of days on ventilator on the time to resumption of normal activities.  
The ordinal scale outcomes will be measured daily from Day 1 (baseline) through Day 14, inclusive, using a seven-
level hierarchical scale with the classifications ordered from the worst to the best clinical outcomes (see Section 
10.6.1). For use in overall summary statistical presentations, the ordinal categories will be assigned decreasing 
integer scores, with death a score of 6 and discharge with full resumption of normal activities a score of 0. The 
primary outcome comparison of Ordinal Scale scores at Day 7 between treatment groups will be evaluated by 
proportional odds ratio analysis, as implemented by logistic regression, including a test of the proportional odds 
assumption. For this analysis, the response categories will be ordered from best (Discharge with full resumption of 
normal activities) to worst (Death). Additional exploratory analyses may be conducted to obtain a more complete 
understanding of the relationship of treatment to the ordinal response, including exact Mantel-Haenszel tests or 
partial proportional odds models.  
The area under the curve (AUC) over time for a given patient will be calculated as the sum of the maximum ordinal 
score for each day up through 7 and 14 days. An analysis of treatment group differences will be performed on these 
per-patient AUC values using analysis of variance, with treatment group and strata as fixed factors. A sensitivity 
analysis will be performed that excludes the category of death on study, to determine if death as an outcome skews 
the results; death as an outcome will also be analyzed as an independent secondary endpoint. A secondary analysis 
of treatment group effect on the difference in proportions of patients with the worst (death) versus the best outcome 
(discharge from hospital and resumption of normal activities) will also be performed. This analysis does not use 
scores for the ordinal outcome but does account for ordinality, and is therefore not dependent on the relationship of 
score to severity of outcome. An exploratory analysis will be performed through an exact categorical analysis of 
treatment group difference in the ordinal scale results using the worst outcome on a per-patient basis. 
Additional ordinal scale outcome assessments will include comparison of total numbers of days at more severe scale 
values (death, time on ventilator, time in ICU) and proportions of patients with ordinal scale worsening post 
enrollment. Proportion outcomes will be analyzed by categorical data analysis methods, including Mantel-Haenszel 
chi-square tests adjusted for strata; additional exploratory subgroup analyses may also be performed, for example, 
based on various age categories. Time from onset of symptoms to study treatment and the number of doses of 
oseltamivir (Tamiflu) prior to VIS410 treatment for the current case of influenza may be included as covariates in 
the analyses. 
Secondary and exploratory endpoints will be analyzed for descriptive purposes, with significance levels (p-values) 
provided to illustrate the strength of evidence for treatment effects, and to provide a basis for the choice of endpoints 
for further study in a confirmatory study. These analyses will also provide estimates for potentially powering 
additional efficacy endpoints, and to assist in hierarchical ordering of secondary endpoints to provide alpha-control 
in confirmatory studies and for labelling purposes. 
Time to cessation of O2 support resulting in a stable SpO2 will be analyzed using a Cox proportional hazards 
regression model including data from patients on O2 support. A P-value (using the Wald statistic) for each VIS410 
dose vs placebo will be presented.  
The total number of days in the hospital and/or ICU from admission to discharge and the rate of rehospitalization 
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due to influenza A relapse/reinfection will be summarized descriptively by treatment group. 
The probability of time to clinical response (defined as resolution of vital signs) will be calculated via 
Kaplan-Meier. A significance test (using the log-rank test) for each VIS410 dose vs placebo will be presented. 
Results will be tabulated and presented graphically as well. The number and percentage of subjects in each treatment 
group with clinical response will be summarized. 
Serum Pharmacokinetics 
Serum concentrations will be listed by subject for VIS410 and summary statistics by group will be presented, 
including means, geometric means, standard deviations, coefficient of variation (CV), medians, and ranges, as 
appropriate. Summary graphs, including mean concentration-time profiles by group, will also be presented. The 
serum concentration data will be analyzed by population PK methods using nonlinear mixed effects modeling as 
implemented in NONMEM or equivalent software. Additional analyses and summaries may be generated as 
appropriate. 
Pharmacokinetics of Nasopharyngeal Secretions and Tracheal Aspirates 
Nasopharyngeal secretion and tracheal aspirate concentrations will be listed by subject for VIS410 and summary 
statistics by group will be reported as described for the serum concentrations. The computed PK parameters will be 
listed by subject for VIS410. Summary statistics and PK parameters will be presented including means, geometric 
means, standard deviations, CV, medians, and ranges, as appropriate. Summary graphs, including mean 
concentration-time profiles by group, will also be presented. The nasopharyngeal concentration data may also be 
analyzed by population PK methods using nonlinear mixed effects modeling as implemented in NONMEM or 
equivalent software. Additional analyses and summaries may be generated as appropriate. 
Adverse Events 
The original terms in the electronic data capture (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). 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 (ie, TEAEs) will be summarized. 
AEs will be summarized overall and 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, hypersensitivity reaction, anaphylactic reaction, AEs of 
special interest (AESIs), and SAEs between treatment groups will be calculated. 
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 will be provided, as appropriate. 
Injection Site Tolerability 
Injection site tolerability is defined as AEs demonstrating injection site irritation or tissue damage. Injection site 
tolerability 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 
Division of Microbiology and Infectious Diseases (DMID) Adult Toxicity Table (see Appendix 14.3) 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 toxicity grade 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, SBP, and diastolic blood 
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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)13 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 ms) and changes from baseline (increase > 30 and 
> 60 ms), a frequency table by assessment time point and by treatment group will be provided. 
Signs and Symptoms of Influenza 
Descriptive statistics will be used to compare the duration of symptoms of influenza-like illness by treatment group 
in the subset of subjects able to complete the FluPRO Questionnaire at baseline and post-dose. 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 will be generated. The number and percentage of subjects who were not able to 
complete the assessment at each visit will be summarized. 
Complications of Influenza 
Complications of influenza are defined as pneumonia, myocarditis, worsening of chronic bronchitis, sinusitis, otitis 
or other chronic pulmonary diseases, encephalopathy, and death. Complications of influenza and use of antibiotic 
therapy for bacterial pneumonia will be reported by variable, treatment group, and time point. Diagnosis of bacterial 
pneumonia will be based on local clinical practice, usually an assessment of clinical features and any radiographic 
evidence of bacterial pneumonia (eg, infiltrate) and/or microbiologic evidence of bacterial pneumonia. All-cause and 
attributable mortality will be evaluated on Day 14 and 28. 
Healthcare Resource Utilization 
Descriptive statistics will be used to compare the total duration of hospitalization, number of subjects requiring ICU 
admission post-randomization, overall number of days in the ICU, number of hours on ventilation, rehospitalization 
due to influenza-like illness, duration of oseltamivir therapy, and number of days to resumption of usual activities 
between treatment arms. Time to resumption of usual activities will be determined from the visual analog scale 
(VAS) (scale ranges from 0 to 10, where 0 indicates subject is unable to perform any of his/her usual activities prior 
to influenza onset, and 10 indicates subject is able to fully perform all usual activities). 
Viral Load 
One-way ANOVA or Mann-Whitney U test will be used to assess the difference between treatment groups (each 
VIS410 dose vs placebo) in the viral load AUC based on qRT-PCR and TCID50 from nasopharyngeal swabs. 
Descriptive statistics will be used for viral load data (AUC, time to resolution of viral load, duration of viral 
shedding, and peak viral load based on qRT-PCR and TCID50) from nasopharyngeal swabs as well as tracheal 
aspirate by treatment group and VIS410 overall vs placebo. Tables and graphs will be generated as appropriate by 
dose group. Additional exploratory statistical analyses may be conducted as appropriate. Exploratory dose and 
exposure response will be evaluated using various statistical and graphical approaches as appropriate. 
Immunology 
Immunological assessments will be summarized by parameter, treatment group, and time point using descriptive 
statistics: 
 
Anti-influenza A antibodies by HAI in serum 
 
ADA titers 
Exploratory Pharmacokinetic/Pharmacodynamic Analyses 
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Various techniques will be used to explore exposure-response relationships and to compare the strength of the 
relationship between each independent variable (eg, AUC, Cmax, concentration at specific time point) and the 
dependent variables (eg, viral AUC, peak viral load, 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). 
Emergence of Viral Resistance to VIS410 and Oseltamivir 
Viral sensitivity to VIS410 and oseltamivir will be assessed during the study.  
 
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SCHEDULE OF ASSESSMENTS 
Table 1. 
Schedule of Assessments 
Study Time Point 
Screening1 
Day 1 
Day 
3 
5 (± 1) 
7 (± 1) 
14 (± 3) 
28 (± 3) 
56 (± 7) 
Baseline 
Predose 
0 Hour 
End of  
Infusion 
 
 
 
 
 
LFU/ET 
Visit2 
Screening/Administrative Assessments 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
Medical history and demographics 
X 
 
 
 
 
 
 
 
 
 
 
Nasopharyngeal swab for rapid flu test3 
X 
 
 
 
 
 
 
 
 
 
 
Onset of symptoms interview 
X 
 
 
 
 
 
 
 
 
 
 
Prior medications4 
X 
X 
 
 
 
 
 
 
 
 
 
Randomization5 
 
X 
 
 
 
 
 
 
 
 
 
Subject Diary6 
 
X–––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––X  
Safety Assessments 7 
Supine ECG8 
X 
X9 
 
 
X 
 
 
 
 
 
 
Vital signs10 
X 
X9  
X  
 
X 
X 
X 
X 
X 
X 
X 
SpO2
11 
X 
X9 
X 
X––––––––––––––––––––––––––––––––––––––––––––––––––X 
Body temperature12 
X 
X9 
X  
 
X 
X 
X 
X 
X 
X 
X 
Physical exam13 
X 
 
 
 
 
 
 
 
 
 
 
FluPRO Questionnaire14 
 
X–––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––X 
 
 
Seven-Level ordinal scale15 
 
X–––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––X 
 
 
Pregnancy test16 
X 
X17 
 
 
 
 
 
 
 
 
X 
Chemistry, hematology, urinalysis18,19 
 
X 
 
 
 
 
X 
 
X 
X 
X 
Serum creatinine20 
X 
 
 
 
 
 
 
 
 
 
 
C-reactive protein (CRP)  
 
X 
 
 
 
 
X 
 
 
 
 
Erythrocyte sedimentation rate (ESR)20a  
 
X 
 
 
 
 
X 
 
X 
 
 
Chest x-ray / CT scan21 
X 
 
 
 
 
 
 
 
 
 
 
Procalcitonin 
 
X 
 
 
 
 
 
 
 
 
 
AEs, SAEs, and AESIs 
 
X–––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––X 
Concomitant therapy 
 
X–––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––X 
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Study Time Point 
Screening1 
Day 1 
Day 
3 
5 (± 1) 
7 (± 1) 
14 (± 3) 
28 (± 3) 
56 (± 7) 
Baseline 
Predose 
0 Hour 
End of  
Infusion 
 
 
 
 
 
LFU/ET 
Visit2 
Influenza complications 
 
X–––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––X 
VAS for assessment of resumption of normal 
activities 
 
X–––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––X 
Healthcare utilization22 
 
X–––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––X 
Study Agent Administration/Virologic/PK, and Immunology Assessments 
Pretreatment medications 60 minutes (± 5 min) 
prior to start of infusion23 
 
 
X 
 
 
 
 
 
 
 
 
VIS410/placebo infusion24 
 
 
 
X 
 
 
 
 
 
 
 
Oseltamivir therapy25 
 
 
 
X––––––––––––––––––––––––X 
 
 
 
 
Serum PK 
 
X 
 
 
X26 
 
X 
 
X 
X 
X 
Nasopharyngeal swab27,28  
 
 
X 
 
X26 
X 
X 
X 
X 
X 
X 
Tracheal aspirate29 
 
 
X 
 
X 
X 
X 
X 
 
 
 
Serum ADA 
 
X 
 
 
 
 
 
 
 
X 
X 
Serum HAI sample 
 
X 
 
 
 
 
 
 
 
X 
 
 
e
                                                 
1 Screening and baseline activities may be performed on the same day. 
2 Subjects who terminate the study participation early are encouraged to have all follow-up safety assessments done at the time of study termination. All other subjects will return for a final 
follow-up visit at Day 56 ± 7 days. 
3 Single nasopharyngeal swab will be obtained from one nostril for influenza A rapid test. This screening test is not necessary if the subject has a prior influenza A positive test by Rapid 
Antigen Test or with another commercially available test including PCR, FIA, or ELISA within the prior 48 hours of screening. 
4 Collect all medications taken, including over-the-counter, within 7 days prior to VIS410/placebo administration. 
5 Randomization will be stratified by presence or absence of positive pressure ventilation (PPV) at baseline to ensure an even distribution across treatment arms. 
6 Subject diary will be provided upon discharge from the hospital and will record daily oseltamivir dosing (as applicable) and will have a daily VAS for assessing resumption of usual 
activities until either the subject reports that all usual activities (prior to influenza onset) can be performed or Day 56, whichever comes first. In addition, the Influenza Patient Reported 
Outcomes (FluPRO) Questionnaire will be provided and completed daily up until Day 14 (if applicable).  
7 Additional safety assessments may be performed outside of the defined protocol criteria, at the Investigator’s discretion. 
8 Single 12-lead ECG will be performed after a 5-minute rest in supine position. 
9 To be repeated only if screening and baseline visits are more than 24 hours apart. 
 
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10 Vital signs should be measured after 5 minutes of rest in a supine position and include heart rate, respiratory rate, and blood pressure. During hospitalization, vital signs will be measured at 
the end of the infusion on Day 1 and then BID (preferably at the same time each day) up until Day 14 or discharge from the hospital if this occurs prior to Day 14. 
11 Baseline SpO2 on room air to be documented, if available. Once randomized, SpO2 to be measured using pulse oximetry 3 times daily (approximately every 8 hours) at approximately the 
same time each day until stable. Stable SpO2 is defined as two consecutive SpO2 values of > 92% on room air that are at least 8 hours apart. 
12 During hospitalization, body temperature will be recorded at the end of infusion on Day 1 then BID up until Day 14 or discharge from the hospital if discharge occurs prior to Day 14. In 
cases where obtaining oral temperature is not possible, core temperature will be obtained. While hospitalized, the maximum temperature should be recorded for each 12-hour interval 
(from 12 AM to 12 PM and from 12 PM to 12 AM). 
13 Additional targeted physical exam may be performed throughout the study as needed at the Investigator’s or his/her designee’s discretion. 
14 The Influenza Patient Reported Outcomes (FluPRO) Questionnaire (Appendix 14.1) must be completed (ie, self-reported) by the subject at baseline (Day 1) and daily thereafter through 
Day 14. Subjects who are not able to complete the questionnaire at baseline (Day 1) will be exempt from this assessment throughout the study. The FluPRO will be completed at home for 
subjects that are discharged from the hospital prior to Day 14.  
15 The ordinal scale will be completed from baseline (Day 1) and daily thereafter through Day 14. For each day, subjects will be classified by the worst clinical outcome for which they 
qualify. 
16 A urine or serum pregnancy test must be performed at screening locally (ie, by the investigative site) within 2 days prior to dosing. Negative results must be obtained prior to 
randomization.  
17 A serum pregnancy test will be performed at the central lab for all female subjects of childbearing potential following randomization at baseline 
18 Subjects to be enrolled based on the Investigator’s discretion including any local laboratory results per SOC at institution.  
19 See Laboratory Assessments for list of tests to be performed by the Central Lab in Appendix 14.2. 
20 Serum creatinine to be done locally within 24 hours prior to randomization, the result is required for oseltamivir dosing. 
20a ESR to be performed locally. 
21 A chest x-ray or computed tomography (CT) scan taken per SOC within 72 hours before dosing is acceptable. 
22 Healthcare utilization (total length of hospital stay, length of ICU stay, and rehospitalization) will be captured through the last follow-up visit.  
23 If the subject has any history of delayed gastric emptying, including premenstruation syndrome or menstruation, he or she may receive oral premedications 120 minutes prior to IV 
VIS410/placebo infusion. 
24 VIS410/placebo will be administered over 2 hours. Infusion time can be extended to up to 4 hours at discretion of the Investigator only if local infusion site–related symptoms occur. 
25 Minimum of 10 doses of oseltamivir treatment (BID for 5 days) is required. Treatment with oseltamivir may be extended for up to 5 additional days (up to 20 doses of total therapy) if 
clinical symptoms warrant further treatment as assessed by the Investigator. Note: based on SOC, subjects may have started oseltamivir therapy prior to randomization. For patients unable 
to swallow, oseltamivir capsules can be opened and mixed with liquid for ease of administration. 
26 To be obtained up to 2 hours post-VIS410 administration. 
27 Nasopharyngeal swabs will be obtained for virology and/or PK from both nostrils (1 swab per nostril). The first 50 randomized subjects will have nasopharyngeal swabs collected up to 
Day 56 (predose, end of infusion, Days 3, 5, 7, 14, 28 and 56); while in the remaining subjects, nasopharyngeal swabs will be obtained up to Day 14 only.  
28 If the subject remains in the hospital on Day 10, additional nasopharyngeal swabs will be obtained on Day 10. 
29 One tracheal aspirate sample for virology and PK will be obtained (ventilated subjects only).  
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END OF FOOTNOTES TO SCHEDULE OF ASSESSMENTS TABLE
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TABLE OF CONTENTS – ABBREVIATED 
SIGNATURES ...........................................................................................................................2 
SYNOPSIS .................................................................................................................................4 
SCHEDULE OF ASSESSMENTS ..........................................................................................14 
LIST OF TABLES ...................................................................................................................22 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................23 
1.0 INTRODUCTION ...........................................................................................................25 
2.0 STUDY OBJECTIVES ....................................................................................................39 
3.0 STUDY ENDPOINTS .....................................................................................................41 
4.0 STUDY DESIGN.............................................................................................................43 
5.0 STUDY POPULATION ..................................................................................................45 
6.0 STUDY ASSESSMENTS ...............................................................................................47 
7.0 STUDY TREATMENTS .................................................................................................57 
8.0 STUDY METHODS AND PROCEDURES ...................................................................62 
9.0 ADVERSE EVENTS .......................................................................................................65 
10.0 STATISTICAL METHODS ............................................................................................71 
11.0 STUDY TERMINATION AND COMPLETION ...........................................................80 
12.0 ETHICAL AND ADMINISTRATIVE CONSIDERATIONS ........................................82 
13.0 REFERENCES ................................................................................................................92 
14.0 APPENDICES .................................................................................................................93 
 
 
 
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TABLE OF CONTENTS 
SIGNATURES ...........................................................................................................................2 
SYNOPSIS .................................................................................................................................4 
SCHEDULE OF ASSESSMENTS ..........................................................................................14 
END OF FOOTNOTES TO SCHEDULE OF ASSESSMENTS TABLE ..............................17 
TABLE OF CONTENTS – ABBREVIATED ........................................................................17 
TABLE OF CONTENTS .........................................................................................................18 
LIST OF TABLES ...................................................................................................................22 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................23 
1.0 INTRODUCTION ...........................................................................................................25 
 
Background Information ........................................................................................25 
1.1
 
Nonclinical Studies ................................................................................................25 
1.2
1.2.1 
Pharmacology, Pharmacokinetics, and Metabolism ....................................25 
1.2.2 
Toxicology ...................................................................................................26 
 
Clinical Studies ......................................................................................................27 
1.3
1.3.1 
Phase 1 Study (VIS-C001) ...........................................................................27 
1.3.2 
Phase 2a Challenge Study (VIS410-201) ....................................................28 
1.3.3 
Phase 1 Study (VIS410-102) .......................................................................30 
 
Overall Rationale for the Study .............................................................................32 
1.4
 
Risk-Benefit Analysis ............................................................................................33 
1.5
1.5.1 
Potential Risks .............................................................................................34 
1.5.2 
Potential Benefits .........................................................................................37 
1.5.3 
Dose Selection Rationale .............................................................................38 
2.0 STUDY OBJECTIVES ....................................................................................................39 
 
Primary Objectives.................................................................................................39 
2.1
2.1.1 
Primary Efficacy Objective ..........................................................................39 
2.1.2 
Primary Safety Objective .............................................................................39 
 
Secondary Objectives.............................................................................................39 
2.2
 
Exploratory Objectives ..........................................................................................40 
2.3
3.0 STUDY ENDPOINTS .....................................................................................................41 
 
Primary Endpoints .................................................................................................41 
3.1
3.1.1 
Primary Efficacy Endpoint ..........................................................................41 
3.1.2 
Primary Safety Endpoint ..............................................................................41 
 
Secondary Endpoints .............................................................................................41 
3.2
 
Exploratory Endpoints ...........................................................................................42 
3.3
4.0 STUDY DESIGN.............................................................................................................43 
 
Overview ................................................................................................................43 
4.1
 
Study Duration .......................................................................................................44 
4.2
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Data Safety Monitoring Board ...............................................................................44 
4.3
 
Discussion of Study Design ...................................................................................44 
4.4
5.0 STUDY POPULATION ..................................................................................................45 
 
Number of Subjects................................................................................................45 
5.1
 
Selection of Study Population ................................................................................45 
5.2
5.2.1 
Inclusion Criteria .........................................................................................45 
5.2.2 
Exclusion Criteria ........................................................................................46 
6.0 STUDY ASSESSMENTS ...............................................................................................47 
 
Prescreening, Screening, and Study Procedures ....................................................47 
6.1
6.1.1 
Prescreening Procedures ..............................................................................47 
6.1.2 
Screening Procedures ...................................................................................47 
6.1.3 
Study Procedures .........................................................................................47 
6.1.4 
Unscheduled Visits ......................................................................................48 
6.1.5 
Early Withdrawal Procedures ......................................................................48 
6.1.6 
Treatment of VIS410 Overdose ...................................................................48 
 
Pregnancy Safeguards ............................................................................................48 
6.2
 
Procedures for Sample and Data Collection ..........................................................50 
6.3
6.3.1 
SpO2 Oxygen Support ..................................................................................50 
6.3.2 
Viral Load ....................................................................................................50 
6.3.3 
Time to Cessation of Ventilator Support .....................................................50 
6.3.4 
Resumption of Normal Activities ................................................................50 
6.3.5 
Health Resource Utilization .........................................................................50 
6.3.6 
Signs and Symptoms of Influenza ...............................................................51 
6.3.7 
Serum Pharmacokinetics ..............................................................................51 
6.3.8 
Viral Resistance ...........................................................................................51 
6.3.9 
Clinical Outcomes per Seven-Level Ordinal Scale .....................................51 
6.3.10 
Pharmacokinetics of Nasopharyngeal Samples ...........................................52 
6.3.11 
Pharmacokinetics and Viral Load in Tracheal Aspirate ..............................52 
6.3.12 
Immunology .................................................................................................52 
 
Safety of Total Blood Sampling Volume...............................................................53 
6.4
 
Safety Evaluations .................................................................................................53 
6.5
6.5.1 
Adverse Events ............................................................................................53 
6.5.2 
Injection Site Tolerability ............................................................................53 
6.5.3 
Complications of Influenza ..........................................................................53 
6.5.4 
Clinical Laboratory Tests .............................................................................54 
6.5.5 
Vital Signs and Body Temperature ..............................................................54 
6.5.6 
Electrocardiography .....................................................................................55 
6.5.7 
Physical Examination...................................................................................55 
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6.5.8 
Radiological Assessment .............................................................................55 
 
Appropriateness of Measurements .........................................................................56 
6.6
7.0 STUDY TREATMENTS .................................................................................................57 
 
Test Product, Dose, Mode of Administration ........................................................57 
7.1
 
Reference Product, Dose, Mode of Administration ...............................................57 
7.2
 
Instructions for Preparation, Use, and Administration ..........................................58 
7.3
 
The Use of Oseltamivir as Standard of Care .........................................................58 
7.4
 
Pretreatment Regimen ............................................................................................59 
7.5
 
Other Medications Administered in This Study ....................................................60 
7.6
 
Treatment Compliance ...........................................................................................60 
7.7
 
Storage and Drug Accountability ...........................................................................60 
7.8
8.0 STUDY METHODS AND PROCEDURES ...................................................................62 
 
Prior & Concomitant Therapy ...............................................................................62 
8.1
8.1.1 
Permitted Prior Therapy ...............................................................................62 
8.1.2 
Permitted Concomitant Therapies................................................................62 
 
Prohibited Prior & Concomitant Medications .......................................................62 
8.2
8.2.1 
Prohibited Prior Medications .......................................................................62 
8.2.2 
Prohibited Concomitant Medications ..........................................................62 
 
Schedule of Examination Procedures by Study Visit ............................................63 
8.3
8.3.1 
Sequence of Assessments at a Single Visit ..................................................63 
8.3.2 
Day of Treatment Procedures (Day 1) .........................................................63 
8.3.3 
Post-Treatment Procedures (Day 3 to 56) ....................................................63 
 
Subject Diary .........................................................................................................64 
8.4
9.0 ADVERSE EVENTS .......................................................................................................65 
 
Definitions..............................................................................................................65 
9.1
9.1.1 
Adverse Event ..............................................................................................65 
9.1.2 
Signs and Symptoms of Influenza vs Adverse Events.................................65 
9.1.3 
Adverse Event of Special Interest ................................................................65 
9.1.4 
Serious Adverse Events ...............................................................................66 
9.1.5 
Discontinuation Due to an Adverse Event ...................................................66 
9.1.6 
Unlisted (Unexpected) Adverse Events .......................................................66 
9.1.7 
Suspected Unexpected Serious Adverse Reactions .....................................66 
9.1.8 
Treatment-Emergent Adverse Event ............................................................67 
 
Grading of Adverse Event Intensity ......................................................................67 
9.2
 
Causality Assessment.............................................................................................67 
9.3
 
Action Taken Regarding Investigational Product ..................................................68 
9.4
 
Outcome .................................................................................................................68 
9.5
 
Recording Adverse Events .....................................................................................68 
9.6
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Reporting Procedures .............................................................................................69 
9.7
9.7.1 
Reporting Serious Adverse Events ..............................................................69 
9.7.2 
Reporting SAEs to Competent Authorities/Ethics Committees ..................69 
9.7.3 
Reporting a Pregnancy .................................................................................70 
10.0 STATISTICAL METHODS ............................................................................................71 
 
Determination of Sample Size ...............................................................................71 
10.1
 
Randomization and Blinding .................................................................................71 
10.2
 
Analysis Populations ..............................................................................................73 
10.3
 
Initial Characteristics of the Subject Sample .........................................................73 
10.4
 
Handling of Missing Data ......................................................................................74 
10.5
 
Efficacy Analyses ..................................................................................................74 
10.6
10.6.1 
Day 7 Ordinal Scale Status ..........................................................................74 
10.6.2 
Time to Cessation of O2 Support .................................................................74 
10.6.3 
Time to Clinical Response ...........................................................................75 
10.6.4 
Time to Cessation of Ventilator Support .....................................................75 
10.6.5 
Healthcare Resource Utilization ..................................................................75 
10.6.6 
Signs and Symptoms of Influenza ...............................................................75 
 
Safety Analyses ......................................................................................................76 
10.7
10.7.1 
Adverse Events ............................................................................................76 
10.7.2 
Local Injection Site Tolerability ..................................................................76 
10.7.3 
Complications of Influenza ..........................................................................76 
10.7.4 
Clinical Laboratory Tests .............................................................................77 
10.7.5 
Vital Signs ....................................................................................................77 
10.7.6 
Electrocardiography .....................................................................................77 
 
Pharmacokinetic/Pharmacodynamic Analyses ......................................................78 
10.8
10.8.1 
Serum Pharmacokinetics ..............................................................................78 
10.8.2 
Pharmacokinetics of Nasopharyngeal Secretions and Tracheal Aspirate ....78 
10.8.3 
Exploratory Pharmacokinetic/Pharmacodynamic Analyses ........................78 
 
Viral Load ..............................................................................................................79 
10.9
 Immunological Analyses .......................................................................................79 
10.10
 Viral Resistance .....................................................................................................79 
10.11
11.0 STUDY TERMINATION AND COMPLETION ...........................................................80 
 
Study Completion ..................................................................................................80 
11.1
 
Study Drug Discontinuation ..................................................................................80 
11.2
 
Subject Withdrawal from Study .............................................................................80 
11.3
 
Stopping Rules or Discontinuation Criteria ...........................................................81 
11.4
 
Protocol Compliance ..............................................................................................81 
11.5
12.0 ETHICAL AND ADMINISTRATIVE CONSIDERATIONS ........................................82 
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Ethical Conduct of the Study .................................................................................82 
12.1
12.1.1 
Study-Specific Design Considerations ........................................................82 
12.1.2 
Subject Informed Consent............................................................................82 
12.1.3 
Independent Ethics Committee or Institutional Review Board ...................83 
12.1.4 
Protection of Subject Data ...........................................................................84 
 
Investigator Responsibilities ..................................................................................84 
12.2
 
Administration .......................................................................................................85 
12.3
12.3.1 
Protocol Amendments ..................................................................................85 
12.3.2 
Subject Identification, Enrollment, and Screening ......................................85 
12.3.3 
Source Documentation .................................................................................85 
12.3.4 
Case Report Form Completion ....................................................................86 
 
Monitoring and Quality Assurance ........................................................................86 
12.4
12.4.1 
Data Management ........................................................................................87 
12.4.2 
Data Quality Assurance ...............................................................................87 
12.4.3 
On-Site Audits .............................................................................................88 
 
Study Termination .................................................................................................88 
12.5
12.5.1 
Record Retention .........................................................................................88 
12.5.2 
Use of Information and Publication .............................................................89 
12.5.3 
Registration of Clinical Studies and Disclosure of Results .........................90 
12.5.4 
Confidentiality .............................................................................................90 
13.0 REFERENCES ................................................................................................................92 
14.0 APPENDICES .................................................................................................................93 
 
Influenza Patient Reported Outcomes Questionnaire ............................................93 
14.1
 
Laboratory Assessments ........................................................................................95 
14.2
 
Division of Microbiology and Infectious Diseases Adult Toxicity Table .............96 
14.3
 
LIST OF TABLES 
Table 1. Schedule of Assessments ............................................................................................. 14 
Table 2. Summary ADA Data – Phase 1 Study VIS-C001 ........................................................ 28 
Table 3. Distribution of Subjects ............................................................................................... 29 
Table 4. Viral Load and AUC Data............................................................................................ 29 
Table 5. Annual Mortality Rates from Infectious Diseases in the United States ....................... 32 
Table 6. Permuted Block Randomization Method ..................................................................... 43 
Table 7. Recommended Dosage Modifications for Treatment of Influenza in Adults 
with Renal Impairment or End-Stage Renal Disease on Dialysis a.............................. 59 
Table 8. Hierarchical Seven-Level Ordinal Scale for Clinical Outcomes ................................. 74 
 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADA 
antidrug antibody 
AE 
adverse event 
AESI 
adverse event of special interest 
AUC 
Area under curve 
ASA 
acetylsalicylic acid 
AUC 
area under the concentration–time curve 
BID 
Latin bis in die (two times (twice) daily) 
BiPAP 
bi-level positive airway pressure 
BMI 
body mass index; weight in kilograms divided by the square of height in meters 
CD-1 
cluster of differentiation 1 
CIOMS  
Council for International Organizations of Medical Science 
Cmax 
maximum concentration 
CPAP 
continuous positive airway pressure 
CRO 
contract research organization 
CT (scan) 
computed tomography 
CV  
coefficient of variation  
DBP 
diastolic blood pressure 
DMID 
Division of Microbiology and Infectious Diseases 
DSMB 
Data Safety Monitoring Board 
EC 
ethics committee 
EC50  
half-maximal effective concentration 
ECG 
electrocardiogram 
EDC 
electronic data capture (system) 
ELISA 
enzyme-linked immunosorbent assay 
ESRD 
end-stage renal disease 
ET 
end of therapy 
FDA 
Food and Drug Administration 
FIA 
fluorescent immunoassay 
FluPRO Questionnaire 
Influenza Patient Reported Outcomes (FluPRO) Questionnaire 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GLP 
Good Laboratory Practice 
HAI 
hemagglutination inhibition assay 
IC50 
half-maximal inhibitory concentration 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ICU 
intensive care unit 
IEC 
independent ethics committee 
IgG1 
immunoglobulin G1 
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Abbreviation 
Definition 
IRB 
institutional review board 
ITT 
intent-to-treat 
IV 
intravenous 
IWRS 
Interactive Web Response System 
LFU 
last follow-up 
LSLV 
last subject last visit 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
modified intent-to-treat 
NOAEL 
no-observed–adverse-effect level 
NONMEM 
software used for population pharmacokinetic modeling 
NSAID 
nonsteroidal anti-inflammatory drug 
O2 
oxygen 
PCR 
polymerase chain reaction 
PK 
pharmacokinetic 
PO 
Latin per os (by mouth) 
PP 
per protocol 
PPV 
positive pressure ventilation 
PR interval 
an ECG parameter 
QRS interval 
an ECG parameter 
qRT-PCR 
quantitative reverse transcriptase polymerase chain reaction 
QT interval 
an ECG parameter 
QTc 
an ECG parameter; values for QT corrected for heart rate 
QTcF 
QTc corrected according to Fridericia 
RBC 
red blood cell 
RSV 
respiratory syncytial virus 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SOC 
standard of care 
SSRE 
sample size re-estimation 
Study drug 
VIS410 or placebo 
SUSAR 
suspected unexpected serious adverse reaction 
TCID50 
half-maximal tissue culture infective dose 
TEAE 
treatment-emergent adverse event 
VAS 
visual analog scale 
VIS410 
investigational product 
WHO 
World Health Organization 
 
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1.0 
INTRODUCTION 
 
Background Information 
1.1
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®), zanamivir (Relenza®), and peramivir (Rapivab®), 
10% to 44% of hospitalized patients require intensive care and 25% to 50% of these patients die. 
It is estimated that as many as 400,000 patients are hospitalized with influenza each year in the 
United States, with up to 49,000 deaths per year.3  
The World Health Organization (WHO) has reported incidence rates of 3 to 5 million severe 
cases and about 250,000 to 500,000 influenza-related deaths annually.4 The 2009 influenza A 
pandemic (H1N1) spread rapidly to every continent with more than 399,232 reported cases and 
4735 deaths.5 
The therapeutic use of passive polyclonal antibodies to prevent viral infections, including 
hepatitis B, varicella, cytomegalovirus, rabies, and respiratory syncytial virus (RSV) has been 
well established. More recently, monoclonal antibodies for viral infections have been developed, 
including palivizumab (Synagis®), a Food and Drug Administration (FDA)-licensed treatment 
for the prevention of RSV 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 A strains, in both 
treatment and prevention models of influenza, was developed. Visterra intends to develop this 
product for the treatment of influenza A, specifically in hospitalized patients. 
This study will provide the first indications of efficacy, safety, and tolerability of VIS410 in 
hospitalized subjects with influenza A infection requiring oxygen support. Efficacy will be 
assessed by comparison of clinical status ordinal Day 7 scores between treatment groups. 
 
Nonclinical Studies 
1.2
1.2.1 
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 (IC50) of approximately 0.1 to 11 µg/mL. Mechanistic studies 
indicate that VIS410 inhibits hemagglutinin-mediated cell membrane fusion, thus preventing 
viral replication. 
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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 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.6 
1.2.2 
Toxicology 
In a cynomolgus monkey Good Laboratory Practice (GLP) toxicity/toxicokinetics study, 4 doses 
of VIS410 were administered intravenously (IV) 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 of VIS410 was determined to 
be 8 to 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 (4 doses of VIS410 IV administered 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. 
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Clinical Studies 
1.3
1.3.1 
Phase 1 Study (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 in Section 1.3.1.1 and Section 1.3.1.2. 
1.3.1.1 
Pharmacokinetic Results 
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 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 
PK. 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. 
1.3.1.2 
Safety Results 
In the Phase 1 study, VIS410 was administered IV over 2 hours. Overall, VIS410 was generally 
safe and well tolerated at all dose levels studied. TEAEs were reported for 20 of 30 subjects 
(66.7%) receiving VIS410 and 7 of 11 subjects (63.6%) receiving placebo. There were no drug-
related SAEs, no drug-related discontinuations, and no infusion-related reactions, such as 
anaphylaxis or injection site reactions. 
Notable AEs included one unrelated SAE of leukopenia and esophagitis secondary to primary 
herpes simplex virus-1 infection in 1 subject (VIS410, 30-mg/kg cohort). This SAE resolved, and 
the subject did well. Another unrelated SAE of acute appendicitis was also reported (placebo 
cohort). 
The most common AEs observed were diarrhea (10 of 41 [24.4%]) and headache (8 of 
41 [19.5%]; 5 subjects received VIS410). All diarrheal or loose stool AEs were observed in the 
VIS410-treated subjects and were usually mild to moderate, started ~2 to 4 hours after dosing, 
were transient, and resolved spontaneously within 24 hours after dosing with no associated 
dehydration. There were no associated elevations in alanine aminotransferase, aspartate 
aminotransferase, or bilirubin parameters. 
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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 antidrug 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. 
Table 2. 
Summary ADA Data – Phase 1 Study VIS-C001 
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 
1.3.2 
Phase 2a Challenge Study (VIS410-201) 
The Phase 2a study is a randomized, double-blind, placebo-controlled study to assess the safety, 
tolerability and antiviral activity of a single IV dose of VIS410 in healthy subjects after a viral 
inoculation with influenza A (H1N1) (Study VIS410-201). 
The study 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 received a single IV administration of VIS410 (2300-mg 
fixed dose, equivalent of 30 mg/kg) or placebo (7:5 randomization to VIS410:placebo) in Part 1 
of the study. 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 gastrointestinal (GI) events observed with VIS410. Preliminary findings from the 
first 31 subjects are presented in Section 1.3.2.1 and Section 1.3.2.2; the study has now 
completed enrollment and the data are pending final analysis. 
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1.3.2.1 
Preliminary Efficacy Data 
A partially blinded prespecified 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 a 
MITT b 
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. 
a  Subjects with HAI > 10 at baseline excluded per inclusion/exclusion criteria. 
b All randomized subjects who received study drug, met the inclusion criterion of seronegative by HAI (≤ 10) on 
Day 1, and were infected. 
Based on the preliminary results, VIS410 2300-mg demonstrated a statistically significant 
antiviral effect with a 76% and 91% reduction in nasopharyngeal viral load area under the curve 
(AUC) by qRT-PCR and TCID50, respectively, compared to placebo (Table 4). 
Table 4. 
Viral Load and AUC Data 
Viral Measure 
Placebo 
(n = 7) 
VIS410 
(n = 13) 
Reduction  
(%) 
P Value a 
Median viral AUC TCID50 (log10 x hours/mL) 
552 
47 
91 
0.019 
Median viral AUC qPCR (log10 x hours/mL) 
1033 
232 
76 
0.024 
Median peak viral load TCID50 (log10/mL) 
5.0 
2.75 
2.25 
0.009 
Median peak viral load qPCR (log10/mL) 
7.1 
5.6 
1.53 
0.043 
a 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. 
1.3.2.2 
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 the infusion, these AEs were all considered possibly related to the study drug. In 
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subsequent cohorts, the addition of a pretreatment regimen 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 analysis was 
conducted 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, virologic 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 (Group 1); 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 Group 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 4600-mg dose of VIS410 
following viral challenge. Overall, 4600 mg of 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; one 
event was considered unrelated to study drug. 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. 
1.3.3 
Phase 1 Study (VIS410-102) 
The Phase 1 study (VIS410-102) is a Phase 1, randomized, placebo-controlled study to evaluate 
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 as 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). 
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The 3800-mg VIS410 dose was evaluated as 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 is presented in 
Section 1.3.3.1. 
1.3.3.1 
Preliminary Safety Data 
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 the 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 aspirin 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 aspirin) mitigated the GI events compared with the no-pretreatment cohorts. The 
rate (13 GI events in 7 subjects) and severity of events (12 of 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 aspirin 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 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; 1 of the 
2 subjects reported mild nausea as well. 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, 1 subject at the 3800-mg dose 
discontinued study drug infusion due to AEs of nausea, vomiting, chills, and hot flashes. 
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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/nonsteroidal 
anti-inflammatory drug (NSAID), such as ibuprofen or aspirin, to an antihistamine was necessary 
to further reduce the frequency and severity of the 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’s Brochure.8 
 
Overall Rationale for the Study 
1.4
Visterra is developing VIS410, a fully human IgG1 antibody, as a broad spectrum therapeutic 
agent against all strains of influenza A virus. New alternative treatments for influenza are 
urgently needed. Severe influenza disease occurs seasonally in many high-risk groups, such as 
young children, older adults, patients with pulmonary conditions, inflammatory conditions, 
malignancies, and pregnant women.1,2 Current influenza therapies are limited to the 
neuraminidase inhibitors, including oseltamivir (Tamiflu), zanamivir (Relenza) and peramivir 
(Rapivab). In spite of these available treatments, 10% to 44% of hospitalized patients require 
intensive care, and 25% to 50% of these patients die. In the United States, it is estimated that as 
many as 400,000 patients are hospitalized with influenza each year, with up to 49,000 deaths per 
year.3 A comparison of annual mortality rates from infectious disease in the United States further 
demonstrates the lack of effective interventions against this deadly disease (Table 5). 
Table 5. 
Annual Mortality Rates from Infectious Diseases in the United States 
Disease 
Approximate No. of  
Deaths per Year 
Influenza (varies by season) 
25,000-49,000 
Methicillin-resistant Staphylococcus aureus (2005) 
18,650 
Hepatitis C (2007) 
15,000 
Acquired immune deficiency syndrome (2007) 
12,700 
Invasive pneumococcal disease from Streptococcus pneumoniae (2009) 
5,000 
Hepatitis B 
1,800 
Furthermore, certain strains of influenza have comparatively high mortality rates: the 1918 
H1N1 Spanish flu strain resulted in deaths of 1% to 3% of the world’s population, compared 
with the 1968 pandemic strain that killed 0.03% of the world’s population. In more recent years, 
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avian H5 and H7 strains have been documented to have 33% to 60% mortality rates despite the 
use of currently licensed antiviral treatments. Furthermore, the continued emergence of 
resistance to current antiviral drugs increases the need for new therapeutics. 
This study will be used to determine the efficacy and safety of VIS410 in hospitalized subjects 
with influenza A infection requiring oxygen support, and is an important study for progression of 
the program toward evaluating VIS410 in severe influenza and those at high risk. 
 
Risk-Benefit Analysis 
1.5
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 study VIS-C001 in 41 subjects (see 
Section1.3.1), 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. Based 
on preliminary data from the Phase 2a challenge study (VIS410-201), administration of 2300 mg 
of VIS410 in the context of an influenza infection resulted in 6 of 12 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 9 pretreated subjects 
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 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 were mostly related 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. 
The pretreatment regimen of diphenhydramine with an NSAID (ibuprofen or acetylsalicylic 
acid) was further evaluated in a Phase 1 study and was shown to be safe and well tolerated with 
minimal GI AEs. 
Considering the potential benefit of VIS410 in the treatment of severe influenza A infection and 
the types and severity of AEs observed to date following a pretreatment regimen of an 
antihistamine and an NSAID, the benefit outweighs the risk of further evaluation of VIS410 in 
more severe influenza A infection in hospitalized subjects. 
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1.5.1 
Potential Risks 
1.5.1.1 
Potential Risks of VIS410 Administration 
The potential human toxicity of VIS410 should be evaluated in the context of the human 
experience in clinical studies. As described in Section 1.3, GI AEs, such as transient loose 
stool/diarrhea and abdominal cramping, were the most commonly observed AEs in the clinical 
studies. The frequency and severity of these events were greatly mitigated with administration of 
a pretreatment regimen consisting of an antihistamine and an NSAID. 
In mice treated with 4 doses of VIS410 over 14 days, 14 of 384 animals had severe systemic 
hypersensitivity (anaphylaxis) with death within 1 to 2 hours after the fourth dose. 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. ADAs were found in 
8 animals at the end of the 28-day recovery period; other human antibodies have elicited ADA in 
mice without clinical problems in humans. 
Administration of VIS410, IV once weekly for 4 weeks in 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 or immune modulating cytokines often administered as multiple doses 
over a long period) will be observed with VIS410.  
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 with an NSAID (ibuprofen or acetylsalicylic acid) 
substantially 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 
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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. 
For more detailed information on VIS410, refer to the current Investigator’s Brochure.8 
1.5.1.2 
Potential Risks of Oseltamivir Administration 
Oseltamivir (Tamiflu) is indicated for the treatment of uncomplicated influenza infection in 
patients who have been symptomatic for no more than 2 days. 
Oseltamivir is contraindicated in patients with known hypersensitivity to any of the components 
of the product. 
The following reactions have also been reported following treatment with oseltamivir therapy 
during clinical studies or post-marketing: 
 Body as a whole: Swelling of the face or tongue, allergy, anaphylactic/anaphylactoid 
reactions 
 Dermatologic: Dermatitis, rash, eczema, urticaria, erythema multiforme, Stevens-
Johnson syndrome, toxic epidermal necrolysis 
 Digestive: Hepatitis, liver function tests abnormal 
 Cardiac: Arrhythmia 
 Gastrointestinal: Nausea, vomiting, GI bleeding, hemorrhagic colitis 
 Neurologic: Seizure 
 Metabolic: Aggravation of diabetes 
 Psychiatric: Delirium, including symptoms such as altered level of consciousness, 
confusion, abnormal behavior, delusions, hallucinations, agitation, anxiety, 
nightmares 
For more information, refer to the prescribing information for oseltamivir.9 
1.5.1.3 
Potential Risks of Diphenhydramine, Ibuprofen, and Acetylsalicylic Acid 
Administration 
The risk associated with the use of a single over-the-counter dose of diphenhydramine, 
ibuprofen, and acetylsalicylic acid in this study is considered low. 
Many of the adverse reactions due to NSAIDs, such as acetylsalicylic acid or ibuprofen, are dose 
and duration dependent. 
Ibuprofen and acetylsalicylic acid are contraindicated in patients with known hypersensitivity to 
NSAIDs and acetylsalicylic acid–induced asthma. Ibuprofen is contraindicated for treatment of 
perioperative pain in the setting of coronary artery bypass graft surgery. 
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Ibuprofen may cause an increased risk of serious cardiovascular thrombotic events, myocardial 
infarction, and stroke, which can be fatal. Patients with cardiovascular disease or risk factors for 
cardiovascular disease may be at greater risk. 
NSAIDs cause an increased risk of serious GI AEs, including bleeding, ulceration, and 
perforation of the stomach or intestines, which can be fatal. Elderly patients are at greater risk for 
serious GI events. 
Long-term administration of NSAIDs has resulted in renal injury. Patients at greatest risk of this 
reaction are those with impaired renal function, heart failure, liver dysfunction, those taking 
diuretics and ACE inhibitors, and the elderly. NSAIDs should be avoided in patients with severe 
renal failure. 
NSAIDs can cause serious skin AEs, such as exfoliative dermatitis, Stevens-Johnson syndrome, 
and toxic epidermal necrolysis. 
Acetylsalicylic acid can result in GI side effects, such as stomach pain, heartburn, nausea, 
vomiting, dyspepsia, and GI bleed. Patients with history of active peptic ulcer disease should 
avoid acetylsalicylic acid. 
The following adverse reactions have been reported following acetylsalicylic acid 
administration: 
 Body as a whole: Fever, hypothermia, thirst 
 Cardiovascular: Dysrhythmias, hypotension, tachycardia 
 Central nervous system: Agitation, cerebral edema, coma, confusion, dizziness, headache, 
subdural or intracranial hemorrhage, lethargy, seizures 
 Fluid and electrolyte: Dehydration, hyperkalemia, metabolic acidosis, respiratory alkalosis 
 Gastrointestinal: Dyspepsia, GI bleeding, ulceration and perforation, nausea, vomiting, 
transient elevations of hepatic enzymes, hepatitis, Reye syndrome, pancreatitis 
 Hematologic: Prolongation of the prothrombin time, disseminated intravascular coagulation, 
coagulopathy, thrombocytopenia 
 Hypersensitivity: Acute anaphylaxis, angioedema, asthma, bronchospasm, laryngeal edema, 
urticaria 
 Musculoskeletal: Rhabdomyolysis 
 Metabolism: Hypoglycemia (in children), hyperglycemia 
 Reproductive: Prolonged pregnancy and labor, stillbirths, lower birth weight infants, 
antepartum and postpartum bleeding 
 Respiratory: Hyperpnea, pulmonary edema, tachypnea 
 Special senses: Hearing loss, tinnitus. Patients with higher frequency hearing loss may have 
difficulty perceiving tinnitus. In these patients, tinnitus cannot be used as a clinical indicator 
of salicylism. 
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 Urogenital: Interstitial nephritis, papillary necrosis, proteinuria, renal insufficiency and 
failure 
For more information, refer to the prescribing information for ibuprofen10 and acetylsalicylic 
acid.11 
Diphenhydramine is contraindicated in patients with hypersensitivity to diphenhydramine 
hydrochloride and other antihistamines of similar chemical structure. Antihistamines should be 
used with caution in patients with narrow-angle glaucoma, stenosing peptic ulcer, 
pyloroduodenal obstruction, symptomatic prostatic hypertrophy, or bladder-neck obstruction. 
Diphenhydramine may cause drowsiness, and patients should be warned about engaging in 
activities requiring mental alertness, such as driving a car or operating appliances, machinery, 
etc. Diphenhydramine may diminish mental alertness, and is more likely to cause dizziness, 
sedation, and hypotension in elderly patients. 
Diphenhydramine should be used with caution in patients with a history of bronchial asthma, 
increased intraocular pressure, hyperthyroidism, cardiovascular disease, or hypertension. 
The following reactions have also been reported following treatment with diphenhydramine: 
 General: Urticaria, drug rash, anaphylactic shock, photosensitivity, excessive perspiration, 
chills, and dryness of mouth, nose, and throat 
 Cardiovascular: Hypotension, headache, palpitations, tachycardia, extrasystoles 
 Hematologic: Hemolytic anemia, thrombocytopenia, agranulocytosis 
 Central nervous system: Sedation, sleepiness, dizziness, disturbed coordination, fatigue, 
confusion, restlessness, excitation, nervousness, tremor, irritability, insomnia, euphoria, 
paresthesia, blurred vision, diplopia, vertigo, tinnitus, acute labyrinthitis, neuritis, 
convulsions 
 Gastrointestinal: Epigastric distress, anorexia, nausea, vomiting, diarrhea, constipation 
 Genitourinary: Urinary frequency, difficult urination, urinary retention, early menses 
 Respiratory: Thickening of bronchial secretions, tightness of chest or throat and wheezing, 
nasal stuffiness 
For more information, refer to the prescribing information for diphenhydramine.12 
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. 
At this time, the actual benefits of VIS410 for the treatment of influenza patients are unknown. 
However, data from a recently conducted Phase 2a human challenge study in 31 healthy 
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volunteers given influenza A demonstrated a statistically significant reduction in viral AUC 
following treatment with VIS410 compared with placebo with a shorter duration of symptoms 
(2 days) in the VIS410-treated group compared with the placebo group. 
1.5.3 
Dose Selection Rationale 
A variety of methods were utilized to determine the efficacious dose of VIS410 for the treatment 
of influenza in humans. These methods included evaluating doses and exposures to ascertain the 
VIS410 levels that satisfied such in vitro susceptibility measures as neutralization EC50 and 
binding affinity; utilizing mg/kg dose and PK data to bridge the efficacious dose from preclinical 
species to humans; and performing exploratory PK/PD analyses of serum and nasal exposure vs 
VIS410 antiviral activity in a human influenza virus challenge study. 
VIS410 broadly 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 
hemagglutinin across Group 1 and Group 2 subtypes. VIS410 doses of approximately 2300 mg, 
as used in the human challenge model, will result in Cmax serum levels of ~873 µg/mL for the 
duration of viral shedding (well above the median of EC50 value of 3.15 µg/mL). 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 a 1500- to 2300-mg dose 
in humans (assuming a 75-kg subject). 
In a human influenza virus challenge study, a single dose of 2300 mg demonstrated a significant 
reduction in viral 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 2b 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 study, doses of 2300 and 3800 mg were well tolerated following a pretreatment 
regimen of diphenhydramine plus ibuprofen or acetylsalicylic acid. 
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2.0 
STUDY OBJECTIVES 
 
Primary Objectives 
2.1
2.1.1 
Primary Efficacy Objective 
 Evaluation of the effect of 2 dose levels of VIS410 + oseltamivir on clinical outcome as 
assessed by comparison of clinical status ordinal scale Day 7 scores between treatment 
groups, and between all VIS410 recipients versus placebo.   
2.1.2 
Primary Safety Objective 
 Safety and tolerability of 2 dose levels of a single IV dose of VIS410 when administered in 
combination with oseltamivir in hospitalized subjects with influenza A infection 
 
Secondary Objectives 
2.2
 Among patients requiring supplemental oxygen therapy at the time of enrollment with 
baseline room air oxygen saturation of ≤ 92%, time to cessation of oxygen (O2) support 
resulting in stable oxygen saturation (SpO2) by pulse oximetry. Stable SpO2 is defined as two 
consecutive SpO2 values of > 92% on room air that are at least 8 hours apart. 
 For any patient requiring supplemental oxygen therapy at the time of enrollment (regardless 
of oxygen saturation), time to cessation of oxygen support. 
 Evaluate the effect of VIS410 + oseltamivir vs oseltamivir alone on the following endpoints: 
 Viral load in upper respiratory samples 
 Time to clinical response 
 Time to cessation of ventilator support 
 Time to resumption of normal activities 
 All-cause and attributable Day 14, 28, and 56 mortality 
 Clinical status ordinal scale mean area under the curve for Days 1-7 and Days 1-14 using 
linear numeric scores for the ordinal categories. 
 Comparison of clinical status ordinal scale scores for selected individual days (ie, Days 3, 
4, 5, and 6)  
 Comparison of clinical status ordinal scale scores using modified ordinal scale criteria 
(ie, pooling of selected severity criteria scores) 
 
Comparison of discrete ordinal scale parameters, including days of ventilator support, 
days in intensive care, and duration of hospitalization 
 Healthcare resource utilization 
 Analysis of time to alleviation of signs and symptoms of influenza in the subset of 
subjects able to complete the Influenza Patient Reported Outcomes (FluPRO) 
Questionnaire at baseline and post-dose by Kaplan Meier analysis 
 Proportion of subjects with new documented bacterial pneumonia/superinfection 
 Proportion of subjects with influenza-related complications 
 Pharmacokinetics of VIS410 in serum 
 Immunogenicity of VIS410 
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 Emergence of resistance to VIS410 and oseltamivir 
 
Exploratory Objectives 
2.3
 Evaluate the pharmacokinetics of VIS410 from nasopharyngeal secretions and tracheal 
aspirate (ventilated subjects only) 
 Assess the effects of VIS410 on viral load in tracheal aspirate (ventilated subjects only) 
 Assess correlations between virology, safety, VIS410 dose, pharmacokinetics, viral shedding, 
immunology, signs and symptoms of influenza, and other endpoints 
 Assess the anti-influenza immune response 
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3.0 
STUDY ENDPOINTS 
 
Primary Endpoints 
3.1
3.1.1 
Primary Efficacy Endpoint 
 The primary efficacy outcome analysis compares Day 7 clinical status ordinal scale scores 
between treatment groups, and between all VIS410 recipients versus placebo. Clinical status 
is measured daily for 14 days using the below seven-level ordinal scale, with the 
classifications presented from the worst clinical outcome to the best clinical outcome in 
descending order; for each day, subject status will be classified by the worst clinical outcome 
for which they qualify  
 Death 
 ICU stay with mechanical ventilation 
 ICU stay without mechanical ventilation 
 Non-ICU hospitalization with supplemental oxygen 
 Non-ICU hospitalization without supplemental oxygen 
 Discharge with partial resumption of normal activities 
 Discharge with full resumption of normal activities 
3.1.2 
Primary Safety Endpoint 
 The proportion of subjects with AEs and SAEs following administration of VIS410. 
 
Secondary Endpoints 
3.2
 Among patients requiring supplemental oxygen therapy at the time of enrollment with 
baseline room air oxygen saturation of ≤ 92%, time to cessation of oxygen (O2) support 
resulting in stable oxygen saturation (SpO2) by pulse oximetry. Stable SpO2 is defined as two 
consecutive SpO2 values of > 92% on room air that are at least 8 hours apart. 
 For any patient requiring supplemental oxygen therapy at the time of enrollment (regardless 
of oxygen saturation), time to cessation of oxygen support. 
 The difference between VIS410 + oseltamivir and oseltamivir alone treatment groups in the 
following endpoints: 
 Peak viral load, viral AUC, duration of viral shedding, and time to resolution of viral load 
from nasopharyngeal swabs by TCID50 and qRT-PCR 
 Time to clinical response defined as resolution of at least 4 of 5 vital signs 
 Afebrile with core temperature ≤ 37.8°C, without use of antipyretics (oral ≤ 37.2°C) 
 Oxygen saturation ≥ 95% on room air without support or a return to pre-infection 
status, if pre-infection status was < 95% 
 Pulse rate ≤ 100/min 
 Systolic blood pressure ≥ 90 mm/Hg, without vasopressor use 
 Respiratory rate ≤ 24 beats per minute 
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 Clinical status ordinal scale mean area under curve for Days 1-7 and Days 1-14, using 
linear numeric scores for the ordinal categories. 
 Comparison of clinical status ordinal scale scores for selected individual days (ie, Days 3, 
4, 5, and 6)  
 Comparison of clinical status ordinal scale scores using modified ordinal scale criteria 
(ie, pooling of selected severity criteria scores) 
 Comparison of discrete ordinal scale parameters, including days of ventilator support, 
days in intensive care, and duration of hospitalization 
 Number of days to resumption of usual activities 
 All-cause and attributable mortality rates at Day 14, 28, and 56 
 Total number of days in hospital and/or intensive care unit (ICU) from admission to 
discharge and rate of rehospitalization due to influenza A relapse/complication 
 The incidence, severity, and duration of signs and symptoms of influenza-like illness as 
assessed by the FluPRO Questionnaire (see Appendix 14.1) 
 Analysis of time to alleviation of signs and symptoms of influenza in the subset of 
subjects able to complete the Influenza Patient Reported Outcomes (FluPRO) 
Questionnaire at baseline and post-dose by Kaplan Meier analysis 
 The percentage of subjects with new bacterial pneumonia/superinfection 
 The percentage of subjects with influenza-related complications 
 VIS410 population pharmacokinetic (PK) parameters in serum 
 Titer of anti-VIS410 antibody positive samples 
 Genotypic and/or phenotypic assessment to determine the emergence of VIS410 and 
oseltamivir-resistant viruses 
 
Exploratory Endpoints 
3.3
 Population PK parameters of VIS410 from nasopharyngeal secretions 
 VIS410 concentrations in tracheal aspirates 
 The difference in viral load between VIS410 + oseltamivir and oseltamivir alone treatment 
groups in tracheal aspirates of subjects on mechanical ventilation 
 Titer of anti-influenza A antibodies by hemagglutinin inhibition assay (HAI) in serum 
 Correlations between serum and/or nasopharyngeal PK with viral load, clinical symptoms, 
presence of ADAs, safety, and additional endpoints 
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4.0 
STUDY DESIGN 
 
Overview 
4.1
This is a Phase 2b multicenter, randomized, double-blind, controlled study comparing the 
efficacy and safety of 2 dose levels of VIS410 (2000 and 4000 mg) in combination with 
oseltamivir vs oseltamivir alone in hospitalized subjects with influenza A infection requiring 
oxygen. Subjects will be randomly assigned at a ratio of 1:1:1 using a permuted block 
randomization method to receive VIS410 at a dose of 2000 mg (low dose) or 4000 mg (high 
dose) or placebo (0.9% sodium chloride), administered as a single IV infusion over 2 hours. 
Randomization will be stratified by presence or absence of positive pressure ventilation (PPV) at 
baseline to ensure an even distribution across treatment arms (see Section 10.2). All subjects will 
receive oseltamivir 75 mg twice daily (BID) for 5 days (total of 10 doses) as part of standard of 
care (SOC). All subjects will also receive a pretreatment regimen of diphenhydramine 50 mg PO 
or IV plus either ibuprofen 400 mg PO or acetylsalicylic acid 320-325 mg PO 60 minutes before 
VIS410/placebo infusion. Approximately 120 evaluable subjects (40/arm) with confirmed 
influenza A infection will be treated.  
Subjects admitted to the hospital within 5 days of onset of initial symptoms who require 
supplemental oxygen will undergo a rapid influenza test (supplied by the Sponsor) or a PCR, 
fluorescent immunoassay (FIA), or enzyme-linked immunosorbent assay (ELISA) test to 
confirm influenza A infection. Subjects diagnosed with influenza A will undergo the screening 
procedures to confirm eligibility. Study assessments are outlined in Table 1, Schedule of 
Assessments. 
Eligible subjects will be randomized to receive either oseltamivir + VIS410 2000 mg, oseltamivir 
+ VIS410 4000 mg, or oseltamivir + placebo (0.9% sodium chloride) at a ratio of 1:1:1 using a 
permuted block randomization method summarized in Table 6. 
Table 6. 
Permuted Block Randomization Method 
Subjects 
Treatment 
VIS410 Dose a 
Oseltamivir Dose b 
Infusion 
n = 40 
VIS410 + oseltamivir 
2000 mg IV 
75 mg administered BID 
for a minimum of 5 days  
Infused over 
120 minutes 
n = 40 
VIS410 + oseltamivir 
4000 mg IV 
n =40 
Placebo c + oseltamivir 
0 mg IV 
a Dose administered in 200 mL. 
b Dosage and administration should follow local prescribing information for oseltamivir based on renal function. 
c 0.9% sodium chloride (200 mL). 
Oseltamivir (Tamiflu) will be provided by the Sponsor. Treatment with oseltamivir may be 
extended for up to 5 additional days (up to 20 doses of total therapy) if clinical symptoms 
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warrant further treatment as assessed by the Investigator. Note: based on SOC, subjects may 
have started oseltamivir therapy prior to randomization.  
Study assessments are outlined in Table 1. Subjects discharged from the hospital prior to Day 14 
will attend the applicable outpatient follow-up visit(s) (eg, Day 3, Day 5, Day 7, Day 14) per 
Table 1. 
 
Study Duration 
4.2
The total study duration for each subject (screening through study exit) will be approximately 
8 weeks (Day 56). 
 
Data Safety Monitoring Board 
4.3
An independent data safety monitoring board (DSMB) will be established to review all available 
safety data after 30 subjects, and subsequently, approximately 70 subjects, have completed study 
Day 14. The assessment of safety will be determined from vital sign measurements, physical 
examinations, hematology, chemistry and urinalysis laboratory testing, 12-lead 
electrocardiograms (ECGs), use of concomitant medications, and review of AEs. Based on the 
safety data provided, the DSMB will determine if it is acceptable to continue the study or reduce 
the dose as appropriate. 
Additional DSMB reviews can occur throughout the trial as deemed necessary by the DSMB or 
Sponsor to ensure subject safety and well-being. Study enrollment and dosing will continue 
while the DSMB evaluates data. 
Further details will be described in a separate DSMB charter. 
 
Discussion of Study Design 
4.4
This study is a Phase 2b, multicenter, randomized, double-blind study of 2 doses of VIS410 vs 
placebo in the treatment of hospitalized subjects with influenza A infection requiring oxygen 
support. VIS410 and placebo will be administered on top of the SOC, ie, oseltamivir. 
The dose of oseltamivir (75 mg BID for 5 days) was chosen for this study based on the approved 
dose in the United States and other regions for the treatment of uncomplicated influenza 
infection. The dosage regimen of oseltamivir as the SOC in this study serves as a clinically 
appropriate, ethically acceptable treatment. 
The study will be blinded using placebo infusion (as described in Section 7.2) to prevent bias in 
the assessment of effect. The investigative site personnel, the Sponsor and their representatives 
involved in the monitoring or conducting the study, and the subjects will all be blinded to the 
study drug codes. 
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5.0 
STUDY POPULATION 
 
Number of Subjects 
5.1
Approximately 120 evaluable subjects will be randomized into 3 treatment arms: VIS410 
2000mg, VIS410 4000 mg, and placebo. 
 
Selection of Study Population 
5.2
The study population comprises subjects at least 18 years of age with confirmed influenza A 
infection who satisfy all inclusion and exclusion criteria, and who do not have any conditions, in 
the opinion of the Investigator, that may place the subject(s) at increased risk, confound study 
data, or significantly interfere with study participation. Section 5.2.1 and Section 5.2.2, which 
describe the inclusion and exclusion criteria, respectively. 
5.2.1 
Inclusion Criteria 
Subjects meeting all of the following criteria are eligible to participate in this study: 
1. Male and female subjects aged ≥ 18 years. For a country where the legal age of consent is 
>18 years old, the country requirements should be followed. 
2. Test positive for influenza A by rapid antigen test or with another commercially available test 
on an adequate nasopharyngeal specimen in accordance with the manufacturer's instructions, 
or an acceptable local test including, PCR, FIA, or ELISA. 
3. Onset of influenza symptoms no more than 5 days before VIS410/placebo infusion; 
symptoms may include cough, dyspnea, sore throat, fever, myalgias, headache, nasal 
symptoms (rhinorrhea, congestion), fatigue, diarrhea, anorexia, nausea, and vomiting. 
4. Requirement for oxygen support including any positive pressure ventilation (PPV). 
5. Women of childbearing potential must have a negative pregnancy test within 2 days prior to 
VIS410/placebo infusion. 
6. 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 relations must be 
willing to use adequate contraception from screening until 60 days 
post-VIS410/placebo infusion (see Section 6.2). 
7. 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 6.2) when having heterosexual intercourse, from screening until 60 days 
post-VIS410/placebo infusion. 
8. Subject is able and willing to comply with study procedures, as per protocol. 
9. Subject, or a legally acceptable representative, is able to understand the purpose and risks of 
the study and willing to give voluntary written informed consent. 
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5.2.2 
Exclusion Criteria 
Subjects meeting any of the following criteria are excluded from participation in this study: 
1. Known or suspected intolerance or hypersensitivity to VIS410, oseltamivir, pretreatment 
medications (diphenhydramine, or to both ibuprofen and acetylsalicylic acid [ASA]), or 
closely related compounds (eg, other monoclonal antibodies). 
2. Subjects who have received VIS410 in the past.  
3. Subjects who have a history of receiving monoclonal antibody products within 3 months 
prior to VIS410/placebo dosing or planned administration of another monoclonal antibody 
during the study period. 
4. Subjects who have taken more than 6 doses of an approved antiviral therapy for influenza 
within the prior 96 hours (eg, oral oseltamivir, inhaled zanamivir, IV peramivir, or oral 
ribavirin) between onset of symptoms and VIS410/placebo dosing. 
5. Subjects with known co-infection with influenza B or other viral respiratory infections (eg, 
RSV, parainfluenza viruses, respiratory adenoviruses). 
6. Subjects with lung transplant or history of severe chronic lung disease, including cystic 
fibrosis or any condition requiring home oxygen therapy. 
7. Subjects on extracorporeal membrane oxygenation at time of randomization. 
8. Subjects with ESRD who are not undergoing hemodialysis. 
9. Subjects with active graft-vs-host disease, hematopoietic stem cell transplant within the 
previous 90 days, or human immunodeficiency virus infection with a CD4 cell count of less 
than 200 per cubic millimeter. 
10. High probability of mortality within 48 hours of randomization as determined by the 
Investigator. 
11. Women who are pregnant, breast-feeding, or considering to become pregnant. 
12. Subjects in whom nasopharyngeal swabbing is not possible. 
13. Subjects weighing less than 45 kg. 
14. 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. 
15. Presence of any preexisting illness that, in the opinion of the Investigator, would place the 
subject at an unreasonably increased risk through participation in this study. 
16. Subjects unable to comply with study protocol procedures and study visit schedules for 
whatever reason. 
17. 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. 
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6.0 
STUDY ASSESSMENTS 
Table 1 summarizes the schedule for study visits and procedures performed at each study visit. 
 
Prescreening, Screening, and Study Procedures 
6.1
6.1.1 
Prescreening Procedures 
Subjects may be asked to sign a Prescreening Consent prior to undergoing a single 
nasopharyngeal swab (one nostril) for rapid influenza A testing. Subjects will be given a full 
explanation of the nature of the study and provide full written informed consent before any 
study-specific assessments or procedures are performed. Note: subjects that tested positive for 
influenza A within 48 hours prior to screening do not need to be retested. 
6.1.2 
Screening Procedures 
Subjects will be given a full explanation of the nature of the study, provide full written informed 
consent before any study-specific assessments or procedures are performed, and undergo full 
screening procedures. 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. Table 1 
lists the procedures performed at screening. Screening and baseline assessments (ie, Day 1 
evaluations and procedures) may be performed on the same day. 
6.1.3 
Study Procedures 
On Day 1, eligibility of the subjects will be confirmed and assessments will be performed as 
described in Table 1. 
All results from the screening procedure needed to evaluate eligibility, including any local 
clinical laboratory results, must be available prior to randomization on Day 1. All clinical 
assessments required for the determination of subject eligibility will be performed by the local 
clinical laboratory, thereby precluding the need to wait for central laboratory data. 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. 
Once a subject has satisfied entry criteria, he/she will be assigned a unique identifier. The site’s 
unblinded pharmacist or properly trained designee will access the Interactive Web Response 
System (IWRS) to obtain the study treatment. Randomization will be stratified by presence or 
absence of PPV at baseline to ensure balance between the treatment arms. Subjects will be 
considered randomized when the pharmacist or designee obtains the subject number and 
treatment assignment from the IWRS. 
Subjects may not be randomized into this study more than once. Subjects who have participated 
in any previous study of VIS410 may not be randomized to this study. Subjects will be 
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monitored daily while in the hospital up to Day 14 (± 3 days) with an additional visit on Day 28 
(± 3 days) and the last follow-up visit on Day 56 (± 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. 
Note: subjects discharged from the hospital prior to Day 14 will attend the applicable outpatient 
follow-up visit(s) (eg, Day 3, Day 5, Day 7, Day 14). 
6.1.4 
Unscheduled Visits 
Unscheduled visits can be planned at the discretion of the Investigator to obtain additional 
information to ensure the safety of the subject. 
Unscheduled visits may be planned to assess, confirm, and follow up on out-of-range clinical 
laboratory test, vital sign, or ECG values that determine a subject’s eligibility. Findings made 
during unscheduled visits should be recorded in the EDC system and the source documents. 
Subjects will be instructed to contact the trial center if they exhibit worsening of symptoms or a 
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. 
6.1.5 
Early Withdrawal Procedures 
Subjects should be encouraged to complete all study assessments. However, subjects who 
terminate the study before completion of the scheduled study procedures for any reason (AE, 
withdrawal of consent, etc.) should be encouraged to complete the early termination assessments 
(ie, identical to end of therapy [ET] assessments), including safety, prior to withdrawal, if 
possible. 
6.1.6 
Treatment of VIS410 Overdose 
Given the absence of previous instances of VIS410 overdosing, clinicians have no specific 
treatment for the treatment of VIS410 overdose. However, high doses (ie, up to 4600 mg) have 
been evaluated in clinical study without any incidents of significant toxicity. In the event of 
VIS410 overdose, treatment administered to the subject(s) should be symptomatic and 
supportive. 
Any overdose in this clinical study, with or without associated AEs, must be reported to the 
contract research organization (CRO) according to the procedures for SAE reporting as outlined 
in Section 9.7.1 and Section 9.7.2. All reports of overdose must be documented in the EDC. Any 
AEs associated with the overdose should be reported on relevant AE/SAE sections in the EDC. 
 
Pregnancy Safeguards 
6.2
Pregnancy will be determined by evaluation of β-human chorionic gonadotropin in serum or 
urine for all women of childbearing potential. Subjects who are pregnant or nursing will be 
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excluded from the study. During the course of the study drug administration period within the 
study, any nursing mother(s) or subject(s) with suspected or confirmed pregnancy will be 
discontinued from study drug therapy but will be encouraged to undergo follow-up for safety 
monitoring for themselves (ie, the pregnant female) and the baby. 
All women of childbearing potential and all male subjects must practice effective contraception 
from screening until 60 days post-VIS410/placebo infusion. For the purposes of this study, 
women who do not satisfy at least one of the following criteria listed below (ie, the criteria for 
defining non-childbearing potential) are considered to be physiologically capable of becoming 
pregnant and are, therefore, defined as women of childbearing potential. 
The criteria for defining women as being of non-childbearing potential are: 
 Post-menopausal: ≥ 12 months of natural (spontaneous) amenorrhea, or 
 Follicle stimulating hormone > 40 mIU/mL as documented in their medical history, 
or 
 Surgical bilateral oophorectomy with or without hysterectomy, or 
 Hysterectomy, or 
 Bilateral tubal ligation 
Women of childbearing potential and all male subjects participating in heterosexual relations 
must be willing to practice effective contraception from screening until 60 days 
post-VIS410/placebo infusion. For the purposes of the study, highly effective contraception is 
defined as: 
 Male vasectomy with negative semen analysis documentation at least 6 months prior 
to dosing.  
OR 
 Combination of an established form of hormonal contraception (oral, injected, or 
implanted) or an intrauterine device or intrauterine system or sponge 
Plus one of the following: 
 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. OR 
 Male vasectomy with negative semen analysis documentation less than 6 months 
prior to dosing. OR 
 Complete abstinence can be considered an acceptable method of contraception at the 
discretion of the Investigator. Periodic abstinences (eg, calendar, ovulation, 
symptothermal, or post-ovulation methods) and withdrawal are NOT considered 
acceptable methods of contraception. 
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The combination of 2 barrier methods, periodic abstinence (eg, calendar, ovulation, 
symptothermal, or post-ovulation methods), and withdrawal are not considered acceptable 
methods of contraception. 
Male subjects should not donate sperm for at least 60 days after receipt of study product. 
Pregnancy reporting is described in Section 9.7.3. 
 
Procedures for Sample and Data Collection 
6.3
6.3.1 
SpO2 Oxygen Support 
Baseline SpO2 on room air to be documented, if available. Once randomized, SpO2 will be 
measured using pulse oximetry 3 times per day (approximately every 8 hours) at approximately 
the same time each day until stable according to Table 1. Stable SpO2 is defined as two 
consecutive SpO2 values of > 92% on room air that are at least 8 hours apart. 
6.3.2 
Viral Load 
A nasopharyngeal swab will be collected from each nostril as described in Table 1 and 
Laboratory Manual. These swabs will be sent to a central virology laboratory for processing into 
appropriate aliquots for virology and PK analysis. Further details on sample collection, 
processing, shipment, and storage will be described in the Laboratory Manual. 
The Investigator may also perform additional tests in the local laboratory consistent with SOC 
for the illness being treated. 
Note: Virology samples taken from all subjects may be infectious and will be classified as 
“diagnostic specimens” for dispatch purposes. 
6.3.3 
Time to Cessation of Ventilator Support 
Start and stop time for mechanical ventilation will be documented in EDC. 
6.3.4 
Resumption of Normal Activities 
Subjects will complete a visual analog scale (VAS) daily from Day 1 (baseline) until either the 
subject reports that all usual activities (prior to influenza onset) can be performed or Day 56, 
whichever comes first. The VAS scale ranges from 0 to 10, where 0 indicates subject is unable to 
perform usual activities at all, and 10 indicates subject is able to perform all usual activities 
fully) 
6.3.5 
Health Resource Utilization 
The following parameters for health resource utilization will be documented on an ongoing basis 
during the study: 
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 Hospital admission and discharge date 
 ICU admission and discharge date 
 Rehospitalization and reason for rehospitalization up to the last follow-up visit 
(Day 56 ± 7 days) 
6.3.6 
Signs and Symptoms of Influenza 
The Influenza Patient-Reported Outcome (FluPRO) Questionnaire (see 14.1) must be completed 
(ie, self-reported) by the subject at baseline (Day 1) and post-dose as defined in  
Table 1. Each subject will be evaluated at baseline to determine if subject is able to 
independently report his/her influenza signs and symptoms. Subjects who are not able to 
complete the baseline FluPRO Questionnaire are exempt from this assessment throughout the 
study. The subject’s inability to self-report his/her symptoms of influenza at baseline should be 
documented in the EDC. 
6.3.7 
Serum Pharmacokinetics 
Throughout the study, 5-mL venous blood samples will be collected for analysis of VIS410 in 
serum, according to the time points defined in Table 1. The exact date and time of blood 
sampling and of administration of the study drug must be recorded in the EDC system. Serum 
samples for determination of the concentration of VIS410 will be analyzed under the 
responsibility of the Sponsor. Further procedures for sample collection, shipment, processing, 
and storage will be described in the Laboratory Manual. 
6.3.8 
Viral Resistance 
Samples for virologic and PK analysis will be collected as described in Table 1 and the 
Laboratory Manual. These samples will be sent to a central virology laboratory for processing 
into appropriate aliquots for virology and PK analysis, including resistance testing. 
Further procedures for sample collection, processing, shipment, and storage will be described in 
the Laboratory Manual. 
Note: Nasopharyngeal and tracheal samples taken from all subjects may be infectious and will 
be classified as “diagnostic specimens” for dispatch purposes. 
6.3.9 
Clinical Outcomes per Seven-Level Ordinal Scale 
The ordinal scale outcomes will be measured daily from Day 1 (baseline) through Day 14 using 
the following seven-level hierarchical scale with the classifications presented from the worst 
clinical outcome to the best clinical outcome in descending order. 
For each day, subjects will be classified by the worst clinical outcome for which they qualify. 
For example, a patient with both ventilation and oxygen on the hospital floor on Day 1 will be 
classified as a mechanical ventilation patient for Day 1. 
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 Death 
 ICU stay with mechanical ventilation 
 ICU stay without mechanical ventilation 
 Non-ICU hospitalization with supplemental oxygen 
 Non-ICU hospitalization without supplemental oxygen 
 Discharge with partial resumption of normal activities 
 Discharge with full resumption of normal activities 
6.3.10 
Pharmacokinetics of Nasopharyngeal Samples 
A nasopharyngeal swab will be collected from each nostril as described in Table 1 and 
Laboratory Manual. These swabs will be sent to a central virology laboratory for processing into 
appropriate aliquots for virology and PK analysis. Further details on sample collection, 
processing, shipment, and storage will be described in the Laboratory Manual. 
Note: Nasopharyngeal samples taken from all subjects may be infectious and will be classified 
as “diagnostic specimens” for dispatch purposes. 
6.3.11 
Pharmacokinetics and Viral Load in Tracheal Aspirate 
Tracheal aspirate will be obtained in subjects on mechanical ventilation, at the time points listed 
in Table 1. The samples will be sent to a central virology laboratory for processing into 
appropriate aliquots for virology and PK analysis. Samples for determination of the 
concentration of VIS410 will be analyzed under the responsibility of the Sponsor. Further details 
on sample collection, processing, shipment, and storage will be described in the Laboratory 
Manual. 
Note: Tracheal samples taken from all subjects may be infectious and will be classified as 
“diagnostic specimens” for dispatch purposes. 
6.3.12 
Immunology 
The immunology parameters under evaluation are the detection of ADA titers and 
anti-influenza A antibody titers by HAI. 
Blood samples for immunology assessments will be collected according to the time points 
defined in Table 1. Blood samples will be collected by venipuncture or via indwelling cannula in 
the forearm into standard serum separator tubes. The exact date and time of blood sampling must 
be recorded in the EDC system. Further procedures for sample collection, shipment, processing, 
and storage will be described in the Laboratory Manual. 
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6.3.12.1 
Antidrug Antibody Response 
Anti-VIS410 antibody titers will be determined by Visterra or designee. These samples may be 
stored to assess anti-VIS410 antibodies with neutralizing capabilities in accordance with local 
regulations. 
6.3.12.2 
Anti-Influenza Antibody Response 
Anti-influenza A antibody titers will be determined by Visterra or designee. 
 
Safety of Total Blood Sampling Volume 
6.4
The total volume of blood that will be drawn from each subject will be approximately 178 mL 
over the course of the study. In order to obtain additional information to ensure a subject’s 
safety, additional blood samples (up to 50 mL) may be taken at the discretion of the Investigator. 
 
Safety Evaluations 
6.5
The safety assessment in this study will be based on AEs, clinical laboratory tests, vital signs, 
electrocardiography, and physical examination, as described in the following sections. 
6.5.1 
Adverse Events 
Adverse events (AEs) will be monitored continuously from dosing 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 the completion of 
administration of VIS410/placebo 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. For detailed definitions and reporting procedures of 
AEs (see Section 9.7). 
6.5.2 
Injection Site Tolerability 
Injection site tolerability is defined as AEs demonstrating significant local injection site irritation 
or tissue damage.  
6.5.3 
Complications of Influenza 
Complications of influenza are defined as pneumonia, myocarditis, worsening of chronic 
bronchitis, sinusitis, otitis or other chronic pulmonary diseases, encephalopathy, and death. 
Complications of influenza and use of antibiotic therapy for bacterial pneumonia will be reported 
by variable, treatment group, and time point. Diagnosis of bacterial pneumonia will be based on 
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local clinical practice, usually an assessment of clinical features and any radiographic evidence 
of bacterial pneumonia (eg, infiltrate) and/or microbiologic evidence of bacterial pneumonia. 
All-cause and attributable mortality will be evaluated on Day 14 and Day 28. 
6.5.4 
Clinical Laboratory Tests 
Blood samples will be collected by venipuncture or via indwelling cannula at the time points 
indicated in Table 1. 
Appendix 14.2 lists the biochemistry, hematology, and coagulation tests that will be performed 
by the central laboratory on the safety blood samples. Note: subjects to be enrolled based on the 
Investigator’s discretion including any local laboratory results per SOC at institution.  
Creatine kinase-MB, creatinine kinase, and troponin are to be measured by the central laboratory 
in the event of a subject having chest pain. Subjects with chest pain should be managed per SOC. 
In the event of a subject exhibiting the signs and symptoms of an anaphylactic reaction, when 
possible at the time of the event, a 5-ml serum sample should be collected for further assessment 
(ie, tryptase, chymase) to be measured by the central laboratory. 
A midstream urine sample will be collected for the central laboratory for urinalysis by dipstick, 
flow cytometry, and microscopic examination. Appendix 14.2 lists the urinalysis parameters that 
will be assessed. 
A serum pregnancy test will be performed by the central laboratory for all time points indicated 
in Table 1. In addition, a negative pregnancy test (serum or urine) result within 2 days prior to 
dosing must be available from the local laboratory prior to randomization.  
For oseltamivir dosing, creatinine clearance (Cockcroft-Gault Equation) must be calculated using 
the serum creatinine value from the local laboratory prior to randomization. 
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. 
6.5.5 
Vital Signs and Body Temperature 
Vital sign parameters will be assessed after 5 minutes in supine position at the time points 
indicated in Table 1. The vital sign parameters that will be assessed are supine SBP, DBP, heart 
rate, and respiratory rate. 
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 as an AE. 
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Oral body temperature will be recorded at the end of infusion then BID while in the hospital and 
then throughout the study according to the study procedures outlined in Table 1. In cases where 
obtaining oral temperature is not possible, core temperature (eg, tympanic, axillary) will be 
obtained. 
While the patient is hospitalized, the maximum temperature should be recorded for each 12-hour 
interval (from 12 AM to 12 PM and from 12 PM to 12 AM). Fever is defined as a core body 
temperature ≥ 38°C. 
6.5.6 
Electrocardiography 
Single, 12-lead ECGs will be performed after a 5-minute rest at the time points indicated in 
Table 1. The ECG parameters assessed 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) will be the primary correction parameter.13 QTc parameters can be calculated 
subsequently if not immediately available at the site. 
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. 
6.5.7 
Physical Examination 
A complete physical examination will be performed at the time points indicated in Table 1. 
Physical examination at screening will include height and weight. To obtain the actual body 
weight, subjects must be weighed at screening. The height should be measured barefoot, if 
possible. The screening physical examination will be complete; thereafter, targeted physical 
examinations may be performed at the discretion of the Investigator. 
A complete physical examination includes examination of body systems (including, but not 
limited to, general appearance, skin, neck, eyes, ears, nose, throat, breast, lungs, heart, abdomen, 
back, lymph nodes, extremities, and nervous system). 
The targeted physical examination should be focused, at the Investigator’s discretion, based on 
the subject’s condition and circumstances. The targeted physical examination should note any 
changes in the subject’s condition (body systems) since the last assessment and does not preclude 
examination of any of the body systems as clinically indicated. 
Any change in physical examination occurring during the study that is considered to be clinically 
relevant by the Investigator should be recorded as an AE. 
6.5.8 
Radiological Assessment 
A baseline chest x-ray or CT scan will be performed for the assessment of pneumonia. However, 
a chest x-ray or CT scan performed as part of routine SOC within 72 hours before randomization 
will be acceptable. The results of any such studies will be recorded in the EDC. 
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Appropriateness of Measurements 
6.6
The assessments that will be made in this study are standard, and are generally recognized as 
reliable, accurate, and relevant. 
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7.0 
STUDY TREATMENTS 
 
Test Product, Dose, Mode of Administration 
7.1
The Investigator must ensure that the investigational product will be used only in accordance 
with the protocol. It is forbidden to use investigational drug material for purposes other than as 
defined in this protocol. 
VIS410 (2000 mg or 4000 mg) will be administered IV over 2 hours as a single, 200-mL 
infusion, followed by a 25-mL (or volume equivalent to length of IV line) saline flush to ensure 
all product is administered, in addition to oseltamivir (Tamiflu) 75 mg BID for total of 5 days 
(10 doses). Treatment with oseltamivir may be extended for up to 5 additional days (up to 
20 doses of total therapy) if clinical symptoms warrant further treatment as assessed by the 
Investigator. Note: based on SOC, subjects may have started oseltamivir therapy prior to 
randomization.  No dose adjustment is necessary for VIS410 based on renal or hepatic 
impairment. For patients with renal insufficiency, refer to prescribing information for 
administration of oseltamivir. 
VIS410 is a 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 be sent to the clinical center. 
The investigational drug product is manufactured by Lyophilization Services of New England in 
accordance with Good Manufacturing Practice as required by the current Good Clinical Practice 
(GCP). Manufacturing, packaging, and labeling of the investigational product, VIS410, is 
conducted under the responsibility of the Sponsor. The study drug will be labeled according to 
local law and regulatory requirements. Specific dilution procedures for VIS410 will be described 
in detail in the Pharmacy Manual. 
Placebo will be a normal saline solution (0.9%) and will be prepared by the pharmacist. 
 
Reference Product, Dose, Mode of Administration 
7.2
Placebo (normal saline solution 0.9%) will be administered IV over 2 hours as a single 200-mL 
infusion, followed by a 25-mL (or volume equivalent to volume of IV line) saline flush to ensure 
all product is administered, in addition to oseltamivir (Tamiflu) 75 mg BID for total of 5 days 
(10 doses). Treatment with oseltamivir may be extended for up to 5 additional days (up to 
20 doses of total therapy) if clinical symptoms warrant further treatment as assessed by the 
Investigator. For patients with renal insufficiency, refer to prescribing information for 
administration of oseltamivir. Note: based on SOC, subjects may have started oseltamivir 
therapy prior to randomization.  
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Instructions for Preparation, Use, and Administration 
7.3
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. This infusion will be followed by a 25-mL (or if IV line volume is >25 mL, an 
equivalent volume) saline flush. The saline flush following administration will ensure all 
VIS410/placebo 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, infusion lines will be used, and microfilters will be provided by 
the Sponsor as appropriate. 
The infusion bag will be covered with an opaque sleeve in the pharmacy to maintain the study 
blind. The VIS410/placebo will be administered IV at a rate of 100 mL/h, over 2 hours. 
When 200 mL has been administered, the line will be flushed with normal saline. The infusion 
time may be longer at the Investigator’s discretion based only on local infusion site–related 
symptoms up to a maximum of 4 hours.  
Refer to the Pharmacy Manual for directions on storage, handling, stability data, preparation, and 
use. For more detailed information on VIS410, refer to the current Investigator’s Brochure.8  
 
The Use of Oseltamivir as Standard of Care 
7.4
All subjects will receive oseltamivir 75 mg BID for 5 days as part of SOC. Treatment with 
oseltamivir may be extended for up to 5 additional days (up to 20 doses of total therapy) if 
clinical symptoms warrant further treatment as assessed by the Investigator. Oseltamivir 
(Tamiflu) will be provided by the Sponsor. Note: based on SOC, subjects may have started 
oseltamivir therapy prior to randomization.  
For patients unable to swallow, oseltamivir capsules can be opened and mixed with liquid for 
ease of administration. 
Dose adjustment is recommended for patients with a serum creatinine clearance of 60 mL/min or 
less9 (see Table 7). 
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Table 7. 
Recommended Dosage Modifications for Treatment of Influenza in Adults 
with Renal Impairment or End-Stage Renal Disease on Dialysis a 
Renal Impairment (Creatinine 
Clearance) 
Recommended Treatment Regimen b 
Mild (> 60-90 mL/minute) 
75 mg BID for 5 days 
Moderate (> 30-60 mL/minute) 
30 mg BID for 5 days 
Severe (> 10-30 mL/minute) 
30 mg once daily for 5 days 
ESRD patients on hemodialysis 
30 mg immediately and then 30 mg after every 
hemodialysis cycle (treatment duration not to exceed 5 
days) 
ESRD patients on continuous ambulatory 
peritoneal dialysis c (≤10 mL/minute) 
A single 30-mg dose administered immediately 
ESRD patients not on dialysis 
Tamiflu is not recommended 
ESRD = end-stage renal disease. 
a Creatinine clearance to be calculated using Cockcroft-Gault formula. 
b Capsules or oral suspension can be used for 30-mg dosing. 
c Data derived from studies in continuous ambulatory peritoneal dialysis patients. 
 
For patients with renal insufficiency, refer to prescribing information for administration of 
oseltamivir.9 
The dose of oseltamivir (75 mg BID for 5 days) was chosen for this study based on the approved 
dose in the United States and other regions for the treatment of uncomplicated influenza 
infection. The dosage regimen of oseltamivir as the SOC in this study serves as a clinically 
appropriate, ethically acceptable treatment. 
 
Pretreatment Regimen 
7.5
All subjects will be given a pretreatment regimen of PO or IV diphenhydramine 50 mg plus 
either ibuprofen 400 mg or acetylsalicylic acid 320-325 mg PO or crushed and given through the 
nasogastric tube approximately 60 minutes before IV infusion of VIS410/placebo. 
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 of 
VIS410/placebo. 
Refer to the Pharmacy Manual for directions on storage, handling, stability data, and preparation 
and use of diphenhydramine, ibuprofen, and acetylsalicylic acid. 
For more information, refer to the prescribing information for ibuprofen10 and acetylsalicylic 
acid.11 
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Other Medications Administered in This Study 
7.6
All prescription and over-the-counter medications that the subject received from 7 days prior to 
study drug and throughout the study (up to the LFU evaluation) will be documented in the EDC. 
Herbal, nutritional, and dietary supplements received by the subject within 7 days before 
randomization will be documented in the EDC only if medically indicated. 
Administration of concomitant medications must be reported in the appropriate section of the 
EDC along with dates of administration and reasons for use. Generic names for medications 
should be used, if possible. 
Refer to the Pharmacy Manual for directions on storage, handling, stability data, and preparation 
and use of oseltamivir. 
For more information, refer to the prescribing information for oseltamivir.9 
 
Treatment Compliance 
7.7
Investigative product will be administered by study staff, and all drug administration data will be 
reported in the EDC and the medical records of each subject. 
The number of oseltamivir doses administered while the subject is in the hospital will be 
documented by the Investigator or his/her designee. In case of discharge while on oseltamivir 
therapy, subjects will document the number of doses taken at home and any missed doses; 
subjects self-administering oseltamivir at home will bring the pack(s) to each study visit so study 
staff may count and record the number of pills taken. Any unused capsules must be returned to 
the study site. 
 
Storage and Drug Accountability 
7.8
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. 
For storage of oseltamivir (Tamiflu), diphenhydramine, ibuprofen, and acetylsalicylic acid, refer 
to the manufacturer’s prescribing information. Also refer to the Pharmacy Manual for directions 
on storage, handling, stability data, and preparation and use of diphenhydramine, ibuprofen, and 
acetylsalicylic acid. 
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Regular temperature recordings of the study drug storage room 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, with the Sponsor’s written permission, destroyed at 
the investigative site per the standard operating procedures. 
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. 
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8.0 
STUDY METHODS AND PROCEDURES 
Table 1 summarizes the schedule for study visits and procedures performed at each study visit. 
 
Prior & Concomitant Therapy 
8.1
All medications taken within 7 days prior to signing of the informed consent form will be 
documented in the EDC. All therapies other than the study drug administered from signing the 
informed consent form until the last study visit must be recorded in the EDC system (name of the 
drug, dosage, route, and dates of administration). 
8.1.1 
Permitted Prior Therapy 
Subjects are allowed to receive up to 6 doses of an approved anti-influenza therapy within the 
prior 96 hours (ie, oral oseltamivir, inhaled zanamivir, or oral ribavirin) between onset of 
symptoms and VIS410/placebo dosing. 
8.1.2 
Permitted Concomitant Therapies 
Use of contraception or other concomitant therapy for management of subjects’ other underlying 
medical conditions is permissible during the study. 
All other concomitant medications necessary for the health and well-being of the subject will be 
permitted. In addition, any other treatment (not explicitly excluded) which is considered 
necessary for the subject’s welfare may be given at the discretion of the Investigator. 
 
Prohibited Prior & Concomitant Medications 
8.2
8.2.1 
Prohibited Prior Medications 
Per Exclusion Criterion 2 (Section 5.2.2), subjects are not allowed to receive monoclonal 
antibody products within 3 months prior to VIS410/placebo dosing. 
Per Exclusion Criterion 3 (Section 5.2.2), subjects who have taken more than 6 doses of an 
approved anti-influenza therapy within the prior 96 hours (ie, oral oseltamivir [Tamiflu], inhaled 
zanamivir [Relenza], or oral ribavirin) between onset of symptoms and VIS410/placebo dosing 
will be excluded from the study. 
8.2.2 
Prohibited Concomitant Medications 
Per Exclusion Criterion 2 (Section 5.2.2), subjects will not be allowed to receive additional 
monoclonal antibody products during the study period. Following randomization, use of other 
antiviral therapy for treatment of influenza A infection will not be permitted. Excluded antiviral 
medications include but are not limited to rimantadine, amantadine, peramivir, zanamivir, and 
laninamivir. 
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The use of symptom-modifying drugs, such as NSAIDs, antihistamines, or pseudoephedrine, are 
not specifically excluded; however, their use outside of pretreatment should be discouraged by 
the Investigator, and paracetamol/acetaminophen should be encouraged as a replacement 
medication. 
 
Schedule of Examination Procedures by Study Visit 
8.3
The study comprises up to 8 study visits over approximately 8 weeks. Subjects will attend the 
clinic at every study visit. 
AEs will be recorded from dosing to the subject’s last visit. 
Table 1 summarizes the schedule for study visits and procedures performed at each study visit. 
8.3.1 
Sequence of Assessments at a Single Visit 
If the following assessments are to be performed at the same study visit, the FluPRO 
Questionnaire should be completed first, when possible: 
 FluPRO Questionnaire 
 ECG 
 Blood sampling 
 Nasopharyngeal swab 
8.3.2 
Day of Treatment Procedures (Day 1) 
On Day 1, eligibility of the subjects will be confirmed and assessments will be performed as 
described in Table 1. 
All results from the screening procedures required to evaluate eligibility must be available prior 
to randomization on Day 1. Any abnormal assessment at the screening will be assessed 
according to its clinical relevance, and if found relevant, the subject will not be included in the 
study. 
Once a subject has fulfilled the entry criteria, he/she will be assigned a unique identifier. The 
site’s unblinded pharmacist or properly trained designee will randomize the subject using the 
IWRS. 
On Day 1, all subjects will receive the pretreatment regimen prior to receiving VIS410/placebo. 
8.3.3 
Post-Treatment Procedures (Day 3 to 56) 
Subjects will be monitored daily while in the hospital (up to Day 14) with an additional visit on 
Day 28 (± 3 days), and the last follow-up visit on Day 56 (± 7 days) per the procedures and 
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schedule listed in Table 1. Note: subjects discharged from the hospital prior to Day 14 will attend 
the applicable outpatient follow-up visit(s) (eg, Day 3, Day 5, Day 7, Day 14) per Table 1. 
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. 
 
Subject Diary 
8.4
A subject diary will be provided upon discharge from the hospital and will record the following: 
 Daily oseltamivir dosing to be completed for as long as the subject continues to take 
oseltamivir 
 Daily VAS for assessing resumption of usual activities to be completed up until either the 
subject reports that all pre-influenza usual activities can be performed or Day 56, whichever 
comes first 
 Daily Influenza Patient Reported Outcomes (FluPRO) Questionnaire to be completed until 
Day 14, if applicable 
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9.0 
ADVERSE EVENTS 
 
Definitions 
9.1
9.1.1 
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. 
9.1.2 
Signs and Symptoms of Influenza vs Adverse Events 
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. 
9.1.3 
Adverse Event of Special Interest 
An adverse event of special interest (AESI; serious or non-serious) is one of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing monitoring by 
the Sponsor may be warranted. Such an event should be entered into EDC in a timely manner 
and if applicable, reported as an SAE. Depending on the nature of the event, rapid 
communication by the trial Sponsor to other parties (eg, regulators) might also be warranted 
(based on CIOMS VI). 
For VIS410, the AESIs include the following: 
 Abdominal cramping 
 Diarrhea/Loose stool 
 Nausea  
 Vomiting 
 Pruritus 
 Rash 
 Hypotension 
 Throat tightening 
 Trouble breathing or wheezing 
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9.1.4 
Serious Adverse Events 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose meets any of 
the following conditions: 
 Results in death. 
 Is life-threatening, ie, the patient was at risk of death at the time of the event (eg, 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 preexisting condition that has not worsened, is not an SAE. 
 Results in persistent or significant disability/incapacity, ie, causing substantial disruption of 
the patient’s ability to conduct normal life. 
 Is a congenital anomaly/birth defect. 
 Is medically significant, ie, 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. 
9.1.5 
Discontinuation Due to an Adverse Event 
Study drug may be discontinued due to an AE at the discretion of the subject and/or the 
Investigator. Subjects in whom study drug is discontinued will undergo the early withdrawal 
procedures listed in Section 6.1.5. 
9.1.6 
Unlisted (Unexpected) Adverse Events 
An AE is considered unlisted if the nature or severity is not consistent with the applicable 
product reference safety information (Investigator’s Brochure).8 
9.1.7 
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 ethics committees (ECs)/institutional review boards (IRBs)/ and 
Investigators as required, according to local law. 
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9.1.8 
Treatment-Emergent Adverse Event 
A treatment-emergent adverse event (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. 
 
Grading of Adverse Event Intensity 
9.2
Each AE must be graded on a 4-point scale (Grades 1-4) of increasing intensity according to the 
Division of Microbiology and Infectious Diseases (DMID) Adult Toxicity Table presented in 
Appendix 14.3. 
Criteria in the DMID table are generally grouped by body system, ie, hematology, chemistries, 
enzymes, urinalysis, cardiovascular, respiratory, GI, neurological, musculoskeletal, skin, and 
systemic. 
For abnormalities not specifically listed in the DMID Table (Appendix 14.3), a guide for 
estimating severity grade (mild, moderate, severe, life-threatening) is provided: 
 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 
Note: The semi-colon within the description of the grade indicates ‘and’. 
Any clinical event deemed by the clinician to be serious or life-threatening should be considered 
an SAE. 
 
Causality Assessment 
9.3
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 (eg, 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. 
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Action Taken Regarding Investigational Product 
9.4
The action taken toward the study drug must be described as one of the following: 
 Permanently discontinued 
 Stopped temporarily 
 Modified infusion rate 
 No action Taken 
 Not applicable 
 
Outcome 
9.5
The outcome of each AE must be rated as one of the following: 
 Recovered/resolved 
 Recovering/resolving 
 Not recovered/not resolved 
 Recovered with sequelae/resolved with sequelae 
 Fatal 
 Unknown 
 
Recording Adverse Events 
9.6
All (S)AEs occurring during the clinical investigation must be documented in the EDC system 
from the time of dosing with any study treatment through Day 56. 
Whenever possible, diagnoses should be given when signs and symptoms are due to a common 
etiology (eg, skin erythema, induration, and edema 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 the 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 (eg, 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. 
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Reporting Procedures 
9.7
9.7.1 
Reporting 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.  
Contact details for reporting SAEs: 
 
 
 
 
 
 
The Serious Adverse Event 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 the CRO until 
the event has subsided or, in case of permanent impairment, until the condition stabilizes. 
9.7.2 
Reporting 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 study 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 
VIS410/placebo to the applicable regulatory authorities according to International Conference on 
Harmonisation (ICH) guidelines. In addition, Visterra or designee will be responsible for the 
submission of safety letters to the central IEC/IRB and to participating Investigators of all 
SUSARs involving VIS410 according to applicable regulations. For clinical sites that use a local 
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IEC/IRB, it is the responsibility of the Investigator to promptly notify the local IEC/IRB 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 Visterra or designee as soon as possible to the competent 
authority(ies) concerned together with proposed actions. 
9.7.3 
Reporting a Pregnancy 
Subjects should not become pregnant during the study. 
Pregnancy is not an AE; however, 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 last dose of 
VIS410/placebo by emailing the Pregnancy Notification Form to the Sponsor or designee within 
24 hours of the study site staff becoming aware of the pregnancy. The Investigator will also 
follow up with the subject to determine the outcome of the pregnancy and any fetal or neonatal 
sequelae will be obtained and documented. The Investigator or study site staff must report the 
outcome of the pregnancy to the Sponsor or designee. 
Contact details for reporting Pregnancy: 
 
 
 
 
 
 
Congenital abnormalities and birth defects in the offspring of male or female subjects should be 
reported as an SAE if conception occurred during the study treatment period or in the 60-day 
period after the last dose of VIS410/placebo. 
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10.0 STATISTICAL METHODS 
Further details of the statistical methodology, in addition to those described below, will be 
described in the statistical analysis plan (SAP). The SAP will be prepared and finalized before 
database lock and analysis of the data. Additional efficacy analyses including, but not limited to, 
subgroup efficacy analysis will be specified in the SAP. 
 
Determination of Sample Size 
10.1
The study is exploratory in nature, and is not powered to demonstrate significant differences 
between treatment groups in primary or secondary outcome measures. The protocol intent is to 
collect sufficient information to identify the most appropriate candidate endpoints for subsequent 
Phase 3 study evaluation from among the primary and secondary endpoints described below. 
Statistical significance testing will therefore be used to assess the relative strength of evidence of 
the primary and secondary endpoints, to provide reasonable assurance that the endpoints chosen 
for a confirmatory Phase 3 trial will elucidate treatment differences between VIS410 plus 
oseltamivir versus oseltamivir alone. 
 
Randomization and Blinding 
10.2
An IWRS will be used to allocate the randomized treatments to subjects with stratification by 
presence or absence of positive pressure ventilation (PPV) at baseline. Pharmacists must obtain 
the status of the subject relative to PPV at baseline via query, and this data must be input into the 
IWRS prior to randomization. The randomized treatment assignment will be transferred 
electronically for integration with the clinical study data at the appropriate time. 
PPV includes any respiratory assistance using a mechanical ventilation device and can be either 
invasive or noninvasive ventilation. Invasive PPV includes intubation with endotracheal tube 
with mechanical ventilation (most common) or tracheostomy with mechanical ventilation. 
Noninvasive PPV includes use of facemask, nasal plugs, or nasal mask with mechanical 
ventilation. The devices are named according to the type of mechanical ventilation given 
continuous positive airway pressure (CPAP) or bi-level positive airway pressure (BiPAP). 
Randomization will be used to avoid bias in the assignment of subjects to treatment, to increase 
the likelihood that known and unknown subject attributes (eg, demographic and baseline 
characteristics) are evenly balanced across treatment arms. 
The maintenance of the study blind is critical for an unbiased assessment of the safety and 
efficacy of the study drug. All study staff that evaluate subjects and render decisions regarding 
subject care will remain blinded to the study treatment each subject receives. 
The designated study site pharmacist or designee will remain unblinded. Also, unblinded clinical 
research associates will handle study drug accountability. 
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The study will be conducted in a double-blind manner. The CRO, site study personnel, and 
Visterra personnel will not be aware of which treatment (VIS410 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 
over a 2-hour infusion with pretreatment regimen of PO or IV diphenhydramine 50 mg plus 
either ibuprofen 400 mg PO or acetylsalicylic acid 320-325 mg PO approximately 60 minutes 
before IV infusion of VIS410/placebo. 
Allocation of each subject to a given treatment sequence will be described in a randomization 
schedule prepared by Visterra or designee. The randomization will be balanced using randomly 
permuted blocks across the treatment groups. Based on this randomization code, the site’s 
unblinded pharmacist or trained designee will prepare and dispense VIS410/placebo. 
The randomization schedule 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 schedule. The CRO personnel performing data management and 
statistical activities will receive a copy of the randomization schedule 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 (via IWRS) 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 is 
encouraged to contact the Medical Monitor to discuss and agree to the need for unblinding to 
occur. 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. 
Once a subject's treatment assignment has been unblinded, the Medical Monitor should be 
notified within 24 hours of unblinding of the treatment, without revealing the study treatment. 
Information relating to unblinding (eg, 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. If the code is broken by the Investigator or by someone of his/her staff, the 
subject must be withdrawn from the study and must be followed as appropriate. 
Visterra or designee will also unblind any SAE reports that are serious, unexpected, and 
considered to be related to investigational product, in accordance with safety reporting guidance 
and regulations. If the code is broken by the Sponsor for safety reporting purposes, the subject 
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may remain in the study. To maintain study blinding, the infusion bag will be covered by an 
opaque sleeve in the pharmacy. 
 
Analysis Populations 
10.3
The following analysis populations will be defined for the study: 
 Intent-to-treat (ITT) population – All subjects randomized to treatment. Subjects in the 
ITT population will be analyzed based on the treatment to which they were randomized, 
irrespective of what they actually received. 
 Safety population – All ITT subjects who received IV VIS410/placebo. Subjects in the 
safety population will be analyzed based on the actual treatment they received, irrespective of 
the treatment to which they were randomized. 
 Modified intent-to-treat (MITT) – All subjects of the safety population that have an 
assessment of O2 support after randomization and are confirmed influenza A positive. 
Subjects in the MITT population will be analyzed based on the treatment to which they were 
randomized, irrespective of what they actually received. This population was selected for the 
analysis of the primary endpoint in order to maintain the benefits of randomization and avoid 
the bias associated with the non-random loss of the participants. 
 Per protocol (PP) population – All MITT subjects who adhere to relevant study procedures 
and have an outcome assessment. Further specific details defining the analyses to be 
performed on this population will be described in the SAP. 
 PK population (PK) – All subjects in the safety population that have at least one result that 
can be used in the PK summaries. 
 
Initial Characteristics of the Subject Sample 
10.4
Summary statistics will be provided per treatment group for demographic (eg, age, height, 
weight, body mass index [BMI], race, gender) and other initial subject characteristics (eg, 
medical history, concomitant diseases) will be provided per treatment group and for the total 
group. The ITT population will be used for the summaries. Enrollment, protocol deviations, and 
discontinuations from the study will be summarized by treatment group. Protocol deviations are 
defined as any notable variation from the protocol, including enrollment of a subject who did not 
meet all inclusion and exclusion criteria, and failure to perform the assessments and procedures 
within the required time frame. 
Summary statistics will be provided to show subject exposure to pretreatment medications, 
subject exposure to VIS410/placebo/oseltamivir, and inadvertent administration of 
VIS410/placebo to which subjects were not randomized by treatment group. 
Prior and concomitant medications will be coded using the WHO Drug Dictionary. 
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Handling of Missing Data 
10.5
Procedures for handling missing data will be defined in the Statistical Analysis Plan, and may 
include last observation carried forward or an interpolation method.  
 
Efficacy Analyses 
10.6
Efficacy analyses will be performed using the MITT population. Efficacy analysis will also be 
performed in the PP population to demonstrate consistency with the primary analysis population. 
10.6.1 
Day 7 Ordinal Scale Status 
The ordinal scale outcomes will be measured daily from Day 1 (baseline) through Day 14 using 
the seven-level hierarchical scale with the classifications presented in Table 8. The clinical 
outcomes therein are ordered from the worst clinical outcome to the best clinical outcome in 
descending order. For each day, subjects will be classified by the worst clinical outcome for 
which they qualify. 
The number and percentage of subjects in each treatment group with each classification will be 
summarized for each day from Day 1 through Day 14, inclusive. 
Table 8. 
Hierarchical Seven-Level Ordinal Scale for Clinical Outcomes 
Clinical Parameter 
Death 
ICU stay with mechanical ventilation 
ICU stay without mechanical ventilation 
Non-ICU hospitalization with supplemental oxygen 
Non-ICU hospitalization without supplemental oxygen 
Discharge with partial resumption of normal activities 
Discharge with full resumption of normal activities 
Note: Clinical outcomes listed from worst clinical outcome to best clinical outcome in descending order. 
 
10.6.2 
Time to Cessation of O2 Support 
Time to cessation of O2 support resulting in a stable SpO2will be analyzed using a Cox model. 
Time from onset of symptoms to VIS410 treatment and the number of doses of oseltamivir 
(Tamiflu) prior to VIS410 treatment for the current case of influenza will be included as a 
covariate in the analysis. A P-value (using the Wald statistic) for each VIS410 dose vs placebo 
will be presented. 
Secondarily, subgroup analyses will be performed to describe the time to cessation of O2 for 
subgroups, such as use of positive pressure ventilation, use of endotracheal intubation, time from 
onset of symptom to VIS410 therapy, number of oseltamivir doses prior to VIS410, elderly, and 
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underlying lung disease. Clinical and virologic endpoints will also be evaluated by influenza A 
subtypes. 
10.6.3 
Time to Clinical Response 
Time to clinical response is defined as resolution of 4 of 5 vital signs that will be determined 
upon physical examination. Clinical response is defined as: 
 Afebrile with core temperature ≤ 37.8°C, without use of antipyretics (oral ≤ 37.2°C) 
 Respiratory rate ≤ 24 beats per minute 
 Oxygen saturation ≥ 95% on room air without support or a return to pre-infection 
status, if pre-infection status was < 95% 
 Pulse rate ≤ 100/min 
 SBP ≥ 90 mm/Hg, without vasopressor use 
The probability of time to clinical response (defined as resolution of vital signs) will be 
calculated via Kaplan-Meier. A significance test (using the log-rank test) for each VIS410 dose 
vs placebo will be presented. The number and percentage of subjects in each treatment group 
with clinical response will be summarized. Results will be tabulated and presented graphically as 
well. 
10.6.4 
Time to Cessation of Ventilator Support 
The probability of time to cessation of ventilator support will be calculated via Kaplan-Meier. A 
P-value (using the log-rank test) for each VIS410 dose vs placebo will be presented. Results will 
be tabulated and presented graphically as well. 
10.6.5 
Healthcare Resource Utilization 
Descriptive statistics will be used to compare the total number of days in the hospital and/or ICU 
from admission to discharge, number of subjects requiring ICU admission post-randomization, 
overall number of days in the ICU, number of hours on ventilation, rehospitalization due to 
influenza A relapse/reinfection, the total number of days of oseltamivir therapy, and the total 
number of days to resumption of usual activities by treatment group.  
Time (number of days) to resumption of usual activities will be determined from the VAS (scale 
ranged from 0 to 10, where 0 indicates subject is unable to perform any of his/her usual activities 
prior to influenza onset, and 10 indicates subject is able to fully perform all usual activities). 
This evaluation will be performed using the MITT population. 
10.6.6 
Signs and Symptoms of Influenza 
Descriptive statistics will be used to compare the duration of symptoms of influenza-like illness 
in the subset of subjects able to complete the FluPRO Questionnaire at baseline and post-dose by 
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treatment group. The number and percentage of subjects who were not able to complete the 
assessment at each visit will be summarized. 
Frequency tabulation of the occurrence and severity of each subject-reported symptom of 
influenza-like illness (via FluPRO Questionnaire) will be summarized by assessment time point 
and by treatment group. Time to resolution of symptoms will be evaluated by Kaplan Meier 
analysis.  
Analyses of the signs and symptoms of influenza will be conducted only on the subset of the 
MITT population who had baseline FluPRO Questionnaire assessments. Additional populations 
may be analyzed as described in the SAP. 
 
Safety Analyses 
10.7
Safety analyses will be performed on the safety population. 
10.7.1 
Adverse Events 
The original terms in the electronic data capture (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). 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 (ie, treatment-emergent AEs [TEAEs]) will be summarized. 
AEs will be summarized overall and 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, hypersensitivity reaction, 
anaphylactic reaction, AESIs, and SAEs between treatment groups will be calculated. 
Special attention will be paid to those subjects who died, discontinued due to an AE, or 
experienced a severe or serious AE. Summaries, listings, and narratives will be provided, as 
appropriate. 
10.7.2 
Local Injection Site Tolerability 
Injection site tolerability is defined as AEs demonstrating local injection site irritation or tissue 
damage. Injection site tolerability will be reported by variable, treatment group, and time point. 
10.7.3 
Complications of Influenza 
Complications of influenza are defined as pneumonia, myocarditis, worsening of chronic 
bronchitis, sinusitis, otitis or other chronic pulmonary diseases, encephalopathy, and death. 
Complications of influenza and use of antibiotic therapy for bacterial pneumonia will be reported 
by variable, treatment group, and time point. Diagnosis of bacterial pneumonia will be based on 
local clinical practice, usually an assessment of clinical features and any radiographic evidence 
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of bacterial pneumonia (eg, infiltrate) and/or microbiologic evidence of bacterial pneumonia. 
All-cause and attributable mortality will be evaluated on Days 14 and 28. 
10.7.4 
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 table (see Appendix 14.3) 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 toxicity grade 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. 
10.7.5 
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. 
10.7.6 
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. QTcF will be the primary 
correction parameter.13 
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 ms) and 
changes from baseline (increase > 30 and > 60 ms), a frequency table by assessment time point 
and by treatment group will be provided. 
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Pharmacokinetic/Pharmacodynamic Analyses 
10.8
10.8.1 
Serum Pharmacokinetics 
Serum concentrations will be listed by subject for VIS410 and summary statistics by group will 
be presented, including means, geometric means, standard deviations, coefficient of variation 
(CV), medians, and ranges, as appropriate. Summary graphs, including mean concentration-time 
profiles by group, will also be presented. The serum concentration data will be analyzed by 
population PK methods using nonlinear mixed effects modeling as implemented in NONMEM 
or equivalent software. Population PK analysis will be performed to describe the time course of 
serum concentrations of VIS410. The influence of covariates on PK parameters will be 
investigated, if necessary and appropriate. If necessary, the data may be pooled with data from 
previous studies. Additional analyses and summaries may be generated as appropriate. 
Results of population PK or PK/PD analyses may be reported outside the clinical study report. 
10.8.2 
Pharmacokinetics of Nasopharyngeal Secretions and Tracheal Aspirate 
Nasopharyngeal swabs will be obtained from both nostrils (1 swab per nostril). The first 50 
randomized subjects will have nasopharyngeal swabs collected up to Day 56 (predose, end of 
infusion, Days 3, 5, 7, 14, 28 and 56); while in the remaining subjects, nasopharyngeal swabs 
will be obtained up to Day 14 only. If the subject remains in the hospital on Day 10, then 
additional nasopharyngeal swabs will be obtained on Day 10. The VIS410 concentrations in the 
nasopharyngeal secretions and tracheal aspirate will be listed by subject, and summary statistics 
by group will be reported as described for the serum concentrations. The computed PK 
parameters will be listed by subject for VIS410. Summary statistics and PK parameters will be 
presented, including means, geometric means, standard deviations, CV, medians, and ranges, as 
appropriate. Summary graphs, including mean concentration-time profiles by group, will also be 
presented. The nasopharyngeal concentration data may also be analyzed by population PK 
methods using nonlinear mixed effects modeling as implemented in NONMEM or equivalent 
software. If necessary, the data may be pooled with data from previous studies. Additional 
analyses and summaries may be generated as appropriate. 
Results of population PK or PK/PD analyses may be reported outside the clinical study report. 
10.8.3 
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 (eg, AUC, Cmax, concentration at 
specific time point) and the dependent variables (eg, viral AUC, peak viral load, 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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Results of the PK/PD analyses may be reported outside the clinical study report. 
 
Viral Load 
10.9
Student t-test or Mann-Whitney U test will be used to assess the difference between treatment 
groups in AUC based on qRT-PCR and TCID50 from nasopharyngeal swabs and tracheal 
aspirate, when appropriate (ie, intubated patients). Descriptive statistics will be used for viral 
load data (AUC, time to resolution of viral load, duration of viral shedding, and peak viral load 
based on qRT-PCR and TCID50) from nasopharyngeal swabs as well as tracheal aspirate by 
treatment group and VIS410 overall vs placebo. Tables and graphs will be generated as 
appropriate for the MITT and PP populations by dose group. Additional exploratory statistical 
analyses may be conducted as appropriate. Exploratory dose and exposure response will be 
evaluated using various statistical and graphical approaches as appropriate. 
 Immunological Analyses 
10.10
Immunological assessments will be summarized for the MITT population by parameter, 
treatment group, and time point using descriptive statistics: 
 Anti-influenza A antibodies by HAI in serum 
 ADA titers 
 Viral Resistance 
10.11
Viral sensitivity to VIS410 and oseltamivir will be assessed during the study.  
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11.0 STUDY TERMINATION AND COMPLETION 
 
Study Completion 
11.1
A subject will be considered to have completed the study if he or she has completed the last 
follow-up visit (Day 56 ± 7 days). 
 
Study Drug Discontinuation 
11.2
Subjects may be discontinued from the study drug administration in the event of: 
 A severe AE or SAE 
 A positive pregnancy test of the subject, or if the subject/partner is non-compliant with the 
contraception requirements (see Section 6.2)  
 Development of a medical condition that requires concomitant treatment with a prohibited 
therapy (see Section 8.2) 
Such subjects should be encouraged to continue study participation by undergoing all safety 
evaluations until the scheduled time of study completion, as appropriate. 
 
Subject Withdrawal from Study 
11.3
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. 
Subjects must be withdrawn from the study in the event of: 
 Withdrawal of informed consent 
 Failure of the subject to comply with the protocol requirements or to cooperate with 
the Investigator 
 For safety reasons, it being in the best interest of the subject that he/she be 
withdrawn, in the Investigator’s opinion 
In the event that a subject is withdrawn from the study, the study monitor and Sponsor should be 
informed. In case of withdrawal due to an SAE (for details on AE reporting see Section 9.7), the 
Sponsor should be notified within 24 hours. In case of withdrawal for other reasons, the Sponsor 
should be notified within 2 days of the event. 
If there is a medical reason for withdrawal, the subject will remain under the supervision of the 
Investigator until satisfactory health has returned. 
Subjects who are withdrawn from the study prior to completion of the scheduled study 
procedures for any reason (AE, withdrawal of consent, etc.) should be invited to complete the 
assessments as much as possible. As long as the subject consents, all relevant assessments of the 
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day on which the subject withdrew from the study should be completed, at least those related to 
safety. In case of an AE, the appropriate follow-up will be performed. 
VIS410/placebo assigned to a withdrawn subject must not be assigned to another subject. 
Subjects withdrawn from the study will not be replaced. 
 
Stopping Rules or Discontinuation Criteria 
11.4
The study will be overseen by a DSMB (see Section 4.3). 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 while the DSMB 
evaluates data. 
Dosing will temporarily pause while the DSMB meets if: 
 A total of 4 treatment-related serious adverse events (SAEs) occurred, or 
 A total of 4 severe GI TEAEs requiring intervention occurred. Intervention is defined as 
requiring IV fluid and medication to decrease the frequency of diarrhea (ie, loperamide). 
 
Protocol Compliance 
11.5
In accordance with ICH E6 (R1) Guideline for GCP, the Investigator should not implement any 
deviation from or changes of the protocol without agreement by the Sponsor (or designee) and 
documented approval from the IEC/IRBs of a protocol amendment, except where necessary to 
eliminate an immediate hazard(s) to study subjects, or when the change(s) involves only 
logistical or administrative aspects of the study (eg, change in monitor[s], change of telephone 
number[s]). 
The protocol must be read thoroughly, and the instructions must be followed. However, 
exceptions will be made in emergency situations when the protection, safety, and well-being of 
the subject requires immediate intervention based on the judgment of the Investigator or a 
responsible, appropriately trained, and credentialed professional(s) designated by the Investigator 
as a sub-Investigator. 
In the event of a significant protocol deviation due to an emergency, accident, or error, the 
Investigator (or designee) must contact the Medical Monitor at the earliest possible time. This 
allows for an early joint decision to be made as to whether or not the subject should continue in 
the study. The Investigator, the Sponsor (or designee), and the Medical Monitor will document 
this decision. 
All protocol deviations will be documented in a database. 
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12.0 ETHICAL AND ADMINISTRATIVE CONSIDERATIONS 
 
Ethical Conduct of the Study 
12.1
12.1.1 
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 that they may withdraw 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. 
12.1.2 
Subject Informed Consent 
Each subject or a legally acceptable representative 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 enrolling potential subjects in the study, the Investigator or an authorized member of the 
investigational staff must explain to the subject the aims, methods, reasonably anticipated 
benefits, and potential hazards of the study, and any discomfort that participation in the study 
may entail. Subjects 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 Informed 
Consent Form (ICF) the subject is authorizing such access and agrees to allow his/her study 
physician to recontact 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 nontechnical 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 
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should personally date and sign the ICF after the oral consent of the subject is obtained, if 
permitted by local law. 
12.1.3 
Independent Ethics Committee or Institutional Review Board 
An independent ethics committee (IEC) or institutional review board (IRB) 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’s 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 
 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 
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 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 an 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 
after the LSLV. 
12.1.4 
Protection of Subject 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 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. 
 
Investigator Responsibilities 
12.2
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 
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through up-to-date curriculum vitae and/or other relevant documentation requested by the 
Sponsor, the IEC/IRB, 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. 
 
Administration 
12.3
12.3.1 
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) involve(s) only logistic or administrative aspects of the study, the 
IRB (and IEC where required) only needs to be notified. 
12.3.2 
Subject Identification, Enrollment, and Screening  
The Investigator agrees to complete a subject identification and enrollment record 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 record 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 maintain a subject-screening record, which reports all subjects who 
were seen to determine eligibility for inclusion in the study. 
12.3.3 
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 
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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 system. 
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 the EDC system 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 the EDC system. 
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 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 (eg, 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. 
12.3.4 
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 the 
EDC system will be transferred to the clinical database electronically. 
 
Monitoring and Quality Assurance 
12.4
The monitoring of the study will be conducted 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. At these visits, the monitor will compare the data captured in the EDC system for 
completeness and accuracy and perform source data verification of any data that have been 
captured as paper-based sources 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. 
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Direct access to (e-)source documentation (medical records) must be allowed at all times for the 
purpose of verifying that the data recorded in the 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. 
12.4.1 
Data Management 
Data management of the study will be the responsibility of the Sponsor and will be conducted by 
the CRO. 
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 the 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 an interim analysis. 
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. 
12.4.2 
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 
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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. 
12.4.3 
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, or 
a government or regulatory agency access to all study records. 
The Investigator should promptly notify the Sponsor 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. 
 
Study Termination 
12.5
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. 
12.5.1 
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. 
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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. 
12.5.2 
Use of Information and Publication 
All information, including but not limited to information regarding VIS410 or the Sponsor’s 
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, 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(s) must not submit any part of the data from this protocol for publication 
without the prior consent of Visterra, Inc. 
The Investigator understands that the information developed in this clinical study will be used by 
the Sponsor in connection with the continued development of VIS410, 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) 
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 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, ie, 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 report 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 (LSLV). 
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, the 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 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. 
12.5.3 
Registration of Clinical Studies and Disclosure of Results 
The Sponsor or designee will register and/or disclose the existence of and the results of clinical 
studies as required by law. 
12.5.4 
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 subjects’ anonymity will be maintained. The Investigator will 
keep a separate list with at least the initials, the subjects’ study numbers, names, addresses, and 
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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. 
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13.0 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):1016–24. 
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 WHO. Seasonal Influenza Fact sheet N°211. 2014. 
http://www.who.int/mediacentre/factsheets/fs211/en. Accessed 10 Mar 2014. 
5 World Health Organization (WHO). Pandemic (H1N1) 2009-update 70. 
http://www.who.int/csr/don/2009_10_16/en/index.html. Accessed 25 October 2009. 
6 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. 
7 Hayden FG, Treanor JJ, Betts RF, Lobo M, Esinhart JD, Hussey EK. Safety and efficacy of the 
neuraminidase inhibitor GG167 in experimental human influenza. JAMA. 1996 Jan 24-
31;275(4):295-9. 
8 Investigator’s Brochure of VIS410, version 5.0, 2016. 
9 TAMIFLU® (oseltamivir phosphate) Package Insert. 
http://www.fda.gov/downloads/Drugs/DrugSafety/InformationbyDrugClass/ucm147992.pdf. 
Accessed 31 August 2016. 
10 Motrin® Package Insert. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/017463s105lbl.pdf. Accessed 31 
August 2016. 
11 Aspirin® Package Insert. 
http://www.fda.gov/ohrms/dockets/ac/03/briefing/4012B1_03_Appd%201-
Professional%20Labeling.pdf. Accessed 31 August 2016. 
12 Diphenhydramine hydrochloride Package Insert. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/091526lbl.pdf. Accessed 31 August 
2016. 
13 Fridericia LS. The duration of systole in the electrocardiogram of normal subjects and of 
patients with heart disease. Acta Medica Scandinavica 1920;53:469–86. 
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Laboratory Assessments 
14.2
Urinalysis 
Hematology 
Chemistry 
Dipstick: 
 
Specific gravity 
 
pH 
 
Glucose 
 
Protein 
 
Blood 
 
Ketones 
 
Bilirubin 
 
Urobilinogen 
 
Nitrite 
 
Leukocyte esterase 
Hemoglobin 
Albumin 
Hematocrit 
Alkaline phosphate 
Red blood cells (RBC) 
Alanine amino transferase 
White blood cells (WBC) with 
differential 
Aspartate amino transferase 
Bicarbonate 
Lymphocytes 
Total bilirubin 
Monocytes 
Direct bilirubin b 
Neutrophils a 
Blood urea nitrogen (or urea) 
Eosinophils 
Calcium 
Basophils 
Chloride 
Platelets 
Creatinine 
Urine sedimentation count: 
 
Erythrocytes (RBC) 
 
Leukocytes (WBC) 
 
Epithelial cells 
 
Glucose c 
 
Lactate dehydrogenase 
 
Phosphate, inorganic 
 
Potassium 
 
Total protein 
Microscopy: 
 
Crystals 
 
Casts 
 
Bacteria 
 
Sodium 
 
Creatine kinase-MB d, 
Creatinine kinase d, 
Troponin d, 
Tryptase e, 
Chymase e 
 
Other Assessments 
Coagulation 
Antibody screening test 
(immunoassay), rapid  
Any positive rapid test 
result should be confirmed 
according to local guidelines 
Urine pregnancy test 
Partial thromboplastin time 
Erythrocyte Sedimentation Rate 
(ESR) 
C-Reactive Protein (CRP) 
Activated partial 
thromboplastin time 
a  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. 
b Assay if total bilirubin is above normal range. 
c Baseline only. 
d Only measure if subject has chest pain. 
e In the event of a subject exhibiting the signs and symptoms of an anaphylactic reaction, when 
possible at the time of the event, a 5-mL serum sample should be collected for further assessment 
(ie tryptase, chymase). 
 
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Division of Microbiology and Infectious Diseases Adult Toxicity Table 
14.3
The DMID Adult Toxicity Table appears on the following pages. 
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, 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 supersede 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 
 
MUSCULOSKELETEAL 
 
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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PROTOCOL AMENDMENT – SUMMARY OF CHANGES 
Phase 2b, Multicenter, Randomized, Double-blind, Controlled Study to Evaluate the 
Efficacy and Safety of Intravenous VIS410 in Addition to Oseltamivir (Tamiflu®) 
Compared With Oseltamivir Alone in Hospitalized Adults With Influenza A 
Infection Requiring Oxygen Support 
Product VIS410 
Protocol Number VIS410-203 
EudraCT Number 2016-004009-15 
Clinical Phase 2b 
Clinical Indication Influenza A infection 
 
Sponsor Visterra, Inc. 
One Kendall Square, Suite B3301 
Cambridge, MA 02139 
United States of America 
Sponsor Representative  
  
 
 
 
ORIGINAL PROTOCOL DATE: 
21 October 2016 
AMENDMENT 1 DATE: 
AMENDMENT 2 DATE: 
20 June 2017 
19 April 2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
The information in this document contains trade secrets and commercial information that are privileged or 
confidential and may not be disclosed unless such disclosure is required by applicable law or regulations. In any 
event, persons to whom the information is disclosed must be informed that the information is privileged or 
confidential and may not be further disclosed without written authorization of Visterra, Inc. 
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SUMMARY OF CHANGES TO PROTOCOL VIS410-203 
FROM VERSION 2.0 TO VERSION 3.0 
Substantive changes to the protocol for Amendment 3 and their location within the protocol are noted 
below. Additions are marked as red underlined text and deletions are marked as red strikethrough text. 
Administrative, stylistic and formatting changes that do not alter the conduct of the study are not 
summarized in this document. 
Location in 
Protocol 
Changes 
Rationale 
Cover Page; 
Signature of 
Sponsor 
Representative 
Issue Date (Version): 20 June 2017 (Version 2.0) 
19 April 2018 (Version 3.0) 
 
Sponsor Representative
 
                                        
Updated date and version 
number. 
 
Sponsor representative 
updated. 
Cover page; 
Sponsor 
Address 
Visterra, Inc. 
One Kendall Square, Suite B3301 275 Second Avenue, 4th 
Floor 
Cambridge Waltham, MA 0213902451 
United States of America 
Company moved location 
Synopsis: 
Number of 
Clinical Sites 
Approximately 180 140 sites worldwide 
Reduction in number of sites 
Synopsis: 
Number of 
Subjects 
Approximately 390 120 
Decreasing sample size from 
390 to 120 subjects to enable 
completion in 2 influenza 
seasons. 
Synopsis and 
Section 2.1.1 
Primary 
Efficacy 
Objective 
 
Evaluate Evaluation of the effect of 2 dose levels of 
VIS410 + oseltamivir on the time to normalization of 
respiratory function compared to oseltamivir alone 
clinical outcome as assessed by comparison of clinical 
status ordinal scale Day 7 scores between treatment 
groups, and between all VIS410 recipients versus 
placebo.   
Utility of ordinal scale 
observed in prior trials of 
this size. 
Synopsis and 
Section 2.2 
Secondary 
Objectives 
 
Among patients requiring supplemental oxygen therapy 
at the time of enrollment with baseline room air oxygen 
saturation of ≤ 92%, time to cessation of oxygen (O2) 
support resulting in stable oxygen saturation (SpO2) by 
pulse oximetry. Stable SpO2 is defined as two 
consecutive SpO2 values of > 92% on room air that are 
at least 8 hours apart. 
 
For any patient requiring supplemental oxygen therapy 
at the time of enrollment (regardless of oxygen 
saturation), time to cessation of oxygen support.  
 
Evaluate the effect of 2 dose levels of VIS410 + 
oseltamivir vs oseltamivir alone on the following 
parameters: 
 
Viral load in upper respiratory samples 
 
Time to clinical response 
 
Time to cessation of ventilator support 
 
Time to resumption of normal activities 
 
All-cause and attributable 14-, and 28-, and 56-day 
mortality 
 
Clinical status ordinal scale mean area under the 
Time to cessation of oxygen 
support changed from 
primary endpoint to 
secondary. Some patients 
may be on oxygen with O2 
saturation > 92% at baseline. 
 
 
 
 
 
 
 
 
Added ordinal scale 
parameters to be assessed 
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Location in 
Protocol 
Changes 
Rationale 
curve for Days 1-7 and Days 1-14 using linear 
numeric scores for the ordinal categories. 
 
Comparison of clinical status ordinal scale scores 
for selected individual days (i.e., Days 3, 4, 5, and 
6)  
 
Comparison of clinical status ordinal scale scores 
using modified ordinal scale criteria (i.e. pooling of 
selected severity criteria scores) 
 
Comparison of discrete ordinal scale parameters, 
including days of ventilator support, days in 
intensive care, and duration of hospitalization 
 
Healthcare resource utilization 
 
Analysis of time Time to alleviation of clinical 
signs and symptoms of influenza in the subset of 
subjects able to complete the Influenza Patient 
Reported Outcomes (FluPRO) Questionnaire at 
baseline and post-dose by Kaplan Meier analysis 
 
Proportion of subjects with new documented 
bacterial pneumonia/superinfection 
 
Proportion of subjects with influenza-related 
complications 
 
Pharmacokinetics of VIS410 in serum 
 
Immunogenicity of VIS410 
 
Emergence of resistance to VIS410 and oseltamivir 
Synopsis and 
Section 2.3 
Exploratory 
Objectives 
 
Evaluate the effect of VIS410 + oseltamivir vs 
oseltamivir alone on clinical outcomes as measured by a 
seven level ordinal scale 
 
Evaluate the pharmacokinetics of VIS410 from 
nasopharyngeal secretions and tracheal aspirate 
(ventilated subjects only) 
 
Assess the effects of VIS410 on viral load in tracheal 
aspirate (ventilated subjects only) 
 
Assess correlations between virology, safety, VIS410 
dose, pharmacokinetics, viral shedding, immunology, 
signs and symptoms of influenza, and other endpoints 
 
Assess the anti-influenza immune response 
Removed as components are 
now primary and secondary 
endpoints 
Synopsis  
Study Design 
This is a Phase 2b, multicenter, randomized, double-blind, 
controlled study comparing the efficacy and safety of 2 dose 
levels of VIS410 (2000 and 4000 mg) in combination with 
oseltamivir vs oseltamivir alone in hospitalized subjects with 
influenza A infection requiring oxygen support. Subjects 
will be randomly assigned at a ratio of 1:1:1 using a 
permuted block randomization method to receive VIS410 at 
a dose of 2000 mg (low dose) or 4000 mg (high dose) or 
placebo (0.9% sodium chloride), administered as a single IV 
infusion over 2 hours. Randomization will be stratified by 
presence or absence of positive pressure ventilation (PPV) at 
baseline to ensure an even distribution across treatment 
arms. All subjects will receive oseltamivir 75 mg twice daily 
(BID) for 5 days (total of 10 doses) as part of standard of 
care (SOC). Treatment with oseltamivir may be extended for 
Decreasing sample size from 
390 to 120 subjects to enable 
completion in 2 influenza 
seasons. Table in section 
also updated to reflect 40 
subjects per arm. 
 
 
 
 
 
 
 
 
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Location in 
Protocol 
Changes 
Rationale 
up to 5 additional days (up to 20 doses of total therapy) if 
clinical symptoms warrant further treatment as assessed by 
the Investigator. Note: based on SOC, subjects may have 
started oseltamivir therapy prior to randomization. All 
subjects will also receive a pretreatment regimen of 
diphenhydramine 50 mg PO or IV plus either ibuprofen 
400 mg PO or acetylsalicylic acid 320-325 mg PO 
approximately 60 minutes before infusion. Approximately 
390 120 evaluable subjects (130 40/arm) with confirmed 
influenza A infection will be treated. 
Subjects admitted to the hospital within 5 days of onset of 
initial symptoms who require supplemental oxygen will 
undergo a rapid influenza test or a local polymerase chain 
reaction (PCR) test, fluorescent immunoassay (FIA) test, or 
enzyme-linked immunosorbent assay (ELISA) test to 
confirm influenza A infection. Subjects diagnosed with 
influenza A will undergo the screening procedures to 
confirm eligibility. Study assessments are outlined in Error! 
eference source not found. (Schedule of Assessments). 
Eligible subjects will be randomized to receive either 
oseltamivir + VIS410 2000 mg, oseltamivir + VIS410 
4000 mg, or oseltamivir + placebo (0.9% sodium chloride) at 
a ratio of 1:1:1 using a permuted block randomization 
method according to the table below: 
Oseltamivir (Tamiflu®) will be provided by the Sponsor. 
Treatment with oseltamivir may be extended for up to 
5 additional days (up to 20 doses of total therapy) if clinical 
symptoms \warrant further treatment as assessed by the 
Investigator. Note: based on SOC, subjects may have started 
oseltamivir therapy prior to randomization. 
Study assessments are outlined in Error! Reference source 
ot found.. Subjects discharged from the hospital prior to Day 
14 will attend the applicable outpatient follow-up visit(s) 
(eg, Day 3, Day 5, Day 7, Day 14) per Error! Reference 
source not found.. 
An independent data safety monitoring board (DSMB) will 
be established to review all available safety data after 
30 subjects as well as when and again after approximately 
120 70 subjects have completed study Day 14 assessments. 
The assessment of safety will be determined from vital sign 
measurements, physical examinations, hematology, 
chemistry and urinalysis laboratory testing, 12-lead 
electrocardiograms (ECGs), use of concomitant medications, 
and review of adverse events (AEs). Based on the safety data 
provided, the DSMB will determine if it is acceptable to 
continue the study or reduce the dose as appropriate. Dosing 
will temporarily pause while the DSMB meets if there are 
4 treatment-related serious adverse events (SAEs) or 4 
severe gastrointestinal (GI)  treatment–emergent adverse 
events (TEAEs) that require intervention, which is defined as 
requiring IV fluid and medication to decrease the frequency 
of diarrhea (ie, loperamide). 
Additional DSMB reviews can occur throughout the trial as 
deemed necessary by the DSMB or Sponsor to ensure 
subject safety and well-being. Study enrollment and dosing 
will continue while the DSMB evaluates data. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Performing second DSMB 
review after completion of 
Northern Hemisphere 
season. No need for DSMB 
review after 120 subjects; 
final analysis of data will be 
performed. 
 
 
 
 
 
 
 
 
 
 
 
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Location in 
Protocol 
Changes 
Rationale 
 In addition, following 50% enrollment (195 subjects), an 
interim analysis may be conducted, by an unblinded third 
party, to assess if one of the VIS410 treatment arms can be 
terminated early for futility. A prespecified sample size 
reanalysis may also be conducted based on the observed 
effect size. The interim analysis may also test the primary 
efficacy objective to assess if the primary efficacy endpoint 
has been met. An alpha spending function will be designed 
in order to determine the amount of alpha that will be spent 
at the interim analysis. The effect size for this study was 
estimated without the benefit of any prior randomized 
controlled trial. If the VIS410 effect size proves to be greater 
than anticipated, then it is possible that the primary study 
endpoint will be met by the time the interim efficacy analysis 
is performed. In the event the interim analysis reveals that 
the primary efficacy endpoint has been satisfied, this Phase 2 
study could be terminated for efficacy.   
 
 
 
 
Removed interim analysis as 
sample size decreased to 120 
subjects; final analysis to be 
performed upon completion 
of enrollment. 
Synopsis and 
Section 5.1 
Number of 
Subjects 
Approximately 390 120 evaluable subjects will be enrolled 
in 3 equal arms: VIS410 2000 mg, VIS410 4000 mg, and 
placebo. 
Sample size decreased. 
Synopsis and 
Section 5.2.1 
Inclusion 
Criteria 
9.   Subject, or a legally acceptable authorized representative, 
is able to understand the purpose and risks of the study and 
willing to give voluntary written informed consent. 
Change requested by an 
Ethics Committee 
Synopsis  
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 
(or volume equivalent to IV line volume if greater than 25 
mL) saline flush to ensure all product is administered, in 
addition to oseltamivir (Tamiflu) 75 mg BID for total of 5 
days (10 doses). For patients with renal insufficiency, refer 
to prescribing information for administration of oseltamivir. 
For patients unable to swallow, oseltamivir capsules can be 
opened and mixed with liquid for ease of administration. 
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, followed by a 
25-mL (or volume equivalent IV line volume if greater than 
25 mL) saline flush to ensure all product is administered, in 
addition to oseltamivir (Tamiflu) 75 mg BID for total of 5 
days (10 doses). For patients with renal insufficiency, refer 
to prescribing information for administration of oseltamivir. 
VIS410 and Placebo Preparation 
The required amount of VIS410 to be dosed (2000 mg or 
4000 mg) will be diluted with normal saline up to a 
maximum total volume of 200 mL; for placebo subjects, 200 
mL of normal saline will be prepared. Length of IV line will 
ideally be set for maximum volume of 25 mL, so that the 25-
mL (or increased volume as noted above) saline flush 
following administration will ensure all VIS410/placebo has 
been administered. In the event that the infusion line volume 
is greater than 25 mL the post-administration saline flush 
should be increased to match the volume of the infusion line 
kit.   
Clarification to ensure all 
study product administered. 
Some sites use infusion lines 
with hold-up volumes of 
greater than 25 mL. 
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Location in 
Protocol 
Changes 
Rationale 
The VIS410/placebo 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 whenever possible, 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 
VIS410/placebo 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 an appropriate volume saline flush as described 
above. The infusion time may be extended up to 4 hours at 
the Investigator’s discretion based on local infusion site–
related symptoms.  
All subjects will be given a pretreatment regimen of PO or 
IV diphenhydramine 50 mg plus either ibuprofen 400 mg PO 
or acetylsalicylic acid 320-325 mg PO or crushed and given 
through the nasogastric tube approximately 60 minutes 
before IV infusion of VIS410/placebo. 
Synopsis and 
Section 3.1.1 
Primary 
Efficacy 
Endpoint 
 
Time to cessation of oxygen (O2) support resulting in 
stable oxygen saturation (SpO2) by pulse oximetry. 
Stable SpO2 is defined as two consecutive SpO2 values 
of > 92% on room air that are at least 8 hours apart. 
 
The primary efficacy outcome analysis compares Day 7 
clinical status ordinal scale scores between treatment 
groups, and between all VIS410 recipients versus 
placebo.  Clinical status is measured daily for 14 days 
using the below seven-level ordinal scale, with the 
classifications presented from the worst clinical 
outcome to the best clinical outcome in descending 
order; for each day, subject status will be classified by 
the worst clinical outcome for which they qualify.  
 
Death 
 
ICU stay with mechanical ventilation 
 
ICU stay without mechanical ventilation 
 
Non-ICU hospitalization with supplemental 
oxygen 
 
Non-ICU hospitalization without supplemental 
oxygen 
 
Discharge with partial resumption of normal 
activities 
 
Discharge with full resumption of normal 
activities 
Primary objective changed. 
Synopsis and 
Section 3.2 
Secondary 
Endpoints 
The difference between VIS410 + oseltamivir and 
oseltamivir alone treatment groups in the following 
endpoints:  
 
Among patients requiring supplemental oxygen therapy 
at the time of enrollment with baseline room air oxygen 
saturation of ≤ 92%, time to cessation of oxygen (O2) 
support resulting in stable oxygen saturation (SpO2) by 
pulse oximetry. Stable SpO2 is defined as two 
consecutive SpO2 values of > 92% on room air that are 
at least 8 hours apart. 
 
 
 
Moved from primary 
objective to secondary 
 
 
 
 
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 
For any patient requiring supplemental oxygen therapy 
at the time of enrollment (regardless of oxygen 
saturation), time to cessation of oxygen support 
 
Peak viral load, viral area under the concentration–time 
curve (AUC), duration of viral shedding, and time to 
resolution of viral load from nasopharyngeal swabs by 
TCID50 and qRT-PCR 
 
Time to clinical response defined as resolution of at 
least 4 of 5 vital signs: 
 
Afebrile with core temperature ≤ 37.8°C, without 
use of antipyretics (oral ≤ 37.2°C) 
 
Oxygen saturation ≥ 95% on room air without 
support or a return to pre-infection status, if pre-
infection status was < 95% 
 
Pulse rate ≤ 100/min 
 
Systolic blood pressure (SBP) ≥ 90 mm/Hg, without 
vasopressor use 
 
Respiratory rate ≤24 beats per minute 
 
Total number of days on ventilation 
 
Clinical status ordinal scale mean area under the curve 
for Days 1-7 and Days 1-14 using linear numeric scores 
for the ordinal categories. 
 
Comparison of clinical status ordinal scale scores for 
selected individual days (i.e., Days 3, 4, 5, and 6)  
 
Comparison of clinical status ordinal scale scores using 
modified ordinal scale criteria (i.e. pooling of selected 
severity criteria scores) 
 
Comparison of discrete ordinal scale parameters, 
including days of ventilator support, days in intensive 
care, and duration of hospitalization 
 
Number of days to resumption of normal activities 
 
All-cause and attributable mortality rates at Day 14, and 
28, and 56 
 
Total number of days in hospital and/or intensive care 
unit (ICU) from admission to discharge and rate of 
rehospitalization due to influenza A 
relapse/complication 
 
The incidence, severity, and duration of signs and 
symptoms of influenza-like illness as assessed by the 
FluPRO Questionnaire (see Appendix Error! 
eference source not found.) 
 
Analysis of time to alleviation of signs and symptoms of 
influenza in the subset of subjects able to complete the 
Influenza Patient Reported Outcomes (FluPRO) 
Questionnaire at baseline and post-dose by Kaplan 
Meier analysis 
 
The percentage of subjects with new bacterial 
pneumonia/superinfection 
 
The percentage of subjects with influenza-related 
complications 
 
VIS410 population pharmacokinetic (PK) parameters in 
 
 
 
 
 
 
 
 
 
 
 
 
 
Deleted as covered by next 
two bullets addressing 
ordinal scale assessments 
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serum 
 
Titer of anti-VIS410 antibody positive samples 
 
Genotypic and/or phenotypic assessment to determine 
the emergence of VIS410 and oseltamivir-resistant 
viruses 
Synopsis and 
Section 3.3 
Exploratory 
Endpoints 
 
Clinical outcome will be measured daily for 14 days 
using a seven level ordinal scale; this seven level 
ordinal scale is defined as: 
 
Death 
 
ICU stay with mechanical ventilation 
 
ICU stay without mechanical ventilation 
 
Non ICU hospitalization with supplemental oxygen 
 
Non ICU hospitalization without supplemental oxygen 
 
Discharge with partial resumption of normal activities 
 
Discharge with full resumption of normal activities 
 
Population PK parameters of VIS410 from 
nasopharyngeal secretions 
 
VIS410 concentration in tracheal aspirates 
 
The difference in viral load between VIS410 + 
oseltamivir and oseltamivir alone treatment groups in 
tracheal aspirate of subjects on mechanical ventilation 
 
Titer of anti-influenza A antibodies by hemagglutinin 
inhibition assay (HAI) in serum 
 
Correlations between serum and/or nasopharyngeal PK 
with viral load, clinical symptoms, presence of antidrug 
antibodies (ADAs), safety, and additional endpoints 
Now covered under primary 
efficacy and secondary 
endpoints 
Synopsis 
Statistical Methods 
Sample Size 
Approximately 120 390 evaluable subjects will be enrolled. 
The study is exploratory in nature, and is not powered to 
demonstrate significant differences between treatment 
groups in primary or secondary outcome measures. The 
protocol intent is to collect sufficient information to identify 
the most appropriate candidate endpoints for subsequent 
Phase 3 study evaluation from among the primary and 
secondary endpoints described below. Statistical significance 
testing will therefore be used to assess the relative strength 
of evidence of the primary and secondary endpoints, to 
provide reasonable assurance that the endpoints chosen for a 
confirmatory Phase 3 trial will elucidate treatment 
differences between VIS410 plus oseltamivir versus 
oseltamivir alone.  Using a log rank test, a sample size of 
130 influenza A infected subjects per treatment group will 
provide 80% power to detect a 1.5 day difference (5 days for 
oseltamivir alone and 3.5 days for VIS410 plus oseltamivir) 
in the median time to normalization of respiratory function 
(cessation of O2 support) for VIS410 relative to placebo. A 
two sided alpha of 0.05 was used for the calculation. 
Efficacy 
Efficacy analysis will have two complementary purposes in 
this Phase 2 study, both designed to aid in the optimal design 
 
 
Analysis changed due to the 
decrease in sample size. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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of a confirmatory Phase 3 trial. First, primary and secondary 
endpoints will be analyzed for treatment group differences, 
to determine which endpoints might be most sensitive 
demonstration of treatment group differences using p-values 
as an indicator, Second, the relative contribution of the 
various efficacy endpoints to patient well-being and benefit 
will be assessed, as well as potential correlations of 
endpoints such as the influence of peak viral load or number 
of days on ventilator on the time to resumption of normal 
activities.  
The ordinal scale outcomes will be measured daily from Day 
1 (baseline) through Day 14, inclusive, using a seven-level 
hierarchical scale with the classifications ordered from the 
worst to the best clinical outcomes (see Section 10.6.1). For 
use in overall summary statistical presentations, the ordinal 
categories will be assigned decreasing integer scores, with 
death a score of 6 and discharge with full resumption of 
normal activities a score of 0. The primary outcome 
comparison of Ordinal Scale scores at Day 7 between 
treatment groups will be evaluated by proportional odds ratio 
analysis, as implemented by logistic regression, including a 
test of the proportional odds assumption. For this analysis, 
the response categories will be ordered from best (Discharge 
with full resumption of normal activities) to worst (Death). 
Additional exploratory analyses may be conducted to obtain 
a more complete understanding of the relationship of 
treatment to the ordinal response, including exact Mantel-
Haenszel tests or partial proportional odds models.  
The area under the curve (AUC) over time for a given 
patient will be calculated as the sum of the maximum ordinal 
score for each day up through 7 and 14 days.  An analysis of 
treatment group differences will be performed on these per-
patient AUC values using analysis of variance, with 
treatment group and strata as fixed factors. A sensitivity 
analysis will be performed that excludes the category of 
death on study, to determine if death as an outcome skews 
the results; death as an outcome will also be analyzed as an 
independent secondary endpoint. A secondary analysis of 
treatment group effect on the difference in proportions of 
patients with the worst (death) versus the best outcome 
(discharge from hospital and resumption of normal 
activities) will also be performed. This analysis does not use 
scores for the ordinal outcome but does account for 
ordinality, and is therefore not dependent on the relationship 
of score to severity of outcome. An exploratory analysis will 
be performed through an exact categorical analysis of 
treatment group difference in the ordinal scale results using 
the worst outcome on a per-patient basis. 
Additional ordinal scale outcome assessments will include 
comparison of total numbers of days at more severe scale 
values (death, time on ventilator, time in ICU) and 
proportions of patients with ordinal scale worsening post 
enrollment. Proportion outcomes will be analyzed by 
categorical data analysis methods, including Mantel-
Haenszel chi-square tests adjusted for strata; additional 
exploratory subgroup analyses may also be performed, for 
example, based on various age categories.  Time from onset 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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of symptoms to study treatment and the number of doses of 
oseltamivir (Tamiflu) prior to VIS410 treatment for the 
current case of influenza may be included as covariates in 
the analyses. 
Secondary and exploratory endpoints will be analyzed for 
descriptive purposes, with significance levels (p-values) 
provided to illustrate the strength of evidence for treatment 
effects, and to provide a basis for the choice of endpoints for 
further study in a confirmatory study. These analyses will 
also provide estimates for potentially powering additional 
efficacy endpoints, and to assist in hierarchical ordering of 
secondary endpoints to provide alpha-control in 
confirmatory studies and for labelling purposes. 
Time to cessation of O2 support resulting in a stable SpO2 
will be analyzed using a Cox proportional hazards regression 
model including data from patients on O2 support. Time 
from onset of symptoms to VIS410 treatment and number of 
doses of oseltamivir (Tamiflu) prior to VIS410 treatment for 
the current case of influenza will be included as a covariate 
of the analysis. A P-value (using the Wald statistic) for each 
VIS410 dose vs placebo will be presented.  
The total number of days in the hospital and/or ICU from 
admission to discharge and the rate of rehospitalization due 
to influenza A relapse/reinfection will be summarized 
descriptively by treatment group. 
The probability of time to clinical response (defined as 
resolution of vital signs) will be calculated via 
Kaplan-Meier. A P-value significance test (using the log-
rank test) for each VIS410 dose vs placebo will be presented. 
Results will be tabulated and presented graphically as well. 
The number and percentage of subjects in each treatment 
group with clinical response will be summarized. 
The ordinal scale outcomes will be measured daily from Day 
1 (baseline) through Day 14, inclusive, using a seven level 
hierarchical scale with the classifications ordered from the 
worst to the best clinical outcomes (see Section 0). The 
number and percentage of subjects in each treatment group 
with each classification will be summarized for each day 
from Day 1 through Day 14, inclusive. 
Interim Analyses of Efficacy 
An interim analysis of efficacy may be performed by an 
unblinded third party after 50% of subjects have been 
enrolled (n = 195) and have an assessment of the primary 
endpoint (time to normalization of respiratory function). This 
interim analysis may be conducted to assess if one of the 
active VIS410 treatment arms will need to be terminated for 
futility. The interim analysis may also test the primary 
efficacy objective to assess if the primary efficacy endpoint 
has been met early. A prespecified sample size reanalysis 
will also be conducted based on the observed effect size. The 
DSMB and the unblinded statistician will review the interim 
analysis results to provide their recommendation on 
discontinuation of one of the VIS410 treatment arms, if 
needed, based on pre specified criteria as outlined in the 
SAP. The interim analysis may also review the following 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No interim analysis to be 
performed due to the 
decrease in sample size. 
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key secondary endpoints, when available, to assist in the 
decision of discontinuing a VIS410 treatment arm: 
 
Time to clinical resolution of vital signs 
 
Total number of hours on oxygen support or PPV 
 
Viral load from nasopharyngeal swabs 
A sample size re-estimation (SSRE) will also be performed 
at this point in order to determine if the current sample size 
is sufficient based on the observed effect size in the study. 
The unblinded statisticians will work directly with the 
Sponsor on the SSRE. The details of SSRE and individuals 
with access to the information will be outlined in a separate 
plan. 
///// 
Complications of Influenza 
Complications of influenza are defined as pneumonia, 
myocarditis, worsening of chronic bronchitis, sinusitis, otitis, 
or other chronic pulmonary diseases, encephalopathy, and 
death. Complications of influenza and use of antibiotic 
therapy for bacterial pneumonia will be reported by variable, 
treatment group, and time point. Diagnosis of bacterial 
pneumonia will be based on local clinical practice, usually 
an assessment of clinical features and any radiographic 
evidence of bacterial pneumonia (eg, infiltrate) and/or 
microbiologic evidence of bacterial pneumonia. All-cause 
and attributable mortality will be evaluated on Day 14 and 
28. 
Table 1 
Schedule of 
Assessments  
Table: Erythrocyte sedimentation rate (ESR)20a  
Footnotes: 20a ESR to be performed locally. 
Clarification. 
List of 
Abbreviations 
AUC – Area under curve 
New abbreviation 
Section 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.i, ii Despite available therapy with neuraminidase 
inhibitors, including oseltamivir (Tamiflu®), zanamivir 
(Relenza®), and peramivir (Rapivab®), 10% to 44% of 
hospitalized patients require intensive care and 25% to 50% 
of these patients die. It is estimated that as many as 400,000 
patients are hospitalized with influenza each year in the 
United States, with up to 49,000 deaths per year.iii  
The World Health Organization (WHO) has reported 
incidence rates of 3 to 5 million severe cases and about 
250,000 to 500,000 influenza-related deaths annually.iv The 
2009 influenza A pandemic (H1N1) spread rapidly to every 
continent with more than 399,232 reported cases and 4735 
deaths.v 
The therapeutic use of passive polyclonal antibodies to 
prevent viral infections, including hepatitis B, varicella, 
cytomegalovirus, rabies, and respiratory syncytial virus 
(RSV) has been well established. More recently, monoclonal 
antibodies for viral infections have been developed, 
 
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including palivizumab (Synagis®), a Food and Drug 
Administration (FDA)-licensed treatment for the prevention 
of RSV 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 A 
strains, in both treatment and prevention models of 
influenza, was developed. Visterra intends to develop this 
product for the treatment of influenza A, specifically in 
hospitalized patients. 
This study will provide the first indications of efficacy, 
safety, and tolerability of VIS410 in hospitalized subjects 
with influenza A infection requiring oxygen support. 
Efficacy will be measured by time to cessation of oxygen 
support assessed by comparison of clinical status ordinal 
Day 7 scores between treatment groups. 
Section 4.1 
Overview 
This is a Phase 2b multicenter, randomized, double-blind, 
controlled study comparing the efficacy and safety of 2 dose 
levels of VIS410 (2000 and 4000 mg) in combination with 
oseltamivir vs oseltamivir alone in hospitalized subjects with 
influenza A infection requiring oxygen. Subjects will be 
randomly assigned at a ratio of 1:1:1 using a permuted block 
randomization method to receive VIS410 at a dose of 2000 
mg (low dose) or 4000 mg (high dose) or placebo (0.9% 
sodium chloride), administered as a single IV infusion over 2 
hours. 
Randomization will be stratified by presence or absence of 
positive pressure ventilation (PPV) at baseline to ensure an 
even distribution across treatment arms (see Section Error! 
eference source not found.). All subjects will receive 
oseltamivir 75 mg twice daily (BID) for 5 days (total of 10 
doses) as part of standard of care (SOC). All subjects will 
also receive a pretreatment regimen of diphenhydramine 50 
mg PO or IV plus either ibuprofen 400 mg PO or 
acetylsalicylic acid 320-325 mg PO 60 minutes before 
VIS410/placebo infusion. Approximately 390120 evaluable 
subjects (13040/arm) with confirmed influenza A infection 
will be treated.  
Subjects admitted to the hospital within 5 days of onset of 
initial symptoms who require supplemental oxygen will 
undergo a rapid influenza test (supplied by the Sponsor) or a 
PCR, fluorescent immunoassay (FIA), or enzyme-linked 
immunosorbent assay (ELISA) test to confirm influenza A 
infection. Subjects diagnosed with influenza A will undergo 
the screening procedures to confirm eligibility. Study 
assessments are outlined in Error! Reference source not 
ound., Schedule of Assessments. 
Eligible subjects will be randomized to receive either 
oseltamivir + VIS410 2000 mg, oseltamivir + VIS410 4000 
mg, or oseltamivir + placebo (0.9% sodium chloride) at a 
ratio of 1:1:1 using a permuted block randomization method 
Decreasing sample size from 
390 to 120 subjects to enable 
completion in 2 influenza 
seasons. Table 6 also 
updated to reflect 40 subjects 
per arm. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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summarized in Error! Reference source not found.. 
Oseltamivir (Tamiflu) will be provided by the Sponsor. 
Treatment with oseltamivir may be extended for up to 5 
additional days (up to 20 doses of total therapy) if clinical 
symptoms warrant further treatment as assessed by the 
Investigator. Note: based on SOC, subjects may have started 
oseltamivir therapy prior to randomization. 
 In addition, following 50% enrollment (195 subjects), an 
interim analysis may be conducted, by an unblinded third 
party, to assess if one of the VIS410 treatment arms can be 
terminated early for futility. A prespecified sample size 
reanalysis may also be conducted based on the observed 
effect size. The interim analysis may also test the primary 
efficacy objective to assess if the primary efficacy endpoint 
has been met. An alpha spending function will be designed 
in order to determine the amount of alpha that will be spent 
at the interim analysis. The effect size for this study was 
estimated without the benefit of any prior randomized 
controlled trial. If the VIS410 effect size proves to be greater 
than anticipated, then it is possible that the primary study 
endpoint will be met by the time the interim efficacy analysis 
is performed. In the event the interim analysis reveals that 
the primary efficacy endpoint has been satisfied, this Phase 2 
study could be terminated for efficacy.   
 
 
 
 
 
 
Removed interim analysis as 
sample size decreased to 120 
subjects; final analysis to be 
performed upon completion 
of enrollment. 
Section 4.3 
Data Safety 
Monitoring 
Board 
An independent data safety monitoring board (DSMB) will 
be established to review all available safety data after 30 
subjects, as well as when and subsequently, approximately 
120 70 subjects, have completed study Day 14. The 
assessment of safety will be determined from vital sign 
measurements, physical examinations, hematology, 
chemistry and urinalysis laboratory testing, 12-lead 
electrocardiograms (ECGs), use of concomitant medications, 
and review of AEs. Based on the safety data provided, the 
DSMB will determine if it is acceptable to continue the 
study or reduce the dose as appropriate. 
Additional DSMB reviews can occur throughout the trial as 
deemed necessary by the DSMB or Sponsor to ensure 
subject safety and well-being. Study enrollment and dosing 
will continue while the DSMB evaluates data. 
Further details will be described in a separate DSMB charter. 
Sample size decreased 
therefore second DSMB 
review not required. 
Section 5.2.1 
Inclusion 
Criteria 
9.   Subject, or a legally acceptable authorized representative, 
is able to understand the purpose and risks of the study 
and willing to give voluntary written informed consent. 
Change requested by an 
Ethics Committee 
Section 6.1.3 
Study 
Procedures 
On Day 1, eligibility of the subjects will be confirmed and 
assessments will be performed as described in Error! 
eference source not found.. 
All results from the screening procedure needed to evaluate 
eligibility, including any local clinical laboratory results, 
must be available prior to randomization on Day 1. All 
clinical assessments required for the determination of subject 
eligibility will be performed by the local clinical laboratory, 
thereby precluding the need to wait for central laboratory 
data. 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. 
Clarification 
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Once a subject has satisfied entry criteria, he/she will be 
assigned a unique identifier. The site’s unblinded pharmacist 
or properly trained designee will randomize the subject using 
the access the Interactive Web Response System (IWRS) to 
obtain the study treatment. Randomization will be stratified 
by presence or absence of PPV at baseline to ensure balance 
between the treatment arms. Subjects will be considered 
randomized when the pharmacist or designee obtains the 
subject number and treatment assignment from the IWRS. 
Subjects may not be randomized into this study more than 
once. Subjects who have participated in any previous study 
of VIS410 may not be randomized to this study. Subjects 
will be monitored daily while in the hospital up to Day 14 
(± 3 days) with an additional visit on Day 28 (± 3 days) and 
the last follow-up visit on Day 56 (± 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. Note: subjects 
discharged from the hospital prior to Day 14 will attend the 
applicable outpatient follow-up visit(s) (eg, Day 3, Day 5, 
Day 7, Day 14). 
Section 6.2 
Pregnancy 
Safeguards 
Pregnancy will be determined by evaluation of β-human 
chorionic gonadotropin in serum or urine for all women of 
childbearing potential. Subjects who are pregnant or nursing 
will be excluded from the study. During the course of the 
study drug administration period within the study, any 
nursing mother(s) or subject(s) with suspected or confirmed 
pregnancy will be discontinued from study drug therapy but 
will be encouraged to undergo follow-up for safety 
monitoring for themselves (ie, the pregnant female) and the 
baby. 
All women of childbearing potential and all male subjects 
must practice effective contraception from screening until 60 
days post-VIS410/placebo infusion. For the purposes of this 
study, women who do not satisfy at least one of the 
following criteria listed below (ie, the criteria for defining 
non-childbearing potential) are considered to be 
physiologically capable of becoming pregnant and are, 
therefore, defined as women of childbearing potential. 
The criteria for defining women as being of non-childbearing 
potential are: 
 
Post-menopausal: ≥ 12 months of natural 
(spontaneous) amenorrhea, or 
 
Follicle stimulating hormone > 40 mIU/mL as 
documented in their medical history, or 
 
Surgical bilateral oophorectomy with or 
without hysterectomy, or 
 
Hysterectomy, or 
 
Bilateral tubal ligation 
Women of childbearing potential and all male subjects 
participating in heterosexual relations must be willing to 
practice effective contraception from screening until 60 days 
post-VIS410/placebo infusion. For the purposes of the study, 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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highly effective contraception is defined as: 
 
Male vasectomy with negative semen analysis 
documentation at least 6 months prior to 
dosing.  
OR 
 
Combination of an established form of 
hormonal contraception (oral, injected, or 
implanted) or an intrauterine device or 
intrauterine system or sponge 
Plus one of the following: 
 
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. 
OR 
 
Male vasectomy with negative semen analysis 
documentation less than 6 months prior to 
dosing. OR 
 
Complete abstinence can be considered an 
acceptable method of contraception at the 
discretion of the Investigator. Periodic 
abstinences (eg, calendar, ovulation, 
symptothermal, or post-ovulation methods) and 
withdrawal are NOT considered acceptable 
methods of contraception. 
The combination of 2 barrier methods, periodic abstinence 
(eg, calendar, ovulation, symptothermal, or post-ovulation 
methods), and withdrawal are not considered acceptable 
methods of contraception. 
Male subjects should not donate sperm for at least 60 days 
after receipt of study product. 
Pregnancy reporting is described in Section Error! 
eference source not found.. 
 
 
 
 
 
 
Sponge is an acceptable 
method of contraception 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Added requirement. 
Section 6.5.2 
Injection Site 
Tolerability 
Injection site tolerability is defined as AEs demonstrating 
significant local injection site irritation or tissue damage. 
Injection site tolerability will be reported by variable, 
treatment group, and time point. 
Sentence deleted as belongs 
in SAP 
Section 6.5.3 
Complications 
of Influenza 
Complications of influenza are defined as pneumonia, 
myocarditis, worsening of chronic bronchitis, sinusitis, otitis, 
or other chronic pulmonary diseases, encephalopathy, and 
death. Complications of influenza and use of antibiotic 
therapy for bacterial pneumonia will be reported by variable, 
treatment group, and time point. Diagnosis of bacterial 
pneumonia will be based on local clinical practice, usually 
an assessment of clinical features and any radiographic 
evidence of bacterial pneumonia (eg, infiltrate) and/or 
microbiologic evidence of bacterial pneumonia. All-cause 
and attributable mortality will be evaluated on Day 14 and 
Day 28. 
 
Section 7.1 Test 
product, Dose, 
The Investigator must ensure that the investigational product 
will be used only in accordance with the protocol. It is 
Clarification as some sites 
use lines with greater than 25 
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Mode of 
Administration 
forbidden to use investigational drug material for purposes 
other than as defined in this protocol. 
VIS410 (2000 mg or 4000 mg) will be administered IV over 
2 hours as a single, 200-mL infusion, followed by a 25-mL 
(or volume equivalent to length of IV line) saline flush to 
ensure all product is administered, in addition to oseltamivir 
(Tamiflu) 75 mg BID for total of 5 days (10 doses). 
Treatment with oseltamivir may be extended for up to 5 
additional days (up to 20 doses of total therapy) if clinical 
symptoms warrant further treatment as assessed by the 
Investigator. Note: based on SOC, subjects may have started 
oseltamivir therapy prior to randomization.  No dose 
adjustment is necessary for VIS410 based on renal or hepatic 
impairment. For patients with renal insufficiency, refer to 
prescribing information for administration of oseltamivir. 
VIS410 is a 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 be 
sent to the clinical center. 
The investigational drug product is manufactured by 
Lyophilization Services of New England in accordance with 
Good Manufacturing Practice as required by the current 
Good Clinical Practice (GCP). Manufacturing, packaging, 
and labeling of the investigational product, VIS410, is 
conducted under the responsibility of the Sponsor. The study 
drug will be labeled according to local law and regulatory 
requirements. Specific dilution procedures for VIS410 will 
be described in detail in the Pharmacy Manual. 
Placebo will be a normal saline solution (0.9%) and will be 
prepared by the pharmacist. 
mL hold-up volume 
Section 7.2 
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, followed by a 
25-mL (or volume equivalent to length of IV line) saline 
flush to ensure all product is administered, in addition to 
oseltamivir (Tamiflu) 75 mg BID for total of 5 days (10 
doses). Treatment with oseltamivir may be extended for up 
to 5 additional days (up to 20 doses of total therapy) if 
clinical symptoms warrant further treatment as assessed by 
the Investigator. For patients with renal insufficiency, refer 
to prescribing information for administration of oseltamivir. 
Note: based on SOC, subjects may have started oseltamivir 
therapy prior to randomization. 
Clarification as some sites 
use lines with greater than 25 
mL hold-up volume 
Section 7.3 
Instructions for 
Preparation, 
Use and 
Administration 
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. This infusion will be followed by a 
25-mL saline flush. Length of (or if IV line will be set for 
maximum volume of is >25 mL, so that The 25 mL an 
equivalent volume) saline flush. The saline flush following 
Clarification to ensure all 
study product administered. 
Some sites use infusion lines 
with hold-up volumes of 
greater than 25 mL. 
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administration will ensure all VIS410/placebo 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 as appropriate. 
The infusion bag will be covered with an opaque sleeve in 
the pharmacy to maintain the study blind. The 
VIS410/placebo will be administered IV at a rate of 100 
mL/h, over 2 hours. 
When 200 mL has been administered, the line will be 
flushed with 25 mL of normal saline. The infusion time may 
be longer at the Investigator’s discretion based only on local 
infusion site–related symptoms up to a maximum of 4 hours.  
Refer to the Pharmacy Manual for directions on storage, 
handling, stability data, preparation, and use. For more 
detailed information on VIS410, refer to the current 
Investigator’s Brochure.Error! Bookmark not defined. 
Section 8.3.1 
Sequence of 
Assessments at 
a Single Visit 
If the following assessments are to be performed at the same 
study visit, then the order of assessments should be as 
follows the FluPRO Questionnaire should be completed first, 
when possible: 
 
FluPRO Questionnaire 
 
ECG 
 
Blood sampling 
 
Nasopharyngeal swab 
Clarification 
Section 9.2 
Grading of 
Adverse Event 
Intensity 
Each AE must be graded on a 4-point scale (Grades 1-3 4) of 
increasing intensity according to the Division of 
Microbiology and Infectious Diseases (DMID) Adult 
Toxicity Table presented in Appendix Error! Reference 
ource not found.. 
Criteria in the DMID table are generally grouped by body 
system, ie, hematology, chemistries, enzymes, urinalysis, 
cardiovascular, respiratory, GI, neurological, 
musculoskeletal, skin, and systemic. 
For abnormalities not specifically listed in the DMID Table 
(Appendix Error! Reference source not found.), a guide 
or estimating severity grade (mild, moderate, severe, life-
threatening) is provided: 
 
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 
Note: The semi-colon within the description of the grade 
indicates ‘and’. 
Any clinical event deemed by the clinician to be serious or 
Correction; DMID scale is 1-
4 
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life-threatening should be considered an SAE. 
Section 10.1 
Determination 
of Sample Size 
The study is exploratory in nature, and is not powered to 
demonstrate significant differences between treatment 
groups in primary or secondary outcome measures. The 
protocol intent is to collect sufficient information to identify 
the most appropriate candidate endpoints for subsequent 
Phase 3 study evaluation from among the primary and 
secondary endpoints described below. Statistical significance 
testing will therefore be used to assess the relative strength 
of evidence of the primary and secondary endpoints, to 
provide reasonable assurance that the endpoints chosen for a 
confirmatory Phase 3 trial will elucidate treatment 
differences between VIS410 plus oseltamivir versus 
oseltamivir alone. 
The primary efficacy objective of this study is to evaluate the 
effect of VIS410 + oseltamivir on the time to normalization 
of respiratory function compared to oseltamivir alone in the 
modified intent to treat (MITT) population. 
Using a log rank test, a sample size of 130 influenza A
infected subjects per treatment group will provide 80% 
power to detect a 1.5 day difference (5 days for oseltamivir 
alone and 3.5 days for VIS410 plus oseltamivir) in the 
median time to cessation of O2 support for VIS410 relative 
to placebo. A two sided alpha of 0.05 was used for the 
calculation. 
Approximately 390 evaluable subjects with confirmed 
influenza A infection will be enrolled in this study. 
New paragraph due to 
decreased sample size 
Section 10.2 
Randomization 
and Blinding 
An IWRS will be used to allocate the randomized treatments 
to subjects with stratification by presence or absence of 
positive pressure ventilation (PPV) at baseline. Pharmacists 
must obtain the status of the subject relative to PPV at 
baseline via query, and this data must be input into the 
IWRS prior to randomization. The randomized treatment 
assignment will be transferred electronically for integration 
with the clinical study data at the appropriate time. 
PPV includes any respiratory assistance using a mechanical 
ventilation device and can be either invasive or noninvasive 
ventilation. Invasive PPV includes intubation with 
endotracheal tube with mechanical ventilation (most 
common) or tracheostomy with mechanical ventilation. 
Noninvasive PPV includes use of facemask, nasal plugs, or 
nasal mask with mechanical ventilation. The devices are 
named according to the type of mechanical ventilation given 
continuous positive airway pressure (CPAP) or bi-level 
positive airway pressure (BiPAP). 
Randomization will be used to avoid bias in the assignment 
of subjects to treatment, to increase the likelihood that 
known and unknown subject attributes (eg, demographic and 
baseline characteristics) are evenly balanced across treatment 
arms. 
The maintenance of the study blind is critical for an unbiased 
assessment of the safety and efficacy of the study drug. All 
study staff that evaluate subjects and render decisions 
regarding subject care will remain blinded to the study 
treatment each subject receives. 
 
Explanation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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The designated study site pharmacist or designee will remain 
unblinded. Also, unblinded clinical research associates will 
handle study drug accountability. 
The study will be conducted in a double-blind manner. The 
CRO, site study personnel, and Visterra personnel will not 
be aware of which treatment (VIS410 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 over a 2-hour infusion 
with pretreatment regimen of PO or IV diphenhydramine 50 
mg plus either ibuprofen 400 mg PO or acetylsalicylic acid 
320-325 mg PO approximately 60 minutes before IV 
infusion of VIS410/placebo. 
Allocation of each subject to a given treatment sequence will 
be described in a randomization schedule prepared by 
Visterra or designee. The randomization will be balanced 
using randomly permuted blocks across the treatment 
groups. Based on this randomization code, the site’s 
unblinded pharmacist or trained designee will prepare and 
dispense VIS410/placebo. 
If the interim analysis determines that one of the VIS410 
treatment arms can be terminated early for futility, then a 
second randomization schedule with a unique set of 
randomization numbers will be created for all subsequent 
subject enrollment and randomization. As with the initial 
randomization procedure, randomization will be stratified by 
presence or absence of PPV at baseline to ensure an even 
distribution across treatment arms. 
The randomization schedule 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 schedule. The Sponsor medical 
representative(s) may be partially unblinded during the 
interim analyses. A separate interim analysis plan will 
provide details on access to unblinded data and the level of 
unblinding. The CRO personnel performing data 
management and statistical activities will receive a copy of 
the randomization schedule 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 (via IWRS) 
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 is encouraged to 
contact the Medical Monitor to discuss and agree to the need 
for unblinding to occur. 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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Due to decrease in sample 
size an interim analysis is 
not going to be performed. 
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discussed the situation with the Medical Monitor. 
Once a subject's treatment assignment has been unblinded, 
the Medical Monitor should be notified within 24 hours of 
unblinding of the treatment, without revealing the study 
treatment. Information relating to unblinding (eg, 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. If 
the code is broken by the Investigator or by someone of 
his/her staff, the subject must be withdrawn from the study 
and must be followed as appropriate. 
Visterra or designee will also unblind any SAE reports that 
are serious, unexpected, and considered to be related to 
investigational product, in accordance with safety reporting 
guidance and regulations. If the code is broken by the 
Sponsor for safety reporting purposes, the subject may 
remain in the study. To maintain study blinding, the infusion 
bag will be covered by an opaque sleeve in the pharmacy. 
Section 10.5 
Handling of 
Missing Data 
No imputations Procedures for handling missing data will be 
performed defined in the Statistical Analysis Plan, and may 
include last observation carried forward or an interpolation 
method. 
Clarification 
Section 10.6 
Interim Analysis 
An interim analysis of efficacy may be performed by an 
unblinded third party after 50% of subjects have been 
enrolled (n = 195) and have an assessment of the primary 
endpoint (time to normalization of respiratory function). This 
interim analysis may be conducted to assess if one of the 
active VIS410 treatment arms will need to be terminated for 
futility. Using the methods of Lan and DeMets an alpha 
spending function will be created and if the test statistic for 
one of the active VIS410 treatment arms is less than the 
lower critical point then the VIS410 treatment arm may be 
terminated for futility. The interim analysis may also test the 
primary efficacy objective to assess if the primary efficacy 
endpoint has been met early. 
The effect size for this study was estimated without the 
benefit of any prior randomized, controlled trial. If the 
VIS410 effect size proves to be greater than anticipated, then 
it is possible that the primary study endpoint will be met by 
the time the interim efficacy analysis is performed. In the 
event the interim analysis reveals that the primary efficacy 
endpoint has been satisfied, this Phase 2 study could be 
terminated for efficacy. 
The DSMB and the unblinded statistician will review the 
interim analysis results to provide their recommendation on 
discontinuation of one of the VIS410 treatment arms, if 
needed, based on pre specified criteria as outlined in the 
SAP. The interim analysis may also review the following 
key secondary endpoints, when available, to assist in the 
decision of discontinuing a VIS410 treatment arm: 
 
Time to clinical resolution of vital signs 
 
Total number of hours on oxygen support or PPV 
Due to decrease in sample 
size an interim analysis is 
not going to be performed. 
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 
Viral load from nasopharyngeal swabs 
A sample size re-estimation (SSRE) will also be performed 
at this point in order to determine if the current sample size 
is sufficient based on the observed effect size in the study. 
The unblinded statisticians will work directly with the 
Sponsor on the SSRE. The details of SSRE and individuals 
with access to the information will be outlined in a separate 
plan. The MITT population will be used for the interim 
analysis. 
Section 10.7 
Efficacy 
Analyses 
Section number changed to 10.6  
Efficacy Analyses 
Efficacy analyses will be performed using the MITT 
population. Efficacy analysis will also be performed in the 
PP population to demonstrate consistency with the primary 
analysis population. 
Day 7 Ordinal Scale Status 
The ordinal scale outcomes will be measured daily from Day 
1 (baseline) through Day 14 using the seven-level 
hierarchical scale with the classifications presented in Table 
8Table 2. The clinical outcomes therein are ordered from the 
worst clinical outcome to the best clinical outcome in 
descending order. For each day, subjects will be classified by 
the worst clinical outcome for which they qualify. 
The number and percentage of subjects in each treatment 
group with each classification will be summarized for each 
day from Day 1 through Day 14, inclusive. 
Table 1. 
Hierarchical Seven-Level Ordinal Scale 
for Clinical Outcomes 
Clinical Parameter 
Death 
ICU stay with mechanical ventilation 
ICU stay without mechanical ventilation 
Non-ICU hospitalization with supplemental oxygen 
Non-ICU hospitalization without supplemental oxygen 
Discharge with partial resumption of normal activities 
Discharge with full resumption of normal activities 
Note: Clinical outcomes listed from worst clinical 
outcome to best clinical outcome in descending order. 
 
Time to Cessation of O2 Support 
Time to cessation of O2 support resulting in a stable 
SpO2will be analyzed using a Cox model. Time from onset 
of symptoms to VIS410 treatment and the number of doses 
of oseltamivir (Tamiflu) prior to VIS410 treatment for the 
current case of influenza will be included as a covariate in 
the analysis. A P-value (using the Wald statistic) for each 
VIS410 dose vs placebo will be presented. 
Secondarily, subgroup analyses will be performed to 
describe the time to cessation of O2 for subgroups, such as 
use of positive pressure ventilation, use of endotracheal 
intubation, time from onset of symptom to VIS410 therapy, 
Renumbered due to deletion 
of previous section 10.6 
 
 
 
 
 
Moved this section to the top 
of the efficacy analyses as a 
component of the ordinal 
scale is now the primary 
objective/primary endpoint 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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number of oseltamivir doses prior to VIS410, elderly, and 
underlying lung disease. Clinical and virologic endpoints 
will also be evaluated by influenza A subtypes. 
Time to Clinical Response 
Time to clinical response is defined as resolution of 4 of 5 
vital signs that will be determined upon physical 
examination. Clinical response is defined as: 
 
Afebrile with core temperature ≤ 37.8°C, 
without use of antipyretics (oral ≤ 37.2°C) 
 
Respiratory rate ≤ 24 beats per minute 
 
Oxygen saturation ≥ 95% on room air without 
support or a return to pre-infection status, if 
pre-infection status was < 95% 
 
Pulse rate ≤ 100/min 
 
SBP ≥ 90 mm/Hg, without vasopressor use 
The probability of time to clinical response (defined as 
resolution of vital signs) will be calculated via Kaplan-
Meier. A P value significance test (using the log-rank test) 
for each VIS410 dose vs placebo will be presented. The 
number and percentage of subjects in each treatment group 
with clinical response will be summarized. Results will be 
tabulated and presented graphically as well. 
Time to Cessation of Ventilator Support 
The probability of time to cessation of ventilator support will 
be calculated via Kaplan-Meier. A P-value (using the log-
rank test) for each VIS410 dose vs placebo will be presented. 
Results will be tabulated and presented graphically as well. 
Healthcare Resource Utilization 
Descriptive statistics will be used to compare the total 
number of days in the hospital and/or ICU from admission to 
discharge, number of subjects requiring ICU admission post-
randomization, overall number of days in the ICU, number 
of hours on ventilation, rehospitalization due to influenza A 
relapse/reinfection, the total number of days of oseltamivir 
therapy, and the total number of days to resumption of usual 
activities by treatment group.  
Time (number of days) to resumption of usual activities will 
be determined from the VAS (scale ranged from 0 to 10, 
where 0 indicates subject is unable to perform any of his/her 
usual activities prior to influenza onset, and 10 indicates 
subject is able to fully perform all usual activities). 
This evaluation will be performed using the MITT 
population. 
Signs and Symptoms of Influenza 
Descriptive statistics will be used to compare the duration of 
symptoms of influenza-like illness in the subset of subjects 
able to complete the FluPRO Questionnaire at baseline and 
post-dose by treatment group. The number and percentage of 
subjects who were not able to complete the assessment at 
each visit will be summarized. 
Frequency tabulation of the occurrence and severity of each 
subject-reported symptom of influenza-like illness (via 
FluPRO Questionnaire) will be summarized by assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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time point and by treatment group. Time to resolution of 
symptoms will be evaluated by Kaplan Meier analysis. 
Analyses of the signs and symptoms of influenza will be 
conducted only on the subset of the MITT population who 
had baseline FluPRO Questionnaire assessments. Additional 
populations may be analyzed as described in the SAP. 
Clinical Outcome by Seven Level Ordinal Scale 
The ordinal scale outcomes will be measured daily from Day 
1 (baseline) through Day 14 using the seven level 
hierarchical scale with the classifications presented in Table 
2. The clinical outcomes therein are ordered from the worst 
clinical outcome to the best clinical outcome in descending 
order. For each day, subjects will be classified by the worst 
clinical outcome for which they qualify. 
The number and percentage of subjects in each treatment 
group with each classification will be summarized for each 
day from Day 1 through Day 14, inclusive. 
Table 2. 
Hierarchical Seven Level Ordinal Scale 
for Clinical Outcomes 
Clinical Parameter 
Death 
ICU stay with mechanical ventilation 
ICU stay without mechanical ventilation 
Non ICU hospitalization with supplemental oxygen 
Non-ICU hospitalization without supplemental oxygen 
Discharge with partial resumption of normal activities 
Discharge with full resumption of normal activities 
Note: Clinical outcomes listed from worst clinical 
outcome to best clinical outcome in descending order. 
 
 
 
 
 
 
 
Moved this section to the top 
of the efficacy analyses as a 
component of the ordinal 
scale is now the primary 
objective/primary endpoint. 
Section 10.8.3 
Complications 
of Influenza 
Now Section 10.7.3  
Complications of influenza are defined as pneumonia, 
myocarditis, worsening of chronic bronchitis, sinusitis, otitis 
or other chronic pulmonary diseases, encephalopathy, and 
death. Complications of influenza and use of antibiotic 
therapy for bacterial pneumonia will be reported by variable, 
treatment group, and time point. Diagnosis of bacterial 
pneumonia will be based on local clinical practice, usually 
an assessment of clinical features and any radiographic 
evidence of bacterial pneumonia (eg, infiltrate) and/or 
microbiologic evidence of bacterial pneumonia. All-cause 
and attributable mortality will be evaluated on Days 14 and 
28. 
Clarification 
Sections 10.8 -
10.12 
Renumbered sections due to deletion of original section 
10.6; now 10.7 - 10.11 
Correction 
Section 12.1.2 
Subject 
Informed 
Consent 
Each subject or a legally authorized acceptable 
representative 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 
Change requested by an 
Ethics Committee 
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accordance with principles that originated in the Declaration 
of Helsinki, current ICH and GCP guidelines, applicable 
regulatory requirements, and Sponsor policy. 
Before enrolling potential subjects in the study, the 
Investigator or an authorized member of the investigational 
staff must explain to the subject the aims, methods, 
reasonably anticipated benefits, and potential hazards of the 
study, and any discomfort that participation in the study may 
entail. Subjects 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 Informed Consent Form (ICF) the subject is 
authorizing such access and agrees to allow his/her study 
physician to recontact 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 nontechnical 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. 
Section 14.2 
Laboratory 
Assessments 
Other Assessments 
Urine pregnancy test 
Erythrocyte Sedimentation Rate (ESR) 
C-Reactive Protein (CRP) 
Added to complete the 
assays being performed 
 
                                                 
i 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):1016–24. 
ii Schanzer DL, Langley JM, Tam TW. Co-morbidities associated with influenza attributed 
mortality, 1994-2000, Canada. Vaccine 2008;26(36):4697–703. 
iii CDC. Estimates of deaths associated with seasonal influenza US, 1976-2007. MMWR. 
2012;59(33):1057–62. 
iv WHO. Seasonal Influenza Fact sheet N°211. 2014. 
http://www.who.int/mediacentre/factsheets/fs211/en. Accessed 10 Mar 2014. 
v World Health Organization (WHO). Pandemic (H1N1) 2009-update 70. 
http://www.who.int/csr/don/2009_10_16/en/index.html. Accessed 25 October 2009. 
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SUMMARY OF CHANGES TO PROTOCOL VIS410-203 
FROM VERSION 1.0 TO VERSION 2.0 
Substantive changes to the protocol for Amendment 1 and their location within the protocol are noted 
below. Additions are marked as red underlined text and deletions are marked as red strikethrough text. 
Administrative, stylistic and formatting changes that do not alter the conduct of the study are not 
summarized in this document. 
Location in 
Protocol 
Changes 
Rationale 
Cover Page; 
Signature of 
Sponsor 
Representative 
Issue Date (Version): 21 October 2016 (Version 1.0) 
 
 
 
 
 
20 June 2017 (Version 2.0) 
 
Sponsor Representative
  
                                         
 
Updated date and version 
number. 
 
Sponsor representative 
updated. 
Protocol History 
Protocol History 
Visterra, Inc.  VIS410 203 
Document  
Issue Date 
Amendm
ent Type 
Comments 
Clinical 
Study 
Protocol 
21 October 
2016 
(Version 1) 
 
This 
document 
 
Deleted because changes 
will be summarized in a 
separate Summary of 
Changes document (this 
file). 
Synopsis and 
Section 2.2 
Secondary 
Objectives 
• 
Evaluate the effect of VIS410 + oseltamivir vs 
oseltamivir alone on the following endpoints: 
 
Viral titer load in upper respiratory samples 
 
Time to clinical response 
 
Time to cessation of ventilator support 
 
Time to resumption of normal activities 
 
All-cause and attributable 14- and 28-day mortality 
 
Healthcare resource utilization 
 
Time to alleviation of clinical symptoms of 
influenza in subset of subjects able to complete the 
FluPRO Questionnaire at baseline and post-dose 
 
Proportion of subjects with new documented 
bacterial pneumonia/superinfection 
 
Proportion of subjects with influenza-related 
complications 
Viral load is a more accurate 
term to represent the test 
being conducted. 
Synopsis; 
Section 2.3 
Exploratory 
Objectives; 
Section 3.3 
Exploratory 
Endpoints;  
Section 6.3.12.3 
Serum 
Cytokines 
• 
Evaluate the effect of VIS410 + oseltamivir vs 
oseltamivir alone on clinical outcomes as measured by a 
seven-level ordinal scale 
• 
Evaluate the pharmacokinetics of VIS410 from 
nasopharyngeal secretions and tracheal aspirate 
(ventilated subjects only) 
• 
Assess the effects of VIS410 on viral titer load in 
tracheal aspirate (ventilated subjects only) 
• 
Assess correlations between virology, safety, VIS410 
dose, pharmacokinetics, viral shedding, immunogenicity 
immunology, signs and symptoms of influenza, and 
other endpoints 
• 
Assess the anti-influenza immune response 
• 
Evaluate serum cytokine profiles 
Viral load and immunology 
are more accurate terms. 
 
Exploratory cytokine 
objective removed from 
protocol. 
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Synopsis; 
Section 4.0 
Study Design; 
Section 4.3 
Data Safety 
Monitoring 
Board;  
Section 6.1.3 
Study 
Procedures; 
Section 7.5 
Pretreatment; 
Section 8.3.3 
Post-Treatment 
Procedures 
(Day 3 to 56); 
Section 11.4 
Stopping Rules 
or 
Discontinuation 
Criteria 
This is a Phase 2b multicenter, randomized, double-blind, 
controlled study comparing the efficacy and safety of 2 dose 
levels of VIS410 (2000 and 4000 mg) in combination with 
oseltamivir vs oseltamivir alone in hospitalized severely ill 
subjects with influenza A infection requiring oxygen. 
Subjects will be randomly assigned at a ratio of 1:1:1 using a 
permuted block randomization method to receive VIS410 at 
a dose of 2000 mg (low dose) or 4000 mg (high dose) or 
placebo (0.9% sodium chloride), administered as a single IV 
infusion over 2 hours. 
Randomization will be stratified by presence or absence of 
positive pressure ventilation (PPV) at baseline to ensure an 
even distribution across treatment arms (see Section 10.2). 
All subjects will receive oseltamivir 75 mg twice daily (BID) 
for 5 days (total of 10 doses) as part of standard of care 
(SOC). Treatment with oseltamivir may be extended for up 
to 5 additional days (up to 20 doses of total therapy) if 
clinical symptoms warrant further treatment as assessed by 
the Investigator. Note: based on SOC, subjects may have 
started oseltamivir therapy prior to randomization. All 
subjects will also receive a pretreatment regimen of 
diphenhydramine 50 mg PO or IV plus either ibuprofen 400 
mg PO or acetylsalicylic acid 320-325 mg PO 60 minutes 
before VIS410/placebo infusion. Approximately 390 
evaluable subjects (130/arm) with confirmed influenza A 
infection will be treated.  
Subjects admitted to the hospital within 5 days of onset of 
initial symptoms who require supplemental oxygen of at 
least 40% (4 L/min) and/or hypoxemia defined as SpO2 of 
less than 90% will undergo a rapid influenza test (supplied 
by the Sponsor) or a PCR test, fluorescent immunoassay 
(FIA) test, or enzyme-linked immunosorbent assay (ELISA) 
test to confirm influenza A infection. Subjects diagnosed 
with influenza A will undergo the screening procedures to 
confirm eligibility. Study assessments are outlined in 
Table 1, Schedule of Assessments. 
Eligible subjects will be randomized to receive either 
oseltamivir + VIS410 2000 mg, oseltamivir + VIS410 4000 
mg, or oseltamivir + placebo (0.9% sodium chloride) at a 
ratio of 1:1:1 using a permuted block randomization method 
summarized in Table 6. 
(Randomization table, unchanged) 
Oseltamivir (Tamiflu®) will be provided by the Sponsor. 
Treatment with oseltamivir may be extended for up to 
5 additional days (up to 20 doses of total therapy) if clinical 
symptoms are not resolved by Day 5 or warrant further 
treatment as assessed by the Investigator. Note: based on 
SOC, subjects may have started oseltamivir therapy prior to 
randomization. 
Study assessments are outlined in Table 1. Subjects 
discharged from will be monitored daily while in the hospital 
prior up to Day 14 will attend (± 3 days) with additional 
visits on Day 28 (± 3 days) and the applicable outpatient last 
follow-up visit(s) (eg, Day 3, Day 5, on Day56 (± 7days). 
Study assessments are outlined in, Day 14) per Table 1 
(Schedule of Assessments). 
Based on change to 
Inclusion Criteria regarding 
oxygen requirement, it is 
more accurate to define 
subjects as hospitalized, not 
severely ill.  
 
Clarified that subjects will 
receive either ibuprofen or 
acetylsalicylic acid, not both. 
 
Dose for acetylsalicylic acid 
changed to comply with 
standard dose in various 
countries.  
 
Inclusion Criteria regarding 
oxygen requirement has been 
modified to allow 
participation of less severe 
infections, hence subjects no 
longer require a specific 
concentration or amount of 
oxygen support to be eligible 
for the study. 
 
Clarified that subjects may 
have started oseltamivir 
treatment prior to enrollment 
in the study; total minimum 
and maximum doses the 
same for all subjects 
regardless of when a subject 
began oseltamivir. 
 
Clarified that subjects 
discharged from the hospital 
will attend follow-up visits; 
the number of outpatient 
follow-up visits are 
dependent on when the 
subject is discharged from 
the hospital. 
 
Defined GI TEAEs that 
require intervention. 
 
Updated statistical language 
related to the error rate and 
the interim analysis. 
 
The DSMB will review 
safety data after 
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An independent data safety monitoring board (DSMB) will 
be established to review all available safety data after 
30 subjects as well as when and approximately 120 subjects 
have completed study Day 14 7. The assessment of safety 
will be determined from vital sign measurements, physical 
examinations, hematology, chemistry and urinalysis 
laboratory testing, 12-lead electrocardiograms (ECGs), use 
of concomitant medications, and review of adverse events 
(AEs). Based on the safety data provided, the DSMB will 
determine if it is acceptable to continue the study or reduce 
the dose as appropriate. Dosing will temporarily pause while 
the DSMB meets if there are 4 treatment-related serious 
adverse events (SAEs) or 4 severe gastrointestinal (GI) 
treatment–emergent adverse events (TEAEs) that require 
intervention, which is defined as requiring IV fluid and 
medication to decrease the frequency of diarrhea 
(ie, loperamide). 
Additional DSMB reviews can occur throughout the trial as 
deemed necessary by the DSMB or Sponsor to ensure 
subject safety and well-being. Study enrollment and dosing 
will continue while the DSMB evaluates data. 
In addition, following 50% enrollment (195 subjects), an 
interim analysis may will be conducted, by an unblinded 
third party, to assess if one of the VIS410 treatment arms can 
be terminated early for futility. A prespecified sample size 
reanalysis may also be conducted based on the observed 
effect size. The interim analysis may will also test the 
primary efficacy objective to assess if the primary efficacy 
endpoint has been met. An alpha spending function will be 
designed in order to determine the amount of alpha that will 
be spent at the interim analysis. The effect size for this study 
was estimated without the benefit of any prior randomized 
controlled trial. If the VIS410 effect size proves to be greater 
than anticipated, then it is possible that the primary study 
endpoint will be met by the time the interim efficacy analysis 
is performed. In the event the interim analysis reveals that 
the primary efficacy endpoint has been satisfied, this Phase 2 
study could be terminated for efficacy. 
approximately 30 subjects 
and 120 subjects complete 
Day 14 to allow more safety 
data to be reviewed. 
Synopsis and 
Section 5.2.1 
Inclusion 
Criteria 
Only revised list items shown: 
4. Requirement for oxygen support including any positive 
pressure ventilation (PPV). 
4. Need for supplemental oxygen of at least 40% (4 L/min) 
and/or hypoxemia defined as SpO2 of less than 90% 
 
Inclusion Criteria regarding 
oxygen requirement has been 
modified to allow 
participation of less severe 
infections, hence subjects no 
longer require a specific 
concentration or amount of 
oxygen support to be eligible 
for the study. 
Synopsis and 
Section 5.2.2 
Exclusion 
Criteria 
Only revised list items shown: 
2. Subjects who have received VIS410 in the past History 
of receiving monoclonal antibody products (including 
VIS410) within 3 months prior to VIS410/placebo 
dosing or planned administration during the study 
period. 
3. Subjects who have a history of receiving monoclonal 
antibody products within 3 months prior to 
VIS410/placebo dosing or planned administration of 
Clarified that subjects are 
not eligible for the study if 
they have received VIS410 
in the past. 
 
Clarified exclusion criteria 
of subjects that have 
Influenza B or another viral 
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another monoclonal antibody during the study period. 
5. Subjects with known co-infection with influenza B or 
other viral respiratory infections (eg, respiratory 
syncytial virus [RSV], parainfluenza viruses, respiratory 
adenoviruses).infection 
6. Subjects with lung transplant or history of severe 
chronic lung disease, including cystic fibrosis or any 
condition requiring > 2 L/minute of home oxygen 
therapy.(ie, severe chronic obstructive pulmonary 
disease [COPD], pulmonary fibrosis) 
7. Subjects on extracorporeal membrane oxygenation 
(ECMO) at time of randomization. 
8. Hospitalization for > 48 hours prior to randomization 
8. Subjects with end-stage renal disease (ESRD) who are 
not undergoing hemodialysis. 
 
respiratory infection. 
 
Clarified exclusion criteria 
of cystic fibroses subjects; 
due to changes in patient 
population , subjects that 
require oxygen therapy at 
home are not eligible for the 
study. 
 
Subjects hospitalized before 
enrollment in the study are 
eligible as long as the onset 
of influenza symptoms are 
no more than 5 days before 
treatment with VIS410/ 
placebo (Inclusion 
Criteria 3). 
 
For consistency with 
oseltamivir prescribing 
information, subjects with 
ESRD who are not 
undergoing hemodialysis are 
excluded from the study. 
Synopsis; 
Section 7.1 
Test Product, 
Dose, Mode of 
Administration; 
Section 7.2 
Reference 
Product, Dose, 
Mode of 
Administration 
¶ 2 only: 
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, in addition 
to oseltamivir (Tamiflu) 75 mg BID for total of 5 days 
(10 doses). Treatment with oseltamivir may be extended for 
up to 5 additional days (up to 20 doses of total therapy) if 
clinical symptoms are not resolved by Day 5 and/or warrant 
further treatment as assessed by the Investigator. Note: based 
on SOC, subjects may have started oseltamivir therapy prior 
to randomization. No dose adjustment is necessary for 
VIS410 based on renal or hepatic impairment. For patients 
with renal insufficiency, rRefer to prescribing information 
for administration of oseltamivir in patients with renal 
insufficiency.  
Clarified that subjects are 
required to be treated with 
oseltamivir for a minimum 
of 5 days but that treatment 
may be extended up to 10 
days. 
 
Clarified that subjects may 
have started oseltamivir 
treatment prior to enrollment 
in the study; the total 
minimum and maximum 
doses are the same for all 
subjects regardless of when a 
subject began oseltamivir. 
Synopsis and 
Section 7.3 
Instructions for 
Preparation, 
Use, and 
Administration 
The infusion bag will be covered with an opaque sleeve in 
the pharmacy to maintain the study blind. The 
VIS410/placebo 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 extended up 
to 4 hours at the Investigator’s discretion based on local 
infusion site–related symptoms. VIS410 or placebo will be 
administered within 48 hours of being prepared by the study 
pharmacist. 
When 200 mL has been administered, the line will be 
flushed with 25 mL of normal saline. The infusion time may 
be longer at the Investigator’s discretion based only on local 
infusion site–related symptoms up to a maximum of 4 hours. 
The window for 
administration of 
VIS410/placebo after 
preparation by the 
pharmacist has been deleted 
and will be noted in the 
Pharmacy Manual. 
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VIS410 or placebo will be administered within 48 hours of 
being prepared by the study pharmacist. After preparation, 
the VIS410/placebo infusion bag should be stored at room 
temperature. 
Synopsis and 
Section 3.1.1 
Primary 
Efficacy 
Endpoint 
Time to cessation of O2 support resulting in a stable SpO2 by 
pulse oximetry. Stable SpO2 is defined as two consecutive 
SpO2 values of > 92% on room air that are> 95% for at least 
86 hours apart. on room air, return to baseline respiratory 
status, or hospital discharge with no need for additional O2 
support, whichever occurs first. 
Time to cessation of O2 
support redefined based on 
update to Inclusion Criteria 
regarding oxygen 
requirement. 
Synopsis and 
Section 3.2 
Secondary 
Endpoints 
Only revised bullet with its sub-bullets  shown: 
• 
Time to clinical response defined as resolution of at 
least 4 of 5 vital signs 
 
Afebrile with core temperature ≤ 37.8°C, without 
use of antipyretics (oral ≤ 37.2°C) 
 
Oxygen saturation ≥> 95% on room air without 
support or a return to pre-infection status, if pre-
infection status was < 95% 
 
Pulse rate ≤ 100/min 
 
Systolic blood pressure (SBP) ≥ 90 mm/Hg, without 
vasopressor use 
 
Respiratory rate ≤< 24 beats per minute 
Specified that temperature 
endpoint specific to core 
temperature; also defined 
equivalent oral temperature. 
 
Updated definition of time to 
clinical response for oxygen 
saturation and respiratory 
rate. 
Section 6.1.1 
Prescreening 
Procedures 
Subjects may be asked to sign a Prescreening Consent prior 
to undergoing a single nasopharyngeal swab (one nostril) for 
rapid influenza A testing. Subjects will be given a full 
explanation of the nature of the study and provide full 
written informed consent before any study-specific 
assessments or procedures are performed. Note: subjects that 
tested positive for influenza A within 48 hours prior to 
screening do not need to be retested. This screening test is 
not necessary if the subject has a prior influenza A positive 
test by RAT or with another commercially available test 
including PCR, FIA, or ELISA within the prior 48 hours of 
screening. 
Clarified that a pre-screening 
consent to perform rapid 
influenza testing is optional 
as this may depend on 
country and site 
requirements. 
Section 6.2 
Pregnancy 
Safeguards 
Pregnancy will be determined by evaluation of β-human 
chorionic gonadotropin in serum or urine for all women of 
childbearing potential. Subjects who are pregnant or nursing 
will be excluded from the study. During the course of the 
study drug administration period within the study, any 
nursing mother(s) or subject(s) with suspected or confirmed 
pregnancy will be discontinued from study drug therapy but 
will be encouraged to undergo follow-up for safety 
monitoring for themselves (ie, the pregnant female) and the 
baby. 
All women of childbearing potential and all male subjects 
must practice effective contraception from screening until 60 
days post-VIS410/placebo infusion. For the purposes of this 
study, women who do not satisfy at least one of the 
following criteria listed below (ie, the criteria for defining 
non-childbearing potential) are considered to be 
physiologically capable of becoming pregnant and are, 
therefore, defined as women of childbearing potential. 
The criteria for defining women as being of non-childbearing 
potential are: 
Clarified that any pregnancy 
should be reported up until 
60 days post VIS410/placebo 
dosing. 
 
Clarified the contraception 
requirements for women of 
childbearing potential and all 
male subjects. 
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• 
Post-menopausal: ≥ 12 months of natural (spontaneous) 
amenorrhea, or 
• 
Six weeks after surgical bilateral oophorectomy with or 
without hysterectomy, or 
• 
Follicle stimulating hormone > 40 mIU/mL as 
documented in their medical history, or 
• 
Surgical bilateral oophorectomy with or without 
hysterectomy, or 
• 
Hysterectomy, or 
• 
Bilateral tubal ligation 
Women of childbearing potential and all male subjects 
participating in heterosexual relations must be willing to 
practice effective contraception from screening until 60 days 
post-VIS410/placebo infusion. For the purposes of the study, 
highly effective contraception is defined as: 
• 
Male vasectomy with negative semen analysis 
documentation at least 6 months prior to dosing.  
OR 
• 
Combination of an established form of hormonal 
contraception (oral, injected, or implanted) or an 
intrauterine device or intrauterine system 
Plus one of the following: 
And 
• 
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. 
OR 
• 
Male vasectomy with negative semen analysis 
documentation less than The use of contraception does 
not apply if the male partner has been vasectomized at 
least 6 months prior to dosing. OR 
• 
Complete abstinence can be considered an acceptable 
method of contraception at the discretion of the 
Investigator. Periodic abstinences (eg, calendar, 
ovulation, symptothermal, or post-ovulation methods) 
and withdrawal are NOT considered acceptable methods 
of contraception. 
The combination of 2 barrier methods, periodic abstinence 
(eg, calendar, ovulation, symptothermal, or post-ovulation 
methods), and withdrawal are not considered acceptable 
methods of contraception. 
Pregnancy reporting is described in Section 9.7.3. 
Section 6.3.1 
SpO2 Oxygen 
Support 
Baseline SpO2 on room air to be documented, if available. 
Once randomized, SpO2 will be measured using pulse 
oximetry 3 times per day (approximately every preferably 8 
hours apart) at approximately the same time each day until 
stable according to Table 1. Stable the schedule of 
assessment. SpO2 is defined as two consecutive SpO2 values 
of > 92% will be measured using pulse oximetry until > 95% 
Clarified time points for 
obtaining SpO2 
measurements and definition 
of stable SpO2. 
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for at least 6 hours on room air that are at least 8 hours apart. 
Synopsis; 
Section 6.3.2; 
Section 6.3.11; 
 
Section 10.10 
Section subheading titles only 
6.3.2  
Viral Load Titer 
6.3.11 
Pharmacokinetics and Viral Load Titer in Tracheal 
Aspirate 
10.10 
Viral Load Titer 
Section heading only 
revised. 
Section 6.3.4 
Resumption of 
Normal 
Activities 
Subjects will complete a visual analog scale (VAS) daily 
from Day 1 (baseline) until either the subject reports that all 
usual activities (prior to influenza onset) can be performed or 
Day 56, whichever comes first. The VAS scale ranges scale 
ranged from 0 to 10, where 0 indicates subject is unable to 
perform usual activities at all, and 10 indicates subject is 
able to perform all usual) according to the time points 
defined in activities fully) 
Added language to require a 
subject to complete VAS 
from baseline until the 
subject reports they are able 
to perform all usual activities 
they were performing prior 
to influenza onset.  
Section 6.3.8 
Viral Resistance 
Samples for virologic and PK analysis A nasopharyngeal 
swab will be collected from each nostril as described in 
Table 1 and the laboratory manual. These samples swabs 
will be sent to a central virology laboratory for processing 
into appropriate aliquots for virology and PK analysis, 
including resistance testing. 
Further procedures for sample collection, processing, 
shipment, and storage will be described in the laboratory 
manual. 
Note: 
Nasopharyngeal and tracheal samples taken from all 
subjects may be infectious and will be classified as 
“diagnostic specimens” for dispatch purposes. 
Updated language to more 
accurately describe virologic 
analysis which includes PK 
analysis and resistance 
testing. 
Section 6.3.12 
Immunology 
Immunogenicity 
¶ 1 only: 
The immunology immunogenicity parameters under 
evaluation are the detection of ADA titers and 
anti-influenza A antibody titers by hemagglutination 
inhibition assay (HAI), and serum cytokine concentrations. 
Updated language to more 
accurately describe 
immunology evaluation. 
Exploratory cytokine 
objective removed from 
protocol. 
Section 6.5.3 
Complications 
of Influenza; 
Section 10.8.3 
Complications 
of Influenza 
Complications of influenza are defined as pneumonia, 
myocarditis, worsening of chronic bronchitis, sinusitis, otitis, 
other chronic pulmonary diseases, encephalopathy, and 
death. Complications of influenza and use of antibiotic 
therapy for bacterial pneumonia will be reported by variable, 
treatment group, and time point. Diagnosis of bacterial 
pneumonia will be based on local clinical practice, usually 
an assessment of clinical features and any radiographic 
evidence of bacterial pneumonia (eg, infiltrate) and/or 
microbiologic evidence of bacterial pneumonia. All-cause 
and attributable mortality will be evaluated on Day 14 and 
Day 28. 
Clarified that diagnosis of 
bacterial pneumonia will be 
based on local clinical 
practice. 
Section 6.5.4 
Clinical 
Laboratory 
Tests 
Blood samples will be collected by venipuncture or via 
indwelling cannula at the time points indicated in Table 1. 
Standard laboratory tests will be performed by a central or 
local laboratory. Appendix 14.2 lists the biochemistry, 
hematology, and coagulation, and serology tests that will be 
performed by the central laboratory on the safety blood 
samples. Note: subjects to be enrolled based on the 
Investigator’s discretion including any local laboratory 
results per SOC at institution.  
Updated language to state 
that the required baseline 
laboratory tests will be sent 
to the central laboratory for 
consistency of data for trial 
analysis. However, for 
enrollment, Investigators 
should use local laboratory 
testing for pregnancy and 
serum creatinine. Subject’s 
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Creatine kinase-MB, creatinine kinase, and troponin are to 
be measured by the central laboratory in the event of a 
subject having chest pain. Subjects with chest pain should be 
managed per SOC. 
In the event of a subject exhibiting the signs and symptoms 
of an anaphylactic reaction, when possible at the time of the 
event, a 5-ml serum sample should be collected for further 
assessment (ie, tryptase, chymase) to be measured by the 
central laboratory. 
A midstream urine sample will be collected for the central 
laboratory for urinalysis by dipstick, flow cytometry, and 
microscopic examination. Appendix 14.2 lists the urinalysis 
parameters that will be assessed. 
A serum Serum or urine pregnancy tests will be performed 
by at the central laboratory for all time points indicated in 
Table 1. In addition, a negative Pregnancy test (serum or 
urine) result within 2 days prior to dosing results must be 
available from the local laboratory prior to randomization. A 
negative result is required for randomization. 
For oseltamivir dosing, creatinine clearance (Cockcroft-
Gault Equation) must be calculated using the serum 
creatinine value from the local laboratory prior to 
randomization. 
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. 
overall health for 
participation in the trial 
should be based on 
institutional practices and 
local laboratory results. 
 
Clarified that laboratory tests 
required in the case of a 
subject experiencing chest 
pain will be sent to the 
central laboratory for 
analysis while these subjects 
should be managed based on 
institutional practices and 
Investigator discretion. 
 
Clarified that all pregnancy 
testing will be performed at 
the central laboratory but 
that a negative pregnancy 
test performed by the local 
laboratory is required within 
2 days of dosing. 
 
Specified that creatinine 
clearance should be 
calculated by using the 
Cockcroft-Gault equation. 
Section 6.5.5 
Vital Signs and 
Body 
Temperature 
Vital sign parameters will be assessed after 5 minutes in 
supine position at the time points indicated in Table 1. The 
vital sign parameters that will be assessed are supine SBP, 
DBP, heart rate, and respiratory rate. 
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 as an AE adverse 
event. 
Oral body temperature will be recorded at the end of infusion 
then BID while in the hospital and then throughout the study 
according to the study procedures outlined in Table 1. In 
cases where obtaining oral temperature is not possible, core 
temperature (eg, tympanic, axillary) will be obtained. 
While the patient is hospitalized, the maximum temperature 
should be recorded for each 12-hour interval (from 12 AM to 
12 PM and from 12 PM to 12 AM). Fever is defined as a core 
body temperature ≥ 38°C. 
Provided examples of core 
temperature methods. 
 
Clarified that fever is 
defined based on core 
temperature. 
Section 6.5.8 
Radiological 
Assessment 
A baseline chest x-ray or CT scan will be performed for the 
assessment of pneumonia. However, a chest x-ray or CT 
scan performed as part of routine SOC standard of care 
within 72 48 hours before randomization will be acceptable. 
The results of any such studies will be recorded in the EDC. 
The window has been 
expanded to allow use of 
local tests for diagnosis of 
pneumonia and minimize 
unnecessary tests for the 
purpose of the study. The 
72-hour window will allow 
detection of pneumonia at 
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baseline, if present. 
Section 7.4 
The Use of 
Oseltamivir as 
Standard of 
Care 
All subjects will receive oseltamivir 75 mg BID for 5 days as 
part of standard of care (SOC.). Treatment with oseltamivir 
may be extended for up to 5 additional days (up to 20 doses 
of total therapy) if clinical symptoms are not resolved by 
Day 5 or warrant further treatment as assessed by the 
Investigator. Oseltamivir (Tamiflu) will be provided by the 
Sponsor. Note: based on SOC, subjects may have started 
oseltamivir therapy prior to randomization.  
For patients unable to swallow, oseltamivir capsules can be 
opened and mixed with liquid for ease of administration. 
Dose adjustment is recommended for patients with a serum 
creatinine clearance of 60 mL/min or less9 (see Table 7). 
Clarified that subjects may 
have started oseltamivir 
treatment prior to enrollment 
in the study. 
 
Added guidelines on 
administration of oseltamivir 
in subjects unable to 
swallow in compliance with 
Tamiflu product information. 
Section 7.7 
Treatment 
Compliance 
¶ 2 only: 
The number of oseltamivir doses administered while the 
subject is in the hospital will be documented by the 
Investigator or his/her designee. In case of discharge while 
on oseltamivir therapy, subjects will document the number 
of doses taken at home and any missed doses; subjects self-
administering oseltamivir at home will bring the pack(s) pill 
bottle to each study visit so study staff may count and record 
the number of pills taken. Any unused capsules must be 
returned to the study site. 
Clarified that oseltamivir 
will be provided in packs, 
not pill bottles. 
Section 8.2.1 
Prohibited 
Prior 
Medications 
¶ 1 only: 
Per Exclusion Criterion 3 (Section 5.2.2) subjects are not 
allowed to receive monoclonal antibody products (including 
VIS410) within 3 months prior to VIS410/placebo dosing. 
Removed incorrect reference 
to VIS410. 
Section 8.2.2 
Prohibited 
Concomitant 
Medications 
¶ 1 only: 
Per Exclusion Criterion 2 (Section 5.2.2), subjects will not 
be allowed to receive additional monoclonal antibody 
products during the study period. Following randomization, 
use of other antiviral therapy for treatment of influenza A 
infection will not be permitted. Excluded antiviral 
medications include but are not limited to rimantadine, 
amantadine, peramivir, zanamivir, and laninamivir. 
Clarified language since 
VIS410 is a monoclonal 
antibody. 
Section 8.4 
Subject Diary 
A subject diary will be provided upon discharge from the 
hospital and will record the following: 
• 
Daily oseltamivir dosing to be completed for as long as 
the subject continues to take oseltamivir 
• 
Daily VAS for assessing resumption of usual activities 
to be completed up until either the subject reports that 
all pre-influenza usual activities can be performed or 
Day 56, whichever comes first 
• 
Daily Influenza Patient Reported Outcomes (FluPRO) 
Questionnaire to be completed until Day 14, if 
applicable 
Added specific list of what 
will be included in the 
subject diary. 
Section 9.1.3 
Adverse Event 
of Special 
Interest 
For VIS410, the AESIs include the following: 
• 
Abdominal cramping 
• 
Diarrhea/Loose stool 
• 
Nausea  
• 
and vomiting 
Updated AESI list to include 
single episodes of loose 
stool.  
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Congenital abnormalities and birth defects in the offspring of 
male or female subjects should be reported as an SAE if 
conception occurred during the study treatment period or in 
the 60 56-day period after the last dose of VIS410/placebo. 
Section 10.1 
Determination 
of Sample Size 
¶ 2 only: 
Using a log-rank test, a sample size of 130 influenza A–
infected subjects per treatment group will provide 80% 
power to detect a 1.5-day difference (5 days for oseltamivir 
alone and 3.5 days for VIS410 plus oseltamivir) in the 
median time to cessation of O2 support resulting in a stable 
SpO2 > 95% for at least 6 hours on room air, return to 
baseline respiratory status, or hospital discharge with no 
need for additional O2 support, whichever occurs first for 
VIS410 relative to placebo. A two-sided alpha of 0.05 was 
used for the calculation. 
Section updated to maintain 
consistency with prior 
changes. 
Section 10.6 
Interim Analysis 
An The first interim analysis of efficacy may will be 
performed by an unblinded third party after 50% of subjects 
have been enrolled (n = 195) and have an assessment of the 
primary endpoint (time to normalization of respiratory 
function). This interim analysis may will be conducted to 
assess if one of the active VIS410 treatment arms will need 
to be terminated for futility. Using the methods of Lan and 
DeMets an alpha spending function will be created and if the 
test statistic for one of the active VIS410 treatment arms is 
less than the lower critical point then the VIS410 treatment 
arm may be terminated for futility. The interim analysis may 
The interim analysis will also test the primary efficacy 
objective to assess if the primary efficacy endpoint has been 
met early. 
The effect size for this study was estimated without the 
benefit of any prior randomized, controlled trial. If the 
VIS410 effect size proves to be greater than anticipated, then 
it is possible that the primary study endpoint will be met by 
the time the interim efficacy analysis is performed. In the 
event the interim analysis reveals that the primary efficacy 
endpoint has been satisfied, this Phase 2 study could be 
terminated for efficacy. 
The DSMB and the unblinded statistician will review the 
interim analysis results to provide their recommendation on 
discontinuation of one of the VIS410 treatment arms, if 
needed, based on pre-specified criteria as outlined in the 
SAP. The interim analysis may will also review the 
following key secondary endpoints, when available, to assist 
in the decision of discontinuing a VIS410 treatment arm: 
• 
Time to clinical resolution of vital signs 
• 
Total number of hours on oxygen support or PPV 
• 
Viral load titer from nasopharyngeal swabs 
A sample size re-estimation (SSRE) will also be performed 
at this point in order to determine if the current sample size 
is sufficient based on the observed effect size in the study. 
The unblinded statisticians will work directly with the 
Sponsor on the SSRE. The details of SSRE and individuals 
with access to the information will be out 
Clarified that an interim 
analysis may (or may not) be 
conducted due to rate of 
enrollment. 
 
Updated statistical methods 
and language to include 
more details related to the 
error rate and the interim 
analysis. 
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Location in 
Protocol 
Changes 
Rationale 
Section 10.7.1 
Time to 
Cessation of O2 
Support 
¶ 1 only: 
Time to cessation of O2 support resulting in a stable SpO2 
will > 95% for at least 6 hours, return to baseline respiratory 
status, or hospital discharge with no need for O2 support, 
whichever occurs first, will be analyzed using a Cox model. 
Time from onset of symptoms to VIS410 treatment and the 
number of doses of oseltamivir (Tamiflu) prior to VIS410 
treatment for the current case of influenza will be included as 
a covariate in the analysis. A P-value (using the Wald 
statistic) for each VIS410 dose vs placebo will be presented. 
Section updated to maintain 
consistency with prior 
changes. 
 
Clarified the statistical 
method planned to determine 
P-value. 
Section 10.7.2 
Time to Clinical 
Response; 
Section 10.7.3 
Time to 
Cessation of 
Ventilator 
Support 
Time to clinical response is defined as resolution of 4 of 5 
vital signs that will be determined upon physical 
examination. Clinical response is defined as: 
• 
Afebrile with core temperature ≤ 37.8°C, without use of 
antipyretics (oral ≤ 37.2°C) 
• 
Respiratory rate ≤< 24 beats per minute 
• 
Oxygen saturation ≥> 95% on room air without support 
or a return to pre-infection status, if pre-infection status 
was < 95% 
• 
Pulse rate ≤ 100/min 
• 
SBP ≥ 90 mm/Hg, without vasopressor use 
The probability of time to clinical response (defined as 
resolution of vital signs) will be calculated via Kaplan-
Meier. A P-value (using the log-rank test) for each VIS410 
dose vs placebo will be presented. The number and 
percentage of subjects in each treatment group with clinical 
response will be summarized. Results will be tabulated and 
presented graphically as well. 
Section updated to maintain 
consistency with prior 
changes. 
 
Added details on statistical 
method planned to determine 
P-value. 
Section 10.7.4 
Healthcare 
Resource 
Utilization 
¶ 2 only: 
Time (number of days) to resumption of usual activities will 
be determined from the VAS visual analog scale (scale 
ranged from 0 to 10, where 0 indicates subject is unable to 
perform any of his/her usual activities prior to influenza 
onset at all, and 10 indicates subject is able to fully perform 
all usual return to his/her normal activities fully). 
Added language to clarify 
that a subject needs to 
complete VAS from baseline 
until the subject reports they 
are able to perform all usual 
activities they were 
performing prior to influenza 
onset. 
Section 10.9.2 
Pharmacokin-
etics of 
Nasopharyngeal 
Secretions and 
Tracheal 
Aspirate 
Nasopharyngeal swabs will be obtained from both nostrils (1 
swab per nostril). The first 50 randomized subjects will have 
nasopharyngeal swabs collected up to Day 56 (predose, end 
of infusion, Days 3, 5, 7, 14, 28 and 56); while in the 
remaining subjects, nasopharyngeal swabs will be obtained 
up to Day 14 only. If the subject remains in the hospital on 
Day 10, then additional nasopharyngeal swabs will be 
obtained on Day 10. The VIS410 concentrations in the 
nasopharyngeal secretions and tracheal aspirate will be listed 
by subject, and summary statistics by group will be reported 
as described for the serum concentrations. The computed PK 
parameters will be listed by subject for VIS410. Summary 
statistics and PK parameters will be presented, including 
means, geometric means, standard deviations, CV, medians, 
and ranges, as appropriate. Summary graphs, including mean 
concentration-time profiles by group, will also be presented. 
The nasopharyngeal concentration data may also be analyzed 
by population PK pharmacokinetic methods using nonlinear 
Updated the planned PK 
analysis on nasopharyngeal 
swabs. to minimize the 
number of nasopharyngeal 
swabs in this study, the full 
nasal PK profile (Day 56) 
will be determined based on 
the first 50 subjects only. 
The remainder of the 
subjects will only have nasal 
PK along with nasal virology 
up to Day 14. PK analysis 
will be extrapolated beyond 
Day 14in these subjects 
based on population PK 
analysis. 
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Location in 
Protocol 
Changes 
Rationale 
mixed effects modeling as implemented in NONMEM or 
equivalent software. If necessary, the data may be pooled 
with data from previous studies. Additional analyses and 
summaries may be generated as appropriate. 
Results of population PK or PK/PD analyses may be 
reported outside the clinical study report. 
Section 10.11 
Immunological 
Analyses 
Immunological assessments will be summarized for the 
MITT population by parameter, treatment group, and time 
point using descriptive statistics: 
• 
Anti-influenza A antibodies by HAI in serum 
• 
ADA titers 
• 
Concentrations of cytokines in serum 
Updated language to more 
accurately describe all 
immunological analyses in 
one section. 
Section 10.12 
Viral Resistance 
Viral sensitivity to VIS410 and oseltamivir will be assessed 
over time during the study. This evaluation will be 
performed using the safety population 
Clarified that viral resistance 
will be assessed. Analysis 
population will be defined in 
the SAP. 
Appendix 14.1 
Footnote to Questionnaire 
Copyright© 2014, 2015, 2016 Leidos Biomedical Research, 
Inc. 
All rights reserved. 
Research Tool in Development: Do NOT copy or distribute 
Added appropriate copyright 
information. 
Schedule of 
Assessments 
Visit window of ± 1 day added to Day 5 and Day 7 
Visit window added to allow 
flexibility for subjects 
discharged from the hospital 
prior to Day 5. 
 
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SUMMARY OF CHANGES TO PROTOCOL VIS410-203 
FROM VERSION 2.1 TO VERSION 3.1 
Substantive changes to the protocol for Amendment 3.1 and their location within the protocol are 
noted below. Additions are marked as red underlined text and deletions are marked as red 
strikethrough text. Administrative, stylistic and formatting changes that do not alter the conduct of the 
study are not summarized in this document. 
Location in 
Protocol 
Changes 
Rationale 
Cover Page; 
Signature of 
Sponsor 
Representative 
Issue Date (Version): 3 July 2017 (Version 2.1  South 
Africa) 
19 April 2018 (Version 3.1 - South Africa) 
 
Sponsor Representative
 
                                        
Updated date and version 
number. 
 
Sponsor representative 
updated. 
Cover page; 
Sponsor 
Address 
Visterra, Inc. 
One Kendall Square, Suite B3301 275 Second Avenue, 4th 
Floor 
Cambridge Waltham, MA 0213902451 
United States of America 
Company moved location 
Synopsis: 
Number of 
Clinical Sites 
Approximately 180 140 sites worldwide 
Reduction in number of 
sites 
Synopsis: 
Number of 
Subjects 
Approximately 390 120 
Decreasing sample size 
from 390 to 120 subjects to 
enable completion in 2 
influenza seasons. 
Synopsis and 
Section 2.1.1 
Primary 
Efficacy 
Objective 
• 
Evaluate Evaluation of the effect of 2 dose levels of 
VIS410 + oseltamivir on the time to normalization of 
respiratory function compared to oseltamivir alone 
clinical outcome as assessed by comparison of clinical 
status ordinal scale Day 7 scores between treatment 
groups, and between all VIS410 recipients versus 
placebo.   
Utility of ordinal scale 
observed in prior trials of 
this size. 
Synopsis and 
Section 2.2 
Secondary 
Objectives 
• 
Among patients requiring supplemental oxygen 
therapy at the time of enrollment with baseline room 
air oxygen saturation of ≤ 92%, time to cessation of 
oxygen (O2) support resulting in stable oxygen 
saturation (SpO2) by pulse oximetry. Stable SpO2 is 
defined as two consecutive SpO2 values of > 92% on 
room air that are at least 8 hours apart. 
• 
For any patient requiring supplemental oxygen therapy 
at the time of enrollment (regardless of oxygen 
saturation), time to cessation of oxygen support.  
• 
Evaluate the effect of 2 dose levels of VIS410 + 
oseltamivir vs oseltamivir alone on the following 
parameters: 
• 
Viral load in upper respiratory samples 
• 
Time to clinical response 
• 
Time to cessation of ventilator support 
• 
Time to resumption of normal activities 
• 
All-cause and attributable 14-, and 28-, and 56-
day mortality 
Time to cessation of oxygen 
support changed from 
primary endpoint to 
secondary. Some patients 
may be on oxygen with O2 
saturation > 92% at 
baseline. 
 
 
 
 
 
 
 
 
Added ordinal scale 
parameters to be assessed 
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Location in 
Protocol 
Changes 
Rationale 
• 
Clinical status ordinal scale mean area under the 
curve for Days 1-7 and Days 1-14 using linear 
numeric scores for the ordinal categories. 
• 
Comparison of clinical status ordinal scale scores 
for selected individual days (i.e., Days 3, 4, 5, and 
6)  
• 
Comparison of clinical status ordinal scale scores 
using modified ordinal scale criteria (i.e. pooling 
of selected severity criteria scores) 
• 
Comparison of discrete ordinal scale parameters, 
including days of ventilator support, days in 
intensive care, and duration of hospitalization 
• 
Healthcare resource utilization 
• 
Analysis of time Time to alleviation of clinical 
signs and symptoms of influenza in the subset of 
subjects able to complete the Influenza Patient 
Reported Outcomes (FluPRO) Questionnaire at 
baseline and post-dose by Kaplan Meier analysis 
• 
Proportion of subjects with new documented 
bacterial pneumonia/superinfection 
• 
Proportion of subjects with influenza-related 
complications 
• 
Pharmacokinetics of VIS410 in serum 
• 
Immunogenicity of VIS410 
• 
Emergence of resistance to VIS410 and oseltamivir 
Synopsis and 
Section 2.3 
Exploratory 
Objectives 
• 
Evaluate the effect of VIS410 + oseltamivir vs 
oseltamivir alone on clinical outcomes as measured by 
a seven level ordinal scale 
• 
Evaluate the pharmacokinetics of VIS410 from 
nasopharyngeal secretions and tracheal aspirate 
(ventilated subjects only) 
• 
Assess the effects of VIS410 on viral load in tracheal 
aspirate (ventilated subjects only) 
• 
Assess correlations between virology, safety, VIS410 
dose, pharmacokinetics, viral shedding, immunology, 
signs and symptoms of influenza, and other endpoints 
• 
Assess the anti-influenza immune response 
Removed as components 
are now primary and 
secondary endpoints 
Synopsis  
Study Design 
This is a Phase 2b, multicenter, randomized, double-blind, 
controlled study comparing the efficacy and safety of 
2 dose levels of VIS410 (2000 and 4000 mg) in 
combination with oseltamivir vs oseltamivir alone in 
hospitalized subjects with influenza A infection requiring 
oxygen support. Subjects will be randomly assigned at a 
ratio of 1:1:1 using a permuted block randomization 
method to receive VIS410 at a dose of 2000 mg (low dose) 
or 4000 mg (high dose) or placebo (0.9% sodium chloride), 
administered as a single IV infusion over 2 hours. 
Randomization will be stratified by presence or absence of 
positive pressure ventilation (PPV) at baseline to ensure an 
even distribution across treatment arms. All subjects will 
receive oseltamivir 75 mg twice daily (BID) for 5 days 
Decreasing sample size 
from 390 to 120 subjects to 
enable completion in 2 
influenza seasons. Table in 
section also updated to 
reflect 40 subjects per arm. 
 
 
 
 
 
 
 
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Location in 
Protocol 
Changes 
Rationale 
(total of 10 doses) as part of standard of care (SOC). 
Treatment with oseltamivir may be extended for up to 
5 additional days (up to 20 doses of total therapy) if 
clinical symptoms warrant further treatment as assessed by 
the Investigator. Note: based on SOC, subjects may have 
started oseltamivir therapy prior to randomization. All 
subjects will also receive a pretreatment regimen of 
diphenhydramine 50 mg PO or IV plus either ibuprofen 
400 mg PO or acetylsalicylic acid 320-325 mg PO 
approximately 60 minutes before infusion. Approximately 
390 120 evaluable subjects (130 40/arm) with confirmed 
influenza A infection will be treated. 
Subjects admitted to the hospital within 5 days of onset of 
initial symptoms who require supplemental oxygen will 
undergo a rapid influenza test or a local polymerase chain 
reaction (PCR) test, fluorescent immunoassay (FIA) test, or 
enzyme-linked immunosorbent assay (ELISA) test to 
confirm influenza A infection. Subjects diagnosed with 
influenza A will undergo the screening procedures to 
confirm eligibility. Study assessments are outlined in 
Error! Reference source not found. (Schedule of 
Assessments). 
Eligible subjects will be randomized to receive either 
oseltamivir + VIS410 2000 mg, oseltamivir + VIS410 
4000 mg, or oseltamivir + placebo (0.9% sodium chloride) 
at a ratio of 1:1:1 using a permuted block randomization 
method according to the table below: 
Oseltamivir (Tamiflu®) will be provided by the Sponsor. 
Treatment with oseltamivir may be extended for up to 
5 additional days (up to 20 doses of total therapy) if 
clinical symptoms \warrant further treatment as assessed by 
the Investigator. Note: based on SOC, subjects may have 
started oseltamivir therapy prior to randomization. 
Study assessments are outlined in Error! Reference 
source not found.. Subjects discharged from the hospital 
prior to Day 14 will attend the applicable outpatient 
follow-up visit(s) (eg, Day 3, Day 5, Day 7, Day 14) per 
Error! Reference source not found.. 
An independent data safety monitoring board (DSMB) will 
be established to review all available safety data after 
30 subjects as well as when and again after approximately 
120 70 subjects have completed study Day 14 assessments. 
The assessment of safety will be determined from vital sign 
measurements, physical examinations, hematology, 
chemistry and urinalysis laboratory testing, 12-lead 
electrocardiograms (ECGs), use of concomitant 
medications, and review of adverse events (AEs). Based on 
the safety data provided, the DSMB will determine if it is 
acceptable to continue the study or reduce the dose as 
appropriate. Dosing will temporarily pause while the 
DSMB meets if there are 4 treatment-related serious 
adverse events (SAEs) or 4 severe gastrointestinal (GI)  
treatment–emergent adverse events (TEAEs) that require 
intervention, which is defined as requiring IV fluid and 
medication to decrease the frequency of diarrhea 
(ie, loperamide). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Performing second DSMB 
review after completion of 
Northern Hemisphere 
season. No need for DSMB 
review after 120 subjects; 
final analysis of data will be 
performed. 
 
 
 
 
 
 
 
 
 
 
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Location in 
Protocol 
Changes 
Rationale 
Additional DSMB reviews can occur throughout the trial as 
deemed necessary by the DSMB or Sponsor to ensure 
subject safety and well-being. Study enrollment and dosing 
will continue while the DSMB evaluates data. 
 In addition, following 50% enrollment (195 subjects), an 
interim analysis may be conducted, by an unblinded third 
party, to assess if one of the VIS410 treatment arms can be 
terminated early for futility. A prespecified sample size 
reanalysis may also be conducted based on the observed 
effect size. The interim analysis may also test the primary 
efficacy objective to assess if the primary efficacy endpoint 
has been met. An alpha spending function will be designed 
in order to determine the amount of alpha that will be spent 
at the interim analysis. The effect size for this study was 
estimated without the benefit of any prior randomized 
controlled trial. If the VIS410 effect size proves to be 
greater than anticipated, then it is possible that the primary 
study endpoint will be met by the time the interim efficacy 
analysis is performed. In the event the interim analysis 
reveals that the primary efficacy endpoint has been 
satisfied, this Phase 2 study could be terminated for 
efficacy.   
 
 
 
 
 
Removed interim analysis 
as sample size decreased to 
120 subjects; final analysis 
to be performed upon 
completion of enrollment. 
Synopsis and 
Section 5.1 
Number of 
Subjects 
Approximately 390 120 evaluable subjects will be enrolled 
in 3 equal arms: VIS410 2000 mg, VIS410 4000 mg, and 
placebo. 
Sample size decreased. 
Synopsis and 
Section 5.2.1 
Inclusion 
Criteria 
9.   Subject, or a legally acceptable authorized 
representative, is able to understand the purpose and risks 
of the study and willing to give voluntary written informed 
consent. 
Change requested by an 
Ethics Committee 
Synopsis  
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 (or volume equivalent to IV line volume if greater 
than 25 mL) saline flush to ensure all product is 
administered, in addition to oseltamivir (Tamiflu) 75 mg 
BID for total of 5 days (10 doses). For patients with renal 
insufficiency, refer to prescribing information for 
administration of oseltamivir. For patients unable to 
swallow, oseltamivir capsules can be opened and mixed 
with liquid for ease of administration. 
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, followed by a 
25-mL (or volume equivalent IV line volume if greater 
than 25 mL) saline flush to ensure all product is 
administered, in addition to oseltamivir (Tamiflu) 75 mg 
BID for total of 5 days (10 doses). For patients with renal 
insufficiency, refer to prescribing information for 
administration of oseltamivir. 
VIS410 and Placebo Preparation 
The required amount of VIS410 to be dosed (2000 mg or 
4000 mg) will be diluted with normal saline up to a 
maximum total volume of 200 mL; for placebo subjects, 
200 mL of normal saline will be prepared. Length of IV 
Clarification to ensure all 
study product administered. 
Some sites use infusion 
lines with hold-up volumes 
of greater than 25 mL. 
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Location in 
Protocol 
Changes 
Rationale 
line will ideally be set for maximum volume of 25 mL, so 
that the 25-mL (or increased volume as noted above) saline 
flush following administration will ensure all 
VIS410/placebo has been administered. In the event that 
the infusion line volume is greater than 25 mL the post-
administration saline flush should be increased to match 
the volume of the infusion line kit.   
The VIS410/placebo 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 whenever possible, 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 
VIS410/placebo 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 an appropriate volume saline flush as described 
above. The infusion time may be extended up to 4 hours at 
the Investigator’s discretion based on local infusion site–
related symptoms.  
All subjects will be given a pretreatment regimen of PO or 
IV diphenhydramine 50 mg plus either ibuprofen 400 mg 
PO or acetylsalicylic acid 320-325 mg PO or crushed and 
given through the nasogastric tube approximately 
60 minutes before IV infusion of VIS410/placebo. 
Synopsis and 
Section 3.1.1 
Primary 
Efficacy 
Endpoint 
• 
Time to cessation of oxygen (O2) support resulting in 
stable oxygen saturation (SpO2) by pulse oximetry. 
Stable SpO2 is defined as two consecutive SpO2 values 
of > 92% on room air that are at least 8 hours apart. 
• 
The primary efficacy outcome analysis compares Day 
7 clinical status ordinal scale scores between treatment 
groups, and between all VIS410 recipients versus 
placebo.  Clinical status is measured daily for 14 days 
using the below seven-level ordinal scale, with the 
classifications presented from the worst clinical 
outcome to the best clinical outcome in descending 
order; for each day, subject status will be classified by 
the worst clinical outcome for which they qualify.  
 
Death 
 
ICU stay with mechanical ventilation 
 
ICU stay without mechanical ventilation 
 
Non-ICU hospitalization with supplemental 
oxygen 
 
Non-ICU hospitalization without supplemental 
oxygen 
 
Discharge with partial resumption of normal 
activities 
 
Discharge with full resumption of normal 
activities 
Primary objective changed. 
Synopsis and 
Section 3.2 
Secondary 
Endpoints 
The difference between VIS410 + oseltamivir and 
oseltamivir alone treatment groups in the following 
endpoints:  
 
 
 
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Location in 
Protocol 
Changes 
Rationale 
• 
Among patients requiring supplemental oxygen 
therapy at the time of enrollment with baseline room 
air oxygen saturation of ≤ 92%, time to cessation of 
oxygen (O2) support resulting in stable oxygen 
saturation (SpO2) by pulse oximetry. Stable SpO2 is 
defined as two consecutive SpO2 values of > 92% on 
room air that are at least 8 hours apart. 
• 
For any patient requiring supplemental oxygen therapy 
at the time of enrollment (regardless of oxygen 
saturation), time to cessation of oxygen support 
• 
Peak viral load, viral area under the concentration–
time curve (AUC), duration of viral shedding, and 
time to resolution of viral load from nasopharyngeal 
swabs by TCID50 and qRT-PCR 
• 
Time to clinical response defined as resolution of at 
least 4 of 5 vital signs: 
• 
Afebrile with core temperature ≤ 37.8°C, without 
use of antipyretics (oral ≤ 37.2°C) 
• 
Oxygen saturation ≥ 95% on room air without 
support or a return to pre-infection status, if pre-
infection status was < 95% 
• 
Pulse rate ≤ 100/min 
• 
Systolic blood pressure (SBP) ≥ 90 mm/Hg, 
without vasopressor use 
• 
Respiratory rate ≤24 beats per minute 
• 
Total number of days on ventilation 
• 
Clinical status ordinal scale mean area under the curve 
for Days 1-7 and Days 1-14 using linear numeric 
scores for the ordinal categories. 
• 
Comparison of clinical status ordinal scale scores for 
selected individual days (i.e., Days 3, 4, 5, and 6)  
• 
Comparison of clinical status ordinal scale scores 
using modified ordinal scale criteria (i.e. pooling of 
selected severity criteria scores) 
• 
Comparison of discrete ordinal scale parameters, 
including days of ventilator support, days in intensive 
care, and duration of hospitalization 
• 
Number of days to resumption of normal activities 
• 
All-cause and attributable mortality rates at Day 14, 
and 28, and 56 
• 
Total number of days in hospital and/or intensive care 
unit (ICU) from admission to discharge and rate of 
rehospitalization due to influenza A 
relapse/complication 
• 
The incidence, severity, and duration of signs and 
symptoms of influenza-like illness as assessed by the 
FluPRO Questionnaire (see Appendix Error! 
Reference source not found.) 
• 
Analysis of time to alleviation of signs and symptoms 
of influenza in the subset of subjects able to complete 
the Influenza Patient Reported Outcomes (FluPRO) 
Moved from primary 
objective to secondary 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Deleted as covered by next 
two bullets addressing 
ordinal scale assessments 
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Location in 
Protocol 
Changes 
Rationale 
Questionnaire at baseline and post-dose by Kaplan 
Meier analysis 
• 
The percentage of subjects with new bacterial 
pneumonia/superinfection 
• 
The percentage of subjects with influenza-related 
complications 
• 
VIS410 population pharmacokinetic (PK) parameters 
in serum 
• 
Titer of anti-VIS410 antibody positive samples 
• 
Genotypic and/or phenotypic assessment to determine 
the emergence of VIS410 and oseltamivir-resistant 
viruses 
Synopsis and 
Section 3.3 
Exploratory 
Endpoints 
• 
Clinical outcome will be measured daily for 14 days 
using a seven level ordinal scale; this seven level 
ordinal scale is defined as: 
• 
Death 
• 
ICU stay with mechanical ventilation 
• 
ICU stay without mechanical ventilation 
• 
Non ICU hospitalization with supplemental oxygen 
• 
Non ICU hospitalization without supplemental oxygen 
• 
Discharge with partial resumption of normal activities 
• 
Discharge with full resumption of normal activities 
• 
Population PK parameters of VIS410 from 
nasopharyngeal secretions 
• 
VIS410 concentration in tracheal aspirates 
• 
The difference in viral load between VIS410 + 
oseltamivir and oseltamivir alone treatment groups in 
tracheal aspirate of subjects on mechanical ventilation 
• 
Titer of anti-influenza A antibodies by hemagglutinin 
inhibition assay (HAI) in serum 
• 
Correlations between serum and/or nasopharyngeal PK 
with viral load, clinical symptoms, presence of 
antidrug antibodies (ADAs), safety, and additional 
endpoints 
Now covered under primary 
efficacy and secondary 
endpoints 
Synopsis 
Statistical Methods 
Sample Size 
Approximately 120 390 evaluable subjects will be enrolled. 
The study is exploratory in nature, and is not powered to 
demonstrate significant differences between treatment 
groups in primary or secondary outcome measures. The 
protocol intent is to collect sufficient information to 
identify the most appropriate candidate endpoints for 
subsequent Phase 3 study evaluation from among the 
primary and secondary endpoints described below. 
Statistical significance testing will therefore be used to 
assess the relative strength of evidence of the primary and 
secondary endpoints, to provide reasonable assurance that 
the endpoints chosen for a confirmatory Phase 3 trial will 
elucidate treatment differences between VIS410 plus 
oseltamivir versus oseltamivir alone.  Using a log rank test, 
a sample size of 130 influenza A infected subjects per 
 
 
Analysis changed due to the 
decrease in sample size. 
 
 
 
 
 
 
 
 
 
 
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treatment group will provide 80% power to detect a 1.5
day difference (5 days for oseltamivir alone and 3.5 days 
for VIS410 plus oseltamivir) in the median time to 
normalization of respiratory function (cessation of O2 
support) for VIS410 relative to placebo. A two sided alpha 
of 0.05 was used for the calculation. 
Efficacy 
Efficacy analysis will have two complementary purposes in 
this Phase 2 study, both designed to aid in the optimal 
design of a confirmatory Phase 3 trial. First, primary and 
secondary endpoints will be analyzed for treatment group 
differences, to determine which endpoints might be most 
sensitive demonstration of treatment group differences 
using p-values as an indicator, Second, the relative 
contribution of the various efficacy endpoints to patient 
well-being and benefit will be assessed, as well as potential 
correlations of endpoints such as the influence of peak viral 
load or number of days on ventilator on the time to 
resumption of normal activities.  
The ordinal scale outcomes will be measured daily from 
Day 1 (baseline) through Day 14, inclusive, using a seven-
level hierarchical scale with the classifications ordered 
from the worst to the best clinical outcomes (see Section 
10.6.1). For use in overall summary statistical 
presentations, the ordinal categories will be assigned 
decreasing integer scores, with death a score of 6 and 
discharge with full resumption of normal activities a score 
of 0. The primary outcome comparison of Ordinal Scale 
scores at Day 7 between treatment groups will be evaluated 
by proportional odds ratio analysis, as implemented by 
logistic regression, including a test of the proportional odds 
assumption. For this analysis, the response categories will 
be ordered from best (Discharge with full resumption of 
normal activities) to worst (Death). Additional exploratory 
analyses may be conducted to obtain a more complete 
understanding of the relationship of treatment to the ordinal 
response, including exact Mantel-Haenszel tests or partial 
proportional odds models.  
The area under the curve (AUC) over time for a given 
patient will be calculated as the sum of the maximum 
ordinal score for each day up through 7 and 14 days.  An 
analysis of treatment group differences will be performed 
on these per-patient AUC values using analysis of 
variance, with treatment group and strata as fixed factors. 
A sensitivity analysis will be performed that excludes the 
category of death on study, to determine if death as an 
outcome skews the results; death as an outcome will also 
be analyzed as an independent secondary endpoint. A 
secondary analysis of treatment group effect on the 
difference in proportions of patients with the worst (death) 
versus the best outcome (discharge from hospital and 
resumption of normal activities) will also be performed. 
This analysis does not use scores for the ordinal outcome 
but does account for ordinality, and is therefore not 
dependent on the relationship of score to severity of 
outcome. An exploratory analysis will be performed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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through an exact categorical analysis of treatment group 
difference in the ordinal scale results using the worst 
outcome on a per-patient basis. 
Additional ordinal scale outcome assessments will include 
comparison of total numbers of days at more severe scale 
values (death, time on ventilator, time in ICU) and 
proportions of patients with ordinal scale worsening post 
enrollment. Proportion outcomes will be analyzed by 
categorical data analysis methods, including Mantel-
Haenszel chi-square tests adjusted for strata; additional 
exploratory subgroup analyses may also be performed, for 
example, based on various age categories.  Time from 
onset of symptoms to study treatment and the number of 
doses of oseltamivir (Tamiflu) prior to VIS410 treatment 
for the current case of influenza may be included as 
covariates in the analyses. 
Secondary and exploratory endpoints will be analyzed for 
descriptive purposes, with significance levels (p-values) 
provided to illustrate the strength of evidence for treatment 
effects, and to provide a basis for the choice of endpoints 
for further study in a confirmatory study. These analyses 
will also provide estimates for potentially powering 
additional efficacy endpoints, and to assist in hierarchical 
ordering of secondary endpoints to provide alpha-control in 
confirmatory studies and for labelling purposes. 
Time to cessation of O2 support resulting in a stable SpO2 
will be analyzed using a Cox proportional hazards 
regression model including data from patients on O2 
support. Time from onset of symptoms to VIS410 
treatment and number of doses of oseltamivir (Tamiflu) 
prior to VIS410 treatment for the current case of influenza 
will be included as a covariate of the analysis. A P-value 
(using the Wald statistic) for each VIS410 dose vs placebo 
will be presented.  
The total number of days in the hospital and/or ICU from 
admission to discharge and the rate of rehospitalization due 
to influenza A relapse/reinfection will be summarized 
descriptively by treatment group. 
The probability of time to clinical response (defined as 
resolution of vital signs) will be calculated via 
Kaplan-Meier. A P value significance test (using the log-
rank test) for each VIS410 dose vs placebo will be 
presented. Results will be tabulated and presented 
graphically as well. The number and percentage of subjects 
in each treatment group with clinical response will be 
summarized. 
The ordinal scale outcomes will be measured daily from 
Day 1 (baseline) through Day 14, inclusive, using a seven
level hierarchical scale with the classifications ordered 
from the worst to the best clinical outcomes (see Section 
0). The number and percentage of subjects in each 
treatment group with each classification will be 
summarized for each day from Day 1 through Day 14, 
inclusive. 
Interim Analyses of Efficacy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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An interim analysis of efficacy may be performed by an 
unblinded third party after 50% of subjects have been 
enrolled (n = 195) and have an assessment of the primary 
endpoint (time to normalization of respiratory function). 
This interim analysis may be conducted to assess if one of 
the active VIS410 treatment arms will need to be 
terminated for futility. The interim analysis may also test 
the primary efficacy objective to assess if the primary 
efficacy endpoint has been met early. A prespecified 
sample size reanalysis will also be conducted based on the 
observed effect size. The DSMB and the unblinded 
statistician will review the interim analysis results to 
provide their recommendation on discontinuation of one of 
the VIS410 treatment arms, if needed, based on 
pre specified criteria as outlined in the SAP. The interim 
analysis may also review the following key secondary 
endpoints, when available, to assist in the decision of 
discontinuing a VIS410 treatment arm: 
• 
Time to clinical resolution of vital signs 
• 
Total number of hours on oxygen support or PPV 
• 
Viral load from nasopharyngeal swabs 
A sample size re estimation (SSRE) will also be performed 
at this point in order to determine if the current sample size 
is sufficient based on the observed effect size in the study. 
The unblinded statisticians will work directly with the 
Sponsor on the SSRE. The details of SSRE and individuals 
with access to the information will be outlined in a separate 
plan. 
///// 
Complications of Influenza 
Complications of influenza are defined as pneumonia, 
myocarditis, worsening of chronic bronchitis, sinusitis, 
otitis, or other chronic pulmonary diseases, 
encephalopathy, and death. Complications of influenza and 
use of antibiotic therapy for bacterial pneumonia will be 
reported by variable, treatment group, and time point. 
Diagnosis of bacterial pneumonia will be based on local 
clinical practice, usually an assessment of clinical features 
and any radiographic evidence of bacterial pneumonia (eg, 
infiltrate) and/or microbiologic evidence of bacterial 
pneumonia. All-cause and attributable mortality will be 
evaluated on Day 14 and 28. 
No interim analysis to be 
performed due to the 
decrease in sample size. 
Table 1 
Schedule of 
Assessments  
Table: Erythrocyte sedimentation rate (ESR)20a  
Footnotes: 20a ESR to be performed locally. 
Clarification. 
List of 
Abbreviations 
AUC – Area under curve 
New abbreviation 
Section 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.i, ii Despite available therapy with neuraminidase 
inhibitors, including oseltamivir (Tamiflu®), zanamivir 
(Relenza®), and peramivir (Rapivab®), 10% to 44% of 
 
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hospitalized patients require intensive care and 25% to 
50% of these patients die. It is estimated that as many as 
400,000 patients are hospitalized with influenza each year 
in the United States, with up to 49,000 deaths per year.iii  
The World Health Organization (WHO) has reported 
incidence rates of 3 to 5 million severe cases and about 
250,000 to 500,000 influenza-related deaths annually.iv 
The 2009 influenza A pandemic (H1N1) spread rapidly to 
every continent with more than 399,232 reported cases and 
4735 deaths.v 
The therapeutic use of passive polyclonal antibodies to 
prevent viral infections, including hepatitis B, varicella, 
cytomegalovirus, rabies, and respiratory syncytial virus 
(RSV) has been well established. More recently, 
monoclonal antibodies for viral infections have been 
developed, including palivizumab (Synagis®), a Food and 
Drug Administration (FDA)-licensed treatment for the 
prevention of RSV 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 A 
strains, in both treatment and prevention models of 
influenza, was developed. Visterra intends to develop this 
product for the treatment of influenza A, specifically in 
hospitalized patients. 
This study will provide the first indications of efficacy, 
safety, and tolerability of VIS410 in hospitalized subjects 
with influenza A infection requiring oxygen support. 
Efficacy will be measured by time to cessation of oxygen 
support assessed by comparison of clinical status ordinal 
Day 7 scores between treatment groups. 
Section 4.1 
Overview 
This is a Phase 2b multicenter, randomized, double-blind, 
controlled study comparing the efficacy and safety of 2 
dose levels of VIS410 (2000 and 4000 mg) in combination 
with oseltamivir vs oseltamivir alone in hospitalized 
subjects with influenza A infection requiring oxygen. 
Subjects will be randomly assigned at a ratio of 1:1:1 using 
a permuted block randomization method to receive VIS410 
at a dose of 2000 mg (low dose) or 4000 mg (high dose) or 
placebo (0.9% sodium chloride), administered as a single 
IV infusion over 2 hours. 
Randomization will be stratified by presence or absence of 
positive pressure ventilation (PPV) at baseline to ensure an 
even distribution across treatment arms (see Section 
Error! Reference source not found.). All subjects will 
receive oseltamivir 75 mg twice daily (BID) for 5 days 
(total of 10 doses) as part of standard of care (SOC). All 
subjects will also receive a pretreatment regimen of 
diphenhydramine 50 mg PO or IV plus either ibuprofen 
400 mg PO or acetylsalicylic acid 320-325 mg PO 60 
minutes before VIS410/placebo infusion. Approximately 
Decreasing sample size 
from 390 to 120 subjects to 
enable completion in 2 
influenza seasons. Table 6 
also updated to reflect 40 
subjects per arm. 
 
 
 
 
 
 
 
 
 
 
 
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390120 evaluable subjects (13040/arm) with confirmed 
influenza A infection will be treated.  
Subjects admitted to the hospital within 5 days of onset of 
initial symptoms who require supplemental oxygen will 
undergo a rapid influenza test (supplied by the Sponsor) or 
a PCR, fluorescent immunoassay (FIA), or enzyme-linked 
immunosorbent assay (ELISA) test to confirm influenza A 
infection. Subjects diagnosed with influenza A will 
undergo the screening procedures to confirm eligibility. 
Study assessments are outlined in Error! Reference 
source not found., Schedule of Assessments. 
Eligible subjects will be randomized to receive either 
oseltamivir + VIS410 2000 mg, oseltamivir + VIS410 4000 
mg, or oseltamivir + placebo (0.9% sodium chloride) at a 
ratio of 1:1:1 using a permuted block randomization 
method summarized in Error! Reference source not 
found.. 
Oseltamivir (Tamiflu) will be provided by the Sponsor. 
Treatment with oseltamivir may be extended for up to 5 
additional days (up to 20 doses of total therapy) if clinical 
symptoms warrant further treatment as assessed by the 
Investigator. Note: based on SOC, subjects may have 
started oseltamivir therapy prior to randomization. 
 In addition, following 50% enrollment (195 subjects), an 
interim analysis may be conducted, by an unblinded third 
party, to assess if one of the VIS410 treatment arms can be 
terminated early for futility. A prespecified sample size 
reanalysis may also be conducted based on the observed 
effect size. The interim analysis may also test the primary 
efficacy objective to assess if the primary efficacy endpoint 
has been met. An alpha spending function will be designed 
in order to determine the amount of alpha that will be spent 
at the interim analysis. The effect size for this study was 
estimated without the benefit of any prior randomized 
controlled trial. If the VIS410 effect size proves to be 
greater than anticipated, then it is possible that the primary 
study endpoint will be met by the time the interim efficacy 
analysis is performed. In the event the interim analysis 
reveals that the primary efficacy endpoint has been 
satisfied, this Phase 2 study could be terminated for 
efficacy.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Removed interim analysis 
as sample size decreased to 
120 subjects; final analysis 
to be performed upon 
completion of enrollment. 
Section 4.3 
Data Safety 
Monitoring 
Board 
An independent data safety monitoring board (DSMB) will 
be established to review all available safety data after 30 
subjects, as well as when and subsequently, approximately 
120 70 subjects, have completed study Day 14. The 
assessment of safety will be determined from vital sign 
measurements, physical examinations, hematology, 
chemistry and urinalysis laboratory testing, 12-lead 
electrocardiograms (ECGs), use of concomitant 
medications, and review of AEs. Based on the safety data 
provided, the DSMB will determine if it is acceptable to 
continue the study or reduce the dose as appropriate. 
Additional DSMB reviews can occur throughout the trial as 
deemed necessary by the DSMB or Sponsor to ensure 
subject safety and well-being. Study enrollment and dosing 
will continue while the DSMB evaluates data. 
Sample size decreased 
therefore second DSMB 
review not required. 
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Further details will be described in a separate DSMB 
charter. 
Section 5.2.1 
Inclusion 
Criteria 
9.   Subject, or a legally acceptable authorized 
representative, is able to understand the purpose and 
risks of the study and willing to give voluntary written 
informed consent. 
Change requested by an 
Ethics Committee 
Section 6.1.3 
Study 
Procedures 
On Day 1, eligibility of the subjects will be confirmed and 
assessments will be performed as described in Error! 
Reference source not found.. 
All results from the screening procedure needed to evaluate 
eligibility, including any local clinical laboratory results, 
must be available prior to randomization on Day 1. All 
clinical assessments required for the determination of 
subject eligibility will be performed by the local clinical 
laboratory, thereby precluding the need to wait for central 
laboratory data. 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. 
Once a subject has satisfied entry criteria, he/she will be 
assigned a unique identifier. The site’s unblinded 
pharmacist or properly trained designee will randomize the 
subject using the access the Interactive Web Response 
System (IWRS) to obtain the study treatment. 
Randomization will be stratified by presence or absence of 
PPV at baseline to ensure balance between the treatment 
arms. Subjects will be considered randomized when the 
pharmacist or designee obtains the subject number and 
treatment assignment from the IWRS. 
Subjects may not be randomized into this study more than 
once. Subjects who have participated in any previous study 
of VIS410 may not be randomized to this study. Subjects 
will be monitored daily while in the hospital up to Day 14 
(± 3 days) with an additional visit on Day 28 (± 3 days) and 
the last follow-up visit on Day 56 (± 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. Note: subjects 
discharged from the hospital prior to Day 14 will attend the 
applicable outpatient follow-up visit(s) (eg, Day 3, Day 5, 
Day 7, Day 14). 
Clarification 
Section 6.2 
Pregnancy 
Safeguards 
Pregnancy will be determined by evaluation of β-human 
chorionic gonadotropin in serum or urine for all women of 
childbearing potential. Subjects who are pregnant or 
nursing will be excluded from the study. During the course 
of the study drug administration period within the study, 
any nursing mother(s) or subject(s) with suspected or 
confirmed pregnancy will be discontinued from study drug 
therapy but will be encouraged to undergo follow-up for 
safety monitoring for themselves (ie, the pregnant female) 
and the baby. 
All women of childbearing potential and all male subjects 
must practice effective contraception from screening until 
60 days post-VIS410/placebo infusion. For the purposes of 
 
 
 
 
 
 
 
 
 
 
 
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this study, women who do not satisfy at least one of the 
following criteria listed below (ie, the criteria for defining 
non-childbearing potential) are considered to be 
physiologically capable of becoming pregnant and are, 
therefore, defined as women of childbearing potential. 
The criteria for defining women as being of non-
childbearing potential are: 
• 
Post-menopausal: ≥ 12 months of natural 
(spontaneous) amenorrhea, or 
• 
Follicle stimulating hormone > 40 mIU/mL 
as documented in their medical history, or 
• 
Surgical bilateral oophorectomy with or 
without hysterectomy, or 
• 
Hysterectomy, or 
• 
Bilateral tubal ligation 
Women of childbearing potential and all male subjects 
participating in heterosexual relations must be willing to 
practice effective contraception from screening until 60 
days post-VIS410/placebo infusion. For the purposes of the 
study, highly effective contraception is defined as: 
• 
Male vasectomy with negative semen 
analysis documentation at least 6 months 
prior to dosing.  
OR 
• 
Combination of an established form of 
hormonal contraception (oral, injected, or 
implanted) or an intrauterine device or 
intrauterine system or sponge 
Plus one of the following: 
• 
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. OR 
• 
Male vasectomy with negative semen 
analysis documentation less than 6 months 
prior to dosing. OR 
• 
Complete abstinence can be considered an 
acceptable method of contraception at the 
discretion of the Investigator. Periodic 
abstinences (eg, calendar, ovulation, 
symptothermal, or post-ovulation methods) 
and withdrawal are NOT considered 
acceptable methods of contraception. 
The combination of 2 barrier methods, periodic abstinence 
(eg, calendar, ovulation, symptothermal, or post-ovulation 
methods), and withdrawal are not considered acceptable 
methods of contraception. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sponge is an acceptable 
method of contraception 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Added requirement. 
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Male subjects should not donate sperm for at least 60 days 
after receipt of study product. 
Pregnancy reporting is described in Section Error! 
Reference source not found.. 
Section 6.5.2 
Injection Site 
Tolerability 
Injection site tolerability is defined as AEs demonstrating 
significant local injection site irritation or tissue damage. 
Injection site tolerability will be reported by variable, 
treatment group, and time point. 
Sentence deleted as belongs 
in SAP 
Section 6.5.3 
Complications 
of Influenza 
Complications of influenza are defined as pneumonia, 
myocarditis, worsening of chronic bronchitis, sinusitis, 
otitis, or other chronic pulmonary diseases, 
encephalopathy, and death. Complications of influenza and 
use of antibiotic therapy for bacterial pneumonia will be 
reported by variable, treatment group, and time point. 
Diagnosis of bacterial pneumonia will be based on local 
clinical practice, usually an assessment of clinical features 
and any radiographic evidence of bacterial pneumonia (eg, 
infiltrate) and/or microbiologic evidence of bacterial 
pneumonia. All-cause and attributable mortality will be 
evaluated on Day 14 and Day 28. 
 
Section 7.1 Test 
product, Dose, 
Mode of 
Administration 
The Investigator must ensure that the investigational 
product will be used only in accordance with the protocol. 
It is forbidden to use investigational drug material for 
purposes other than as defined in this protocol. 
VIS410 (2000 mg or 4000 mg) will be administered IV 
over 2 hours as a single, 200-mL infusion, followed by a 
25-mL (or volume equivalent to length of IV line) saline 
flush to ensure all product is administered, in addition to 
oseltamivir (Tamiflu) 75 mg BID for total of 5 days (10 
doses). Treatment with oseltamivir may be extended for up 
to 5 additional days (up to 20 doses of total therapy) if 
clinical symptoms warrant further treatment as assessed by 
the Investigator. Note: based on SOC, subjects may have 
started oseltamivir therapy prior to randomization.  No 
dose adjustment is necessary for VIS410 based on renal or 
hepatic impairment. For patients with renal insufficiency, 
refer to prescribing information for administration of 
oseltamivir. 
VIS410 is a 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 be 
sent to the clinical center. 
The investigational drug product is manufactured by 
Lyophilization Services of New England in accordance 
with Good Manufacturing Practice as required by the 
current Good Clinical Practice (GCP). Manufacturing, 
packaging, and labeling of the investigational product, 
VIS410, is conducted under the responsibility of the 
Sponsor. The study drug will be labeled according to local 
Clarification as some sites 
use lines with greater than 
25 mL hold-up volume 
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law and regulatory requirements. Specific dilution 
procedures for VIS410 will be described in detail in the 
Pharmacy Manual. 
Placebo will be a normal saline solution (0.9%) and will be 
prepared by the pharmacist. 
Section 7.2 
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, followed by a 
25-mL (or volume equivalent to length of IV line) saline 
flush to ensure all product is administered, in addition to 
oseltamivir (Tamiflu) 75 mg BID for total of 5 days (10 
doses). Treatment with oseltamivir may be extended for up 
to 5 additional days (up to 20 doses of total therapy) if 
clinical symptoms warrant further treatment as assessed by 
the Investigator. For patients with renal insufficiency, refer 
to prescribing information for administration of 
oseltamivir. Note: based on SOC, subjects may have 
started oseltamivir therapy prior to randomization. 
Clarification as some sites 
use lines with greater than 
25 mL hold-up volume 
Section 7.3 
Instructions for 
Preparation, 
Use and 
Administration 
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. This infusion will be 
followed by a 25-mL saline flush. Length of (or if IV line 
will be set for maximum volume of is >25 mL, so that The 
25 mL an equivalent volume) saline flush. The saline flush 
following administration will ensure all VIS410/placebo 
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 as 
appropriate. 
The infusion bag will be covered with an opaque sleeve in 
the pharmacy to maintain the study blind. The 
VIS410/placebo will be administered IV at a rate of 100 
mL/h, over 2 hours. 
When 200 mL has been administered, the line will be 
flushed with 25 mL of normal saline. The infusion time 
may be longer at the Investigator’s discretion based only 
on local infusion site–related symptoms up to a maximum 
of 4 hours.  
Refer to the Pharmacy Manual for directions on storage, 
handling, stability data, preparation, and use. For more 
detailed information on VIS410, refer to the current 
Investigator’s Brochure.Error! Bookmark not defined. 
Clarification to ensure all 
study product administered. 
Some sites use infusion 
lines with hold-up volumes 
of greater than 25 mL. 
Section 8.3.1 
Sequence of 
Assessments at 
a Single Visit 
If the following assessments are to be performed at the 
same study visit, then the order of assessments should be as 
follows the FluPRO Questionnaire should be completed 
first, when possible: 
• 
FluPRO Questionnaire 
• 
ECG 
• 
Blood sampling 
• 
Nasopharyngeal swab 
Clarification 
Section 9.2 
Grading of 
Each AE must be graded on a 4-point scale (Grades 1-3 4) 
of increasing intensity according to the Division of 
Correction; DMID scale is 
1-4 
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Adverse Event 
Intensity 
Microbiology and Infectious Diseases (DMID) Adult 
Toxicity Table presented in Appendix Error! Reference 
source not found.. 
Criteria in the DMID table are generally grouped by body 
system, ie, hematology, chemistries, enzymes, urinalysis, 
cardiovascular, respiratory, GI, neurological, 
musculoskeletal, skin, and systemic. 
For abnormalities not specifically listed in the DMID Table 
(Appendix Error! Reference source not found.), a guide 
for estimating severity grade (mild, moderate, severe, life-
threatening) is provided: 
• 
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 
Note: The semi-colon within the description of the grade 
indicates ‘and’. 
Any clinical event deemed by the clinician to be serious or 
life-threatening should be considered an SAE. 
Section 10.1 
Determination 
of Sample Size 
The study is exploratory in nature, and is not powered to 
demonstrate significant differences between treatment 
groups in primary or secondary outcome measures. The 
protocol intent is to collect sufficient information to 
identify the most appropriate candidate endpoints for 
subsequent Phase 3 study evaluation from among the 
primary and secondary endpoints described below. 
Statistical significance testing will therefore be used to 
assess the relative strength of evidence of the primary and 
secondary endpoints, to provide reasonable assurance that 
the endpoints chosen for a confirmatory Phase 3 trial will 
elucidate treatment differences between VIS410 plus 
oseltamivir versus oseltamivir alone. 
The primary efficacy objective of this study is to evaluate 
the effect of VIS410 + oseltamivir on the time to 
normalization of respiratory function compared to 
oseltamivir alone in the modified intent to treat (MITT) 
population. 
Using a log rank test, a sample size of 130 influenza A
infected subjects per treatment group will provide 80% 
power to detect a 1.5 day difference (5 days for oseltamivir 
alone and 3.5 days for VIS410 plus oseltamivir) in the 
median time to cessation of O2 support for VIS410 relative 
to placebo. A two sided alpha of 0.05 was used for the 
calculation. 
Approximately 390 evaluable subjects with confirmed 
influenza A infection will be enrolled in this study. 
New paragraph due to 
decreased sample size 
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Section 10.2 
Randomization 
and Blinding 
An IWRS will be used to allocate the randomized 
treatments to subjects with stratification by presence or 
absence of positive pressure ventilation (PPV) at baseline. 
Pharmacists must obtain the status of the subject relative to 
PPV at baseline via query, and this data must be input into 
the IWRS prior to randomization. The randomized 
treatment assignment will be transferred electronically for 
integration with the clinical study data at the appropriate 
time. 
PPV includes any respiratory assistance using a mechanical 
ventilation device and can be either invasive or 
noninvasive ventilation. Invasive PPV includes intubation 
with endotracheal tube with mechanical ventilation (most 
common) or tracheostomy with mechanical ventilation. 
Noninvasive PPV includes use of facemask, nasal plugs, or 
nasal mask with mechanical ventilation. The devices are 
named according to the type of mechanical ventilation 
given continuous positive airway pressure (CPAP) or bi-
level positive airway pressure (BiPAP). 
Randomization will be used to avoid bias in the assignment 
of subjects to treatment, to increase the likelihood that 
known and unknown subject attributes (eg, demographic 
and baseline characteristics) are evenly balanced across 
treatment arms. 
The maintenance of the study blind is critical for an 
unbiased assessment of the safety and efficacy of the study 
drug. All study staff that evaluate subjects and render 
decisions regarding subject care will remain blinded to the 
study treatment each subject receives. 
The designated study site pharmacist or designee will 
remain unblinded. Also, unblinded clinical research 
associates will handle study drug accountability. 
The study will be conducted in a double-blind manner. The 
CRO, site study personnel, and Visterra personnel will not 
be aware of which treatment (VIS410 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 over a 2-hour infusion 
with pretreatment regimen of PO or IV diphenhydramine 
50 mg plus either ibuprofen 400 mg PO or acetylsalicylic 
acid 320-325 mg PO approximately 60 minutes before IV 
infusion of VIS410/placebo. 
Allocation of each subject to a given treatment sequence 
will be described in a randomization schedule prepared by 
Visterra or designee. The randomization will be balanced 
using randomly permuted blocks across the treatment 
groups. Based on this randomization code, the site’s 
unblinded pharmacist or trained designee will prepare and 
dispense VIS410/placebo. 
If the interim analysis determines that one of the VIS410 
treatment arms can be terminated early for futility, then a 
second randomization schedule with a unique set of 
randomization numbers will be created for all subsequent 
subject enrollment and randomization. As with the initial 
 
Explanation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Due to decrease in sample 
size an interim analysis is 
not going to be performed. 
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randomization procedure, randomization will be stratified 
by presence or absence of PPV at baseline to ensure an 
even distribution across treatment arms. 
The randomization schedule 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 schedule. The Sponsor medical 
representative(s) may be partially unblinded during the 
interim analyses. A separate interim analysis plan will 
provide details on access to unblinded data and the level of 
unblinding. The CRO personnel performing data 
management and statistical activities will receive a copy of 
the randomization schedule 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 (via 
IWRS) 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 is 
encouraged to contact the Medical Monitor to discuss and 
agree to the need for unblinding to occur. 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. 
Once a subject's treatment assignment has been unblinded, 
the Medical Monitor should be notified within 24 hours of 
unblinding of the treatment, without revealing the study 
treatment. Information relating to unblinding (eg, 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. If the code is broken by the Investigator or by 
someone of his/her staff, the subject must be withdrawn 
from the study and must be followed as appropriate. 
Visterra or designee will also unblind any SAE reports that 
are serious, unexpected, and considered to be related to 
investigational product, in accordance with safety reporting 
guidance and regulations. If the code is broken by the 
Sponsor for safety reporting purposes, the subject may 
remain in the study. To maintain study blinding, the 
infusion bag will be covered by an opaque sleeve in the 
pharmacy. 
Section 10.5 
Handling of 
Missing Data 
No imputations Procedures for handling missing data will 
be performed defined in the Statistical Analysis Plan, and 
may include last observation carried forward or an 
interpolation method. 
Clarification 
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Changes 
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Section 10.6 
Interim 
Analysis 
An interim analysis of efficacy may be performed by an 
unblinded third party after 50% of subjects have been 
enrolled (n = 195) and have an assessment of the primary 
endpoint (time to normalization of respiratory function). 
This interim analysis may be conducted to assess if one of 
the active VIS410 treatment arms will need to be 
terminated for futility. Using the methods of Lan and 
DeMets an alpha spending function will be created and if 
the test statistic for one of the active VIS410 treatment 
arms is less than the lower critical point then the VIS410 
treatment arm may be terminated for futility. The interim 
analysis may also test the primary efficacy objective to 
assess if the primary efficacy endpoint has been met early. 
The effect size for this study was estimated without the 
benefit of any prior randomized, controlled trial. If the 
VIS410 effect size proves to be greater than anticipated, 
then it is possible that the primary study endpoint will be 
met by the time the interim efficacy analysis is performed. 
In the event the interim analysis reveals that the primary 
efficacy endpoint has been satisfied, this Phase 2 study 
could be terminated for efficacy. 
The DSMB and the unblinded statistician will review the 
interim analysis results to provide their recommendation on 
discontinuation of one of the VIS410 treatment arms, if 
needed, based on pre specified criteria as outlined in the 
SAP. The interim analysis may also review the following 
key secondary endpoints, when available, to assist in the 
decision of discontinuing a VIS410 treatment arm: 
• 
Time to clinical resolution of vital signs 
• 
Total number of hours on oxygen support or PPV 
• 
Viral load from nasopharyngeal swabs 
A sample size re estimation (SSRE) will also be performed 
at this point in order to determine if the current sample size 
is sufficient based on the observed effect size in the study. 
The unblinded statisticians will work directly with the 
Sponsor on the SSRE. The details of SSRE and individuals 
with access to the information will be outlined in a separate 
plan. The MITT population will be used for the interim 
analysis. 
Due to decrease in sample 
size an interim analysis is 
not going to be performed. 
Section 10.7 
Efficacy 
Analyses 
Section number changed to 10.6  
Efficacy Analyses 
Efficacy analyses will be performed using the MITT 
population. Efficacy analysis will also be performed in the 
PP population to demonstrate consistency with the primary 
analysis population. 
Day 7 Ordinal Scale Status 
The ordinal scale outcomes will be measured daily from 
Day 1 (baseline) through Day 14 using the seven-level 
hierarchical scale with the classifications presented in 
Table 8Table 2. The clinical outcomes therein are ordered 
from the worst clinical outcome to the best clinical 
outcome in descending order. For each day, subjects will 
be classified by the worst clinical outcome for which they 
qualify. 
Renumbered due to deletion 
of previous section 10.6 
 
 
 
 
 
Moved this section to the 
top of the efficacy analyses 
as a component of the 
ordinal scale is now the 
primary objective/primary 
endpoint 
 
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The number and percentage of subjects in each treatment 
group with each classification will be summarized for each 
day from Day 1 through Day 14, inclusive. 
Table 1. 
Hierarchical Seven-Level Ordinal 
Scale for Clinical Outcomes 
Clinical Parameter 
Death 
ICU stay with mechanical ventilation 
ICU stay without mechanical ventilation 
Non-ICU hospitalization with supplemental oxygen 
Non-ICU hospitalization without supplemental oxygen 
Discharge with partial resumption of normal activities 
Discharge with full resumption of normal activities 
Note: Clinical outcomes listed from worst clinical 
outcome to best clinical outcome in descending order. 
 
Time to Cessation of O2 Support 
Time to cessation of O2 support resulting in a stable 
SpO2will be analyzed using a Cox model. Time from onset 
of symptoms to VIS410 treatment and the number of doses 
of oseltamivir (Tamiflu) prior to VIS410 treatment for the 
current case of influenza will be included as a covariate in 
the analysis. A P-value (using the Wald statistic) for each 
VIS410 dose vs placebo will be presented. 
Secondarily, subgroup analyses will be performed to 
describe the time to cessation of O2 for subgroups, such as 
use of positive pressure ventilation, use of endotracheal 
intubation, time from onset of symptom to VIS410 therapy, 
number of oseltamivir doses prior to VIS410, elderly, and 
underlying lung disease. Clinical and virologic endpoints 
will also be evaluated by influenza A subtypes. 
Time to Clinical Response 
Time to clinical response is defined as resolution of 4 of 5 
vital signs that will be determined upon physical 
examination. Clinical response is defined as: 
• 
Afebrile with core temperature ≤ 37.8°C, 
without use of antipyretics (oral ≤ 37.2°C) 
• 
Respiratory rate ≤ 24 beats per minute 
• 
Oxygen saturation ≥ 95% on room air without 
support or a return to pre-infection status, if 
pre-infection status was < 95% 
• 
Pulse rate ≤ 100/min 
• 
SBP ≥ 90 mm/Hg, without vasopressor use 
The probability of time to clinical response (defined as 
resolution of vital signs) will be calculated via Kaplan-
Meier. A P value significance test (using the log-rank test) 
for each VIS410 dose vs placebo will be presented. The 
number and percentage of subjects in each treatment group 
with clinical response will be summarized. Results will be 
tabulated and presented graphically as well. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Time to Cessation of Ventilator Support 
The probability of time to cessation of ventilator support 
will be calculated via Kaplan-Meier. A P-value (using the 
log-rank test) for each VIS410 dose vs placebo will be 
presented. Results will be tabulated and presented 
graphically as well. 
Healthcare Resource Utilization 
Descriptive statistics will be used to compare the total 
number of days in the hospital and/or ICU from admission 
to discharge, number of subjects requiring ICU admission 
post-randomization, overall number of days in the ICU, 
number of hours on ventilation, rehospitalization due to 
influenza A relapse/reinfection, the total number of days of 
oseltamivir therapy, and the total number of days to 
resumption of usual activities by treatment group.  
Time (number of days) to resumption of usual activities 
will be determined from the VAS (scale ranged from 0 to 
10, where 0 indicates subject is unable to perform any of 
his/her usual activities prior to influenza onset, and 10 
indicates subject is able to fully perform all usual 
activities). 
This evaluation will be performed using the MITT 
population. 
Signs and Symptoms of Influenza 
Descriptive statistics will be used to compare the duration 
of symptoms of influenza-like illness in the subset of 
subjects able to complete the FluPRO Questionnaire at 
baseline and post-dose by treatment group. The number 
and percentage of subjects who were not able to complete 
the assessment at each visit will be summarized. 
Frequency tabulation of the occurrence and severity of 
each subject-reported symptom of influenza-like illness 
(via FluPRO Questionnaire) will be summarized by 
assessment time point and by treatment group. Time to 
resolution of symptoms will be evaluated by Kaplan Meier 
analysis. 
Analyses of the signs and symptoms of influenza will be 
conducted only on the subset of the MITT population who 
had baseline FluPRO Questionnaire assessments. 
Additional populations may be analyzed as described in the 
SAP. 
Clinical Outcome by Seven Level Ordinal Scale 
The ordinal scale outcomes will be measured daily from 
Day 1 (baseline) through Day 14 using the seven-level 
hierarchical scale with the classifications presented in 
Table 2. The clinical outcomes therein are ordered from 
the worst clinical outcome to the best clinical outcome in 
descending order. For each day, subjects will be classified 
by the worst clinical outcome for which they qualify. 
The number and percentage of subjects in each treatment 
group with each classification will be summarized for each 
day from Day 1 through Day 14, inclusive. 
Table 2. 
Hierarchical Seven Level Ordinal 
Scale for Clinical Outcomes 
Clinical Parameter 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moved this section to the 
top of the efficacy analyses 
as a component of the 
ordinal scale is now the 
primary objective/primary 
endpoint. 
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Death 
ICU stay with mechanical ventilation 
ICU stay without mechanical ventilation 
Non ICU hospitalization with supplemental oxygen 
Non ICU hospitalization without supplemental oxygen 
Discharge with partial resumption of normal activities 
Discharge with full resumption of normal activities 
Note: Clinical outcomes listed from worst clinical 
outcome to best clinical outcome in descending order. 
 
Section 10.8.3 
Complications 
of Influenza 
Now Section 10.7.3  
Complications of influenza are defined as pneumonia, 
myocarditis, worsening of chronic bronchitis, sinusitis, 
otitis or other chronic pulmonary diseases, encephalopathy, 
and death. Complications of influenza and use of antibiotic 
therapy for bacterial pneumonia will be reported by 
variable, treatment group, and time point. Diagnosis of 
bacterial pneumonia will be based on local clinical 
practice, usually an assessment of clinical features and any 
radiographic evidence of bacterial pneumonia (eg, 
infiltrate) and/or microbiologic evidence of bacterial 
pneumonia. All-cause and attributable mortality will be 
evaluated on Days 14 and 28. 
Clarification 
Sections 10.8 -
10.12 
Renumbered sections due to deletion of original section 
10.6; now 10.7 - 10.11 
Correction 
Section 12.1.2 
Subject 
Informed 
Consent 
Each subject or a legally authorized acceptable 
representative 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 enrolling potential subjects in the study, the 
Investigator or an authorized member of the investigational 
staff must explain to the subject the aims, methods, 
reasonably anticipated benefits, and potential hazards of 
the study, and any discomfort that participation in the study 
may entail. Subjects 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 Informed Consent Form (ICF) the subject is 
authorizing such access and agrees to allow his/her study 
physician to recontact 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 nontechnical 
Change requested by an 
Ethics Committee 
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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. 
Section 14.2 
Laboratory 
Assessments 
Other Assessments 
Urine pregnancy test 
Erythrocyte Sedimentation Rate (ESR) 
C-Reactive Protein (CRP) 
Added to complete the 
assays being performed 
 
i 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):1016–24. 
ii Schanzer DL, Langley JM, Tam TW. Co-morbidities associated with influenza attributed 
mortality, 1994-2000, Canada. Vaccine 2008;26(36):4697–703. 
iii CDC. Estimates of deaths associated with seasonal influenza US, 1976-2007. MMWR. 
2012;59(33):1057–62. 
iv WHO. Seasonal Influenza Fact sheet N°211. 2014. 
http://www.who.int/mediacentre/factsheets/fs211/en. Accessed 10 Mar 2014. 
v World Health Organization (WHO). Pandemic (H1N1) 2009-update 70. 
http://www.who.int/csr/don/2009_10_16/en/index.html. Accessed 25 October 2009. 
                                                 
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SUMMARY OF CHANGES TO PROTOCOL VIS410-203 
FROM VERSION 1.1 TO VERSION 2.1 (SOUTH AFRICA) 
Substantive changes to the protocol for Amendment 1 and their location within the protocol are noted 
below. Additions are marked as red underlined text and deletions are marked as red strikethrough text. 
Administrative, stylistic and formatting changes that do not alter the conduct of the study are not 
summarized in this document. 
Location in 
Protocol 
Changes 
Rationale 
Cover Page; 
Signature of 
Sponsor 
Representative 
Issue Date (Version): 25 October 2016 (Version 1.1) 
 
 
 
 
 
3 July 2017 (Version 2.1 – South 
                                    Africa) 
Sponsor Representative
  
                                         
 
Updated date and version 
number; added South Africa 
to identify country level 
protocol. 
 
Sponsor representative 
updated. 
Protocol History 
Protocol History 
Visterra, Inc.  VIS410 203 
Document  
Issue Date 
Amendm
ent Type 
Comments 
Clinical 
Study 
Protocol 
25 October 
2016 
(Version 1.1) 
 
This 
document 
 
Deleted because changes 
will be summarized in a 
separate Summary of 
Changes document (this 
file). 
Synopsis and 
Section 2.2 
Secondary 
Objectives 
• 
Evaluate the effect of VIS410 + oseltamivir vs 
oseltamivir alone on the following endpoints: 
 
Viral titer load in upper respiratory samples 
 
Time to clinical response 
 
Time to cessation of ventilator support 
 
Time to resumption of normal activities 
 
All-cause and attributable 14- and 28-day mortality 
 
Healthcare resource utilization 
 
Time to alleviation of clinical symptoms of 
influenza in subset of subjects able to complete the 
FluPRO Questionnaire at baseline and post-dose 
 
Proportion of subjects with new documented 
bacterial pneumonia/superinfection 
 
Proportion of subjects with influenza-related 
complications 
Viral load is a more accurate 
term to represent the test 
being conducted. 
Synopsis; 
Section 2.3 
Exploratory 
Objectives; 
Section 3.3 
Exploratory 
Endpoints;  
Section 6.3.12.3 
Serum 
Cytokines 
• 
Evaluate the effect of VIS410 + oseltamivir vs 
oseltamivir alone on clinical outcomes as measured by a 
seven-level ordinal scale 
• 
Evaluate the pharmacokinetics of VIS410 from 
nasopharyngeal secretions and tracheal aspirate 
(ventilated subjects only) 
• 
Assess the effects of VIS410 on viral titer load in 
tracheal aspirate (ventilated subjects only) 
• 
Assess correlations between virology, safety, VIS410 
dose, pharmacokinetics, viral shedding, immunogenicity 
immunology, signs and symptoms of influenza, and 
other endpoints 
• 
Assess the anti-influenza immune response 
Viral load and immunology 
are more accurate terms. 
 
Exploratory cytokine 
objective removed from 
protocol. 
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Changes 
Rationale 
• 
Evaluate serum cytokine profiles 
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Location in 
Protocol 
Changes 
Rationale 
Synopsis; 
Section 4.0 
Study Design; 
Section 4.3 
Data Safety 
Monitoring 
Board;  
Section 6.1.3 
Study 
Procedures; 
Section 7.5 
Pretreatment; 
Section 8.3.3 
Post-Treatment 
Procedures 
(Day 3 to 56); 
Section 11.4 
Stopping Rules 
or 
Discontinuation 
Criteria 
This is a Phase 2b multicenter, randomized, double-blind, 
controlled study comparing the efficacy and safety of 2 dose 
levels of VIS410 (2000 and 4000 mg) in combination with 
oseltamivir vs oseltamivir alone in hospitalized severely ill 
subjects with influenza A infection requiring oxygen. 
Subjects will be randomly assigned at a ratio of 1:1:1 using a 
permuted block randomization method to receive VIS410 at 
a dose of 2000 mg (low dose) or 4000 mg (high dose) or 
placebo (0.9% sodium chloride), administered as a single IV 
infusion over 2 hours. 
Randomization will be stratified by presence or absence of 
positive pressure ventilation (PPV) at baseline to ensure an 
even distribution across treatment arms (see Section 10.2). 
All subjects will receive oseltamivir 75 mg twice daily (BID) 
for 5 days (total of 10 doses) as part of standard of care 
(SOC). Treatment with oseltamivir may be extended for up 
to 5 additional days (up to 20 doses of total therapy) if 
clinical symptoms warrant further treatment as assessed by 
the Investigator. Note: based on SOC, subjects may have 
started oseltamivir therapy prior to randomization. All 
subjects will also receive a pretreatment regimen of 
diphenhydramine 50 mg PO or IV plus either ibuprofen 400 
mg PO or acetylsalicylic acid 320-325 mg PO 60 minutes 
before VIS410/placebo infusion. Approximately 390 
evaluable subjects (130/arm) with confirmed influenza A 
infection will be treated.  
Subjects admitted to the hospital within 5 days of onset of 
initial symptoms who require supplemental oxygen of at 
least 40% (4 L/min) and/or hypoxemia defined as SpO2 of 
less than 90% will undergo a rapid influenza test (supplied 
by the Sponsor) or a PCR test, fluorescent immunoassay 
(FIA) test, or enzyme-linked immunosorbent assay (ELISA) 
test to confirm influenza A infection. Subjects diagnosed 
with influenza A will undergo the screening procedures to 
confirm eligibility. Study assessments are outlined in 
Table 1, Schedule of Assessments. 
Eligible subjects will be randomized to receive either 
oseltamivir + VIS410 2000 mg, oseltamivir + VIS410 4000 
mg, or oseltamivir + placebo (0.9% sodium chloride) at a 
ratio of 1:1:1 using a permuted block randomization method 
summarized in Table 6. 
(Randomization table, unchanged) 
Oseltamivir (Tamiflu®) will be provided by the Sponsor. 
Treatment with oseltamivir may be extended for up to 
5 additional days (up to 20 doses of total therapy) if clinical 
symptoms are not resolved by Day 5 or warrant further 
treatment as assessed by the Investigator. Note: based on 
SOC, subjects may have started oseltamivir therapy prior to 
randomization. 
Study assessments are outlined in Table 1. Subjects 
discharged from will be monitored daily while in the hospital 
prior up to Day 14 will attend (± 3 days) with additional 
visits on Day 28 (± 3 days) and the applicable outpatient last 
follow-up visit(s) (eg, Day 3, Day 5, on Day56 (± 7days). 
Study assessments are outlined in, Day 14) per Table 1 
(Schedule of Assessments). 
Based on change to 
Inclusion Criteria regarding 
oxygen requirement, it is 
more accurate to define 
subjects as hospitalized, not 
severely ill.  
 
Clarified that subjects will 
receive either ibuprofen or 
acetylsalicylic acid, not both. 
 
Dose for acetylsalicylic acid 
changed to comply with 
standard dose in various 
countries.  
 
Inclusion Criteria regarding 
oxygen requirement has been 
modified to allow 
participation of less severe 
infections, hence subjects no 
longer require a specific 
concentration or amount of 
oxygen support to be eligible 
for the study. 
 
Clarified that subjects may 
have started oseltamivir 
treatment prior to enrollment 
in the study; total minimum 
and maximum doses the 
same for all subjects 
regardless of when a subject 
began oseltamivir. 
 
Clarified that subjects 
discharged from the hospital 
will attend follow-up visits; 
the number of outpatient 
follow-up visits are 
dependent on when the 
subject is discharged from 
the hospital. 
 
Defined GI TEAEs that 
require intervention. 
 
Updated statistical language 
related to the error rate and 
the interim analysis. 
 
The DSMB will review 
safety data after 
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An independent data safety monitoring board (DSMB) will 
be established to review all available safety data after 
30 subjects as well as when and approximately 120 subjects 
have completed study Day 14 7. The assessment of safety 
will be determined from vital sign measurements, physical 
examinations, hematology, chemistry and urinalysis 
laboratory testing, 12-lead electrocardiograms (ECGs), use 
of concomitant medications, and review of adverse events 
(AEs). Based on the safety data provided, the DSMB will 
determine if it is acceptable to continue the study or reduce 
the dose as appropriate. Dosing will temporarily pause while 
the DSMB meets if there are 4 treatment-related serious 
adverse events (SAEs) or 4 severe gastrointestinal (GI) 
treatment–emergent adverse events (TEAEs) that require 
intervention, which is defined as requiring IV fluid and 
medication to decrease the frequency of diarrhea 
(ie, loperamide). 
Additional DSMB reviews can occur throughout the trial as 
deemed necessary by the DSMB or Sponsor to ensure 
subject safety and well-being. Study enrollment and dosing 
will continue while the DSMB evaluates data. 
In addition, following 50% enrollment (195 subjects), an 
interim analysis may will be conducted, by an unblinded 
third party, to assess if one of the VIS410 treatment arms can 
be terminated early for futility. A prespecified sample size 
reanalysis may also be conducted based on the observed 
effect size. The interim analysis may will also test the 
primary efficacy objective to assess if the primary efficacy 
endpoint has been met. An alpha spending function will be 
designed in order to determine the amount of alpha that will 
be spent at the interim analysis. The effect size for this study 
was estimated without the benefit of any prior randomized 
controlled trial. If the VIS410 effect size proves to be greater 
than anticipated, then it is possible that the primary study 
endpoint will be met by the time the interim efficacy analysis 
is performed. In the event the interim analysis reveals that 
the primary efficacy endpoint has been satisfied, this Phase 2 
study could be terminated for efficacy. 
approximately 30 subjects 
and 120 subjects complete 
Day 14 to allow more safety 
data to be reviewed. 
Synopsis and 
Section 5.2.1 
Inclusion 
Criteria 
Only revised list items shown: 
4. Requirement for oxygen support including any positive 
pressure ventilation (PPV). 
4. Need for supplemental oxygen of at least 40% (4 L/min) 
and/or hypoxemia defined as SpO2 of less than 90% 
 
Inclusion Criteria regarding 
oxygen requirement has been 
modified to allow 
participation of less severe 
infections, hence subjects no 
longer require a specific 
concentration or amount of 
oxygen support to be eligible 
for the study. 
Synopsis and 
Section 5.2.2 
Exclusion 
Criteria 
Only revised list items shown: 
2. Subjects who have received VIS410 in the past History 
of receiving monoclonal antibody products (including 
VIS410) within 3 months prior to VIS410/placebo 
dosing or planned administration during the study 
period. 
3. Subjects who have a history of receiving monoclonal 
antibody products within 3 months prior to 
VIS410/placebo dosing or planned administration of 
Clarified that subjects are 
not eligible for the study if 
they have received VIS410 
in the past. 
 
Clarified exclusion criteria 
of subjects that have 
Influenza B or another viral 
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another monoclonal antibody during the study period. 
5. Subjects with known co-infection with influenza B or 
other viral respiratory infections (eg, respiratory 
syncytial virus [RSV], parainfluenza viruses, respiratory 
adenoviruses).infection 
6. Subjects with lung transplant or history of severe 
chronic lung disease, including cystic fibrosis or any 
condition requiring > 2 L/minute of home oxygen 
therapy.(ie, severe chronic obstructive pulmonary 
disease [COPD], pulmonary fibrosis) 
7. Subjects on extracorporeal membrane oxygenation 
(ECMO) at time of randomization. 
8. Hospitalization for > 48 hours prior to randomization 
8. Subjects with end-stage renal disease (ESRD) who are 
not undergoing hemodialysis. 
 
respiratory infection. 
 
Clarified exclusion criteria 
of cystic fibroses subjects; 
due to changes in patient 
population , subjects that 
require oxygen therapy at 
home are not eligible for the 
study. 
 
Subjects hospitalized before 
enrollment in the study are 
eligible as long as the onset 
of influenza symptoms are 
no more than 5 days before 
treatment with VIS410/ 
placebo (Inclusion 
Criteria 3). 
 
For consistency with 
oseltamivir prescribing 
information, subjects with 
ESRD who are not 
undergoing hemodialysis are 
excluded from the study. 
Synopsis; 
Section 7.1 
Test Product, 
Dose, Mode of 
Administration; 
Section 7.2 
Reference 
Product, Dose, 
Mode of 
Administration 
¶ 2 only: 
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, in addition 
to oseltamivir (Tamiflu) 75 mg BID for total of 5 days 
(10 doses). Treatment with oseltamivir may be extended for 
up to 5 additional days (up to 20 doses of total therapy) if 
clinical symptoms are not resolved by Day 5 and/or warrant 
further treatment as assessed by the Investigator. Note: based 
on SOC, subjects may have started oseltamivir therapy prior 
to randomization. No dose adjustment is necessary for 
VIS410 based on renal or hepatic impairment. For patients 
with renal insufficiency, rRefer to prescribing information 
for administration of oseltamivir in patients with renal 
insufficiency.  
Clarified that subjects are 
required to be treated with 
oseltamivir for a minimum 
of 5 days but that treatment 
may be extended up to 10 
days. 
 
Clarified that subjects may 
have started oseltamivir 
treatment prior to enrollment 
in the study; the total 
minimum and maximum 
doses are the same for all 
subjects regardless of when a 
subject began oseltamivir. 
Synopsis and 
Section 7.3 
Instructions for 
Preparation, 
Use, and 
Administration 
The infusion bag will be covered with an opaque sleeve in 
the pharmacy to maintain the study blind. The 
VIS410/placebo 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 extended up 
to 4 hours at the Investigator’s discretion based on local 
infusion site–related symptoms. VIS410 or placebo will be 
administered within 48 hours of being prepared by the study 
pharmacist. 
When 200 mL has been administered, the line will be 
flushed with 25 mL of normal saline. The infusion time may 
be longer at the Investigator’s discretion based only on local 
infusion site–related symptoms up to a maximum of 4 hours. 
The window for 
administration of 
VIS410/placebo after 
preparation by the 
pharmacist has been deleted 
and will be noted in the 
Pharmacy Manual. 
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VIS410 or placebo will be administered within 48 hours of 
being prepared by the study pharmacist. After preparation, 
the VIS410/placebo infusion bag should be stored at room 
temperature. 
Synopsis and 
Section 3.1.1 
Primary 
Efficacy 
Endpoint 
Time to cessation of O2 support resulting in a stable SpO2 by 
pulse oximetry. Stable SpO2 is defined as two consecutive 
SpO2 values of > 92% on room air that are> 95% for at least 
86 hours apart. on room air, return to baseline respiratory 
status, or hospital discharge with no need for additional O2 
support, whichever occurs first. 
Time to cessation of O2 
support redefined based on 
update to Inclusion Criteria 
regarding oxygen 
requirement. 
Synopsis and 
Section 3.2 
Secondary 
Endpoints 
Only revised bullet with its sub-bullets  shown: 
• 
Time to clinical response defined as resolution of at 
least 4 of 5 vital signs 
 
Afebrile with core temperature ≤ 37.8°C, without 
use of antipyretics (oral ≤ 37.2°C) 
 
Oxygen saturation ≥> 95% on room air without 
support or a return to pre-infection status, if pre-
infection status was < 95% 
 
Pulse rate ≤ 100/min 
 
Systolic blood pressure (SBP) ≥ 90 mm/Hg, without 
vasopressor use 
 
Respiratory rate ≤< 24 beats per minute 
Specified that temperature 
endpoint specific to core 
temperature; also defined 
equivalent oral temperature. 
 
Updated definition of time to 
clinical response for oxygen 
saturation and respiratory 
rate. 
Section 6.1.1 
Prescreening 
Procedures 
Subjects may be asked to sign a Prescreening Consent prior 
to undergoing a single nasopharyngeal swab (one nostril) for 
rapid influenza A testing. Subjects will be given a full 
explanation of the nature of the study and provide full 
written informed consent before any study-specific 
assessments or procedures are performed. Note: subjects that 
tested positive for influenza A within 48 hours prior to 
screening do not need to be retested. This screening test is 
not necessary if the subject has a prior influenza A positive 
test by RAT or with another commercially available test 
including PCR, FIA, or ELISA within the prior 48 hours of 
screening. 
Clarified that a pre-screening 
consent to perform rapid 
influenza testing is optional 
as this may depend on 
country and site 
requirements. 
Section 6.2 
Pregnancy 
Safeguards 
Pregnancy will be determined by evaluation of β-human 
chorionic gonadotropin in serum or urine for all women of 
childbearing potential. Subjects who are pregnant or nursing 
will be excluded from the study. During the course of the 
study drug administration period within the study, any 
nursing mother(s) or subject(s) with suspected or confirmed 
pregnancy will be discontinued from study drug therapy but 
will be encouraged to undergo follow-up for safety 
monitoring for themselves (ie, the pregnant female) and the 
baby. 
All women of childbearing potential and all male subjects 
must practice effective contraception from screening until 60 
days post-VIS410/placebo infusion. For the purposes of this 
study, women who do not satisfy at least one of the 
following criteria listed below (ie, the criteria for defining 
non-childbearing potential) are considered to be 
physiologically capable of becoming pregnant and are, 
therefore, defined as women of childbearing potential. 
The criteria for defining women as being of non-childbearing 
potential are: 
Clarified that any pregnancy 
should be reported up until 
60 days post VIS410/placebo 
dosing. 
 
Clarified the contraception 
requirements for women of 
childbearing potential and all 
male subjects. 
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• 
Post-menopausal: ≥ 12 months of natural (spontaneous) 
amenorrhea, or 
• 
Six weeks after surgical bilateral oophorectomy with or 
without hysterectomy, or 
• 
Follicle stimulating hormone > 40 mIU/mL as 
documented in their medical history, or 
• 
Surgical bilateral oophorectomy with or without 
hysterectomy, or 
• 
Hysterectomy, or 
• 
Bilateral tubal ligation 
Women of childbearing potential and all male subjects 
participating in heterosexual relations must be willing to 
practice effective contraception from screening until 60 days 
post-VIS410/placebo infusion. For the purposes of the study, 
highly effective contraception is defined as: 
• 
Male vasectomy with negative semen analysis 
documentation at least 6 months prior to dosing.  
OR 
• 
Combination of an established form of hormonal 
contraception (oral, injected, or implanted) or an 
intrauterine device or intrauterine system 
Plus one of the following: 
And 
• 
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. 
OR 
• 
Male vasectomy with negative semen analysis 
documentation less than The use of contraception does 
not apply if the male partner has been vasectomized at 
least 6 months prior to dosing. OR 
• 
Complete abstinence can be considered an acceptable 
method of contraception at the discretion of the 
Investigator. Periodic abstinences (eg, calendar, 
ovulation, symptothermal, or post-ovulation methods) 
and withdrawal are NOT considered acceptable methods 
of contraception. 
The combination of 2 barrier methods, periodic abstinence 
(eg, calendar, ovulation, symptothermal, or post-ovulation 
methods), and withdrawal are not considered acceptable 
methods of contraception. 
Pregnancy reporting is described in Section 9.7.3. 
Section 6.3.1 
SpO2 Oxygen 
Support 
Baseline SpO2 on room air to be documented, if available. 
Once randomized, SpO2 will be measured using pulse 
oximetry 3 times per day (approximately every preferably 8 
hours apart) at approximately the same time each day until 
stable according to Table 1. Stable the schedule of 
assessment. SpO2 is defined as two consecutive SpO2 values 
of > 92% will be measured using pulse oximetry until > 95% 
Clarified time points for 
obtaining SpO2 
measurements and definition 
of stable SpO2. 
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for at least 6 hours on room air that are at least 8 hours apart. 
Synopsis; 
Section 6.3.2; 
Section 6.3.11; 
 
Section 10.10 
Section subheading titles only 
6.3.2  
Viral Load Titer 
6.3.11 
Pharmacokinetics and Viral Load Titer in Tracheal 
Aspirate 
10.10 
Viral Load Titer 
Section heading only 
revised. 
Section 6.3.4 
Resumption of 
Normal 
Activities 
Subjects will complete a visual analog scale (VAS) daily 
from Day 1 (baseline) until either the subject reports that all 
usual activities (prior to influenza onset) can be performed or 
Day 56, whichever comes first. The VAS scale ranges scale 
ranged from 0 to 10, where 0 indicates subject is unable to 
perform usual activities at all, and 10 indicates subject is 
able to perform all usual) according to the time points 
defined in Error! Reference source not 
found.activities fully) 
Added language to require a 
subject to complete VAS 
from baseline until the 
subject reports they are able 
to perform all usual activities 
they were performing prior 
to influenza onset.  
Section 6.3.8 
Viral Resistance 
Samples for virologic and PK analysis A nasopharyngeal 
swab will be collected from each nostril as described in 
Table 1 and the laboratory manual. These samples swabs 
will be sent to a central virology laboratory for processing 
into appropriate aliquots for virology and PK analysis, 
including resistance testing. 
Further procedures for sample collection, processing, 
shipment, and storage will be described in the laboratory 
manual. 
Note: 
Nasopharyngeal and tracheal samples taken from all 
subjects may be infectious and will be classified as 
“diagnostic specimens” for dispatch purposes. 
Updated language to more 
accurately describe virologic 
analysis which includes PK 
analysis and resistance 
testing. 
Section 6.3.12 
Immunology 
Immunogenicity 
¶ 1 only: 
The immunology immunogenicity parameters under 
evaluation are the detection of ADA titers and 
anti-influenza A antibody titers by hemagglutination 
inhibition assay (HAI), and serum cytokine concentrations. 
Updated language to more 
accurately describe 
immunology evaluation. 
Exploratory cytokine 
objective removed from 
protocol. 
Section 6.5.3 
Complications 
of Influenza; 
Section 10.8.3 
Complications 
of Influenza 
Complications of influenza are defined as pneumonia, 
myocarditis, worsening of chronic bronchitis, sinusitis, otitis, 
other chronic pulmonary diseases, encephalopathy, and 
death. Complications of influenza and use of antibiotic 
therapy for bacterial pneumonia will be reported by variable, 
treatment group, and time point. Diagnosis of bacterial 
pneumonia will be based on local clinical practice, usually 
an assessment of clinical features and any radiographic 
evidence of bacterial pneumonia (eg, infiltrate) and/or 
microbiologic evidence of bacterial pneumonia. All-cause 
and attributable mortality will be evaluated on Day 14 and 
Day 28. 
Clarified that diagnosis of 
bacterial pneumonia will be 
based on local clinical 
practice. 
Section 6.5.4 
Clinical 
Laboratory 
Tests 
Blood samples will be collected by venipuncture or via 
indwelling cannula at the time points indicated in Table 1. 
Standard laboratory tests will be performed by a central or 
local laboratory. Appendix 14.2 lists the biochemistry, 
hematology, and coagulation, and serology tests that will be 
performed by the central laboratory on the safety blood 
samples. Note: subjects to be enrolled based on the 
Investigator’s discretion including any local laboratory 
Updated language to state 
that the required baseline 
laboratory tests will be sent 
to the central laboratory for 
consistency of data for trial 
analysis. However, for 
enrollment, Investigators 
should use local laboratory 
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results per SOC at institution.  
Creatine kinase-MB, creatinine kinase, and troponin are to 
be measured by the central laboratory in the event of a 
subject having chest pain. Subjects with chest pain should be 
managed per SOC. 
In the event of a subject exhibiting the signs and symptoms 
of an anaphylactic reaction, when possible at the time of the 
event, a 5-ml serum sample should be collected for further 
assessment (ie, tryptase, chymase) to be measured by the 
central laboratory. 
A midstream urine sample will be collected for the central 
laboratory for urinalysis by dipstick, flow cytometry, and 
microscopic examination. Appendix 14.2 lists the urinalysis 
parameters that will be assessed. 
A serum Serum or urine pregnancy tests will be performed 
by at the central laboratory for all time points indicated in 
Table 1. In addition, a negative Pregnancy test (serum or 
urine) result within 2 days prior to dosing results must be 
available from the local laboratory prior to randomization. A 
negative result is required for randomization. 
For oseltamivir dosing, creatinine clearance (Cockcroft-
Gault Equation) must be calculated using the serum 
creatinine value from the local laboratory prior to 
randomization. 
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. 
testing for pregnancy and 
serum creatinine. Subject’s 
overall health for 
participation in the trial 
should be based on 
institutional practices and 
local laboratory results. 
 
Clarified that laboratory tests 
required in the case of a 
subject experiencing chest 
pain will be sent to the 
central laboratory for 
analysis while these subjects 
should be managed based on 
institutional practices and 
Investigator discretion. 
 
Clarified that all pregnancy 
testing will be performed at 
the central laboratory but 
that a negative pregnancy 
test performed by the local 
laboratory is required within 
2 days of dosing. 
 
Specified that creatinine 
clearance should be 
calculated by using the 
Cockcroft-Gault equation. 
Section 6.5.5 
Vital Signs and 
Body 
Temperature 
Vital sign parameters will be assessed after 5 minutes in 
supine position at the time points indicated in Table 1. The 
vital sign parameters that will be assessed are supine SBP, 
DBP, heart rate, and respiratory rate. 
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 as an AE adverse 
event. 
Oral body temperature will be recorded at the end of infusion 
then BID while in the hospital and then throughout the study 
according to the study procedures outlined in Table 1Error! 
Reference source not found.. In cases where obtaining oral 
temperature is not possible, core temperature (eg, tympanic, 
axillary) will be obtained. 
While the patient is hospitalized, the maximum temperature 
should be recorded for each 12-hour interval (from 12 AM to 
12 PM and from 12 PM to 12 AM). Fever is defined as a core 
body temperature ≥ 38°C. 
Provided examples of core 
temperature methods. 
 
Clarified that fever is 
defined based on core 
temperature. 
Section 6.5.8 
Radiological 
Assessment 
A baseline chest x-ray or CT scan will be performed for the 
assessment of pneumonia. However, a chest x-ray or CT 
scan performed as part of routine SOC standard of care 
within 72 48 hours before randomization will be acceptable. 
The results of any such studies will be recorded in the EDC. 
The window has been 
expanded to allow use of 
local tests for diagnosis of 
pneumonia and minimize 
unnecessary tests for the 
purpose of the study. The 
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72-hour window will allow 
detection of pneumonia at 
baseline, if present. 
Section 7.4 
The Use of 
Oseltamivir as 
Standard of 
Care 
All subjects will receive oseltamivir 75 mg BID for 5 days as 
part of standard of care (SOC.). Treatment with oseltamivir 
may be extended for up to 5 additional days (up to 20 doses 
of total therapy) if clinical symptoms are not resolved by 
Day 5 or warrant further treatment as assessed by the 
Investigator. Oseltamivir (Tamiflu) will be provided by the 
Sponsor. Note: based on SOC, subjects may have started 
oseltamivir therapy prior to randomization.  
For patients unable to swallow, oseltamivir capsules can be 
opened and mixed with liquid for ease of administration. 
Dose adjustment is recommended for patients with a serum 
creatinine clearance of 60 mL/min or less9 (see Table 7). 
Clarified that subjects may 
have started oseltamivir 
treatment prior to enrollment 
in the study. 
 
Added guidelines on 
administration of oseltamivir 
in subjects unable to 
swallow in compliance with 
Tamiflu product information. 
Section 7.7 
Treatment 
Compliance 
¶ 2 only: 
The number of oseltamivir doses administered while the 
subject is in the hospital will be documented by the 
Investigator or his/her designee. In case of discharge while 
on oseltamivir therapy, subjects will document the number 
of doses taken at home and any missed doses; subjects self-
administering oseltamivir at home will bring the pack(s) pill 
bottle to each study visit so study staff may count and record 
the number of pills taken. Any unused capsules must be 
returned to the study site. 
Clarified that oseltamivir 
will be provided in packs, 
not pill bottles. 
Section 8.2.1 
Prohibited 
Prior 
Medications 
¶ 1 only: 
Per Exclusion Criterion 3 (Section 5.2.2) subjects are not 
allowed to receive monoclonal antibody products (including 
VIS410) within 3 months prior to VIS410/placebo dosing. 
Removed incorrect reference 
to VIS410. 
Section 8.2.2 
Prohibited 
Concomitant 
Medications 
¶ 1 only: 
Per Exclusion Criterion 2 (Section 5.2.2), subjects will not 
be allowed to receive additional monoclonal antibody 
products during the study period. Following randomization, 
use of other antiviral therapy for treatment of influenza A 
infection will not be permitted. Excluded antiviral 
medications include but are not limited to rimantadine, 
amantadine, peramivir, zanamivir, and laninamivir. 
Clarified language since 
VIS410 is a monoclonal 
antibody. 
Section 8.4 
Subject Diary 
A subject diary will be provided upon discharge from the 
hospital and will record the following: 
• 
Daily oseltamivir dosing to be completed for as long as 
the subject continues to take oseltamivir 
• 
Daily VAS for assessing resumption of usual activities 
to be completed up until either the subject reports that 
all pre-influenza usual activities can be performed or 
Day 56, whichever comes first 
• 
Daily Influenza Patient Reported Outcomes (FluPRO) 
Questionnaire to be completed until Day 14, if 
applicable 
Added specific list of what 
will be included in the 
subject diary. 
Section 9.1.3 
Adverse Event 
of Special 
Interest 
For VIS410, the AESIs include the following: 
• 
Abdominal cramping 
• 
Diarrhea/Loose stool 
• 
Nausea  
Updated AESI list to include 
single episodes of loose 
stool.  
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Fax: +44 208 338 0380 
Congenital abnormalities and birth defects in the offspring of 
male or female subjects should be reported as an SAE if 
conception occurred during the study treatment period or in 
the 60 56-day period after the last dose of VIS410/placebo. 
Section 10.1 
Determination 
of Sample Size 
¶ 2 only: 
Using a log-rank test, a sample size of 130 influenza A–
infected subjects per treatment group will provide 80% 
power to detect a 1.5-day difference (5 days for oseltamivir 
alone and 3.5 days for VIS410 plus oseltamivir) in the 
median time to cessation of O2 support resulting in a stable 
SpO2 > 95% for at least 6 hours on room air, return to 
baseline respiratory status, or hospital discharge with no 
need for additional O2 support, whichever occurs first for 
VIS410 relative to placebo. A two-sided alpha of 0.05 was 
used for the calculation. 
Section updated to maintain 
consistency with prior 
changes. 
Section 10.6 
Interim Analysis 
An The first interim analysis of efficacy may will be 
performed by an unblinded third party after 50% of subjects 
have been enrolled (n = 195) and have an assessment of the 
primary endpoint (time to normalization of respiratory 
function). This interim analysis may will be conducted to 
assess if one of the active VIS410 treatment arms will need 
to be terminated for futility. Using the methods of Lan and 
DeMets an alpha spending function will be created and if the 
test statistic for one of the active VIS410 treatment arms is 
less than the lower critical point then the VIS410 treatment 
arm may be terminated for futility. The interim analysis may 
The interim analysis will also test the primary efficacy 
objective to assess if the primary efficacy endpoint has been 
met early. 
The effect size for this study was estimated without the 
benefit of any prior randomized, controlled trial. If the 
VIS410 effect size proves to be greater than anticipated, then 
it is possible that the primary study endpoint will be met by 
the time the interim efficacy analysis is performed. In the 
event the interim analysis reveals that the primary efficacy 
endpoint has been satisfied, this Phase 2 study could be 
terminated for efficacy. 
The DSMB and the unblinded statistician will review the 
interim analysis results to provide their recommendation on 
discontinuation of one of the VIS410 treatment arms, if 
needed, based on pre-specified criteria as outlined in the 
SAP. The interim analysis may will also review the 
following key secondary endpoints, when available, to assist 
in the decision of discontinuing a VIS410 treatment arm: 
• 
Time to clinical resolution of vital signs 
• 
Total number of hours on oxygen support or PPV 
• 
Viral load titer from nasopharyngeal swabs 
A sample size re-estimation (SSRE) will also be performed 
at this point in order to determine if the current sample size 
is sufficient based on the observed effect size in the study. 
The unblinded statisticians will work directly with the 
Sponsor on the SSRE. The details of SSRE and individuals 
with access to the information will be out 
Clarified that an interim 
analysis may (or may not) be 
conducted due to rate of 
enrollment. 
 
Updated statistical methods 
and language to include 
more details related to the 
error rate and the interim 
analysis. 
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Section 10.7.1 
Time to 
Cessation of O2 
Support 
¶ 1 only: 
Time to cessation of O2 support resulting in a stable SpO2 
will > 95% for at least 6 hours, return to baseline respiratory 
status, or hospital discharge with no need for O2 support, 
whichever occurs first, will be analyzed using a Cox model. 
Time from onset of symptoms to VIS410 treatment and the 
number of doses of oseltamivir (Tamiflu) prior to VIS410 
treatment for the current case of influenza will be included as 
a covariate in the analysis. A P-value (using the Wald 
statistic) for each VIS410 dose vs placebo will be presented. 
Section updated to maintain 
consistency with prior 
changes. 
 
Clarified the statistical 
method planned to determine 
P-value. 
Section 10.7.2 
Time to Clinical 
Response; 
Section 10.7.3 
Time to 
Cessation of 
Ventilator 
Support 
Time to clinical response is defined as resolution of 4 of 5 
vital signs that will be determined upon physical 
examination. Clinical response is defined as: 
• 
Afebrile with core temperature ≤ 37.8°C, without use of 
antipyretics (oral ≤ 37.2°C) 
• 
Respiratory rate ≤< 24 beats per minute 
• 
Oxygen saturation ≥> 95% on room air without support 
or a return to pre-infection status, if pre-infection status 
was < 95% 
• 
Pulse rate ≤ 100/min 
• 
SBP ≥ 90 mm/Hg, without vasopressor use 
The probability of time to clinical response (defined as 
resolution of vital signs) will be calculated via Kaplan-
Meier. A P-value (using the log-rank test) for each VIS410 
dose vs placebo will be presented. The number and 
percentage of subjects in each treatment group with clinical 
response will be summarized. Results will be tabulated and 
presented graphically as well. 
Section updated to maintain 
consistency with prior 
changes. 
 
Added details on statistical 
method planned to determine 
P-value. 
Section 10.7.4 
Healthcare 
Resource 
Utilization 
¶ 2 only: 
Time (number of days) to resumption of usual activities will 
be determined from the VAS visual analog scale (scale 
ranged from 0 to 10, where 0 indicates subject is unable to 
perform any of his/her usual activities prior to influenza 
onset at all, and 10 indicates subject is able to fully perform 
all usual return to his/her normal activities fully). 
Added language to clarify 
that a subject needs to 
complete VAS from baseline 
until the subject reports they 
are able to perform all usual 
activities they were 
performing prior to influenza 
onset. 
Section 10.9.2 
Pharmacokin-
etics of 
Nasopharyngeal 
Secretions and 
Tracheal 
Aspirate 
Nasopharyngeal swabs will be obtained from both nostrils (1 
swab per nostril). The first 50 randomized subjects will have 
nasopharyngeal swabs collected up to Day 56 (predose, end 
of infusion, Days 3, 5, 7, 14, 28 and 56); while in the 
remaining subjects, nasopharyngeal swabs will be obtained 
up to Day 14 only. If the subject remains in the hospital on 
Day 10, then additional nasopharyngeal swabs will be 
obtained on Day 10. The VIS410 concentrations in the 
nasopharyngeal secretions and tracheal aspirate will be listed 
by subject, and summary statistics by group will be reported 
as described for the serum concentrations. The computed PK 
parameters will be listed by subject for VIS410. Summary 
statistics and PK parameters will be presented, including 
means, geometric means, standard deviations, CV, medians, 
and ranges, as appropriate. Summary graphs, including mean 
concentration-time profiles by group, will also be presented. 
The nasopharyngeal concentration data may also be analyzed 
by population PK pharmacokinetic methods using nonlinear 
Updated the planned PK 
analysis on nasopharyngeal 
swabs. to minimize the 
number of nasopharyngeal 
swabs in this study, the full 
nasal PK profile (Day 56) 
will be determined based on 
the first 50 subjects only. 
The remainder of the 
subjects will only have nasal 
PK along with nasal virology 
up to Day 14. PK analysis 
will be extrapolated beyond 
Day 14in these subjects 
based on population PK 
analysis. 
Visterra, Inc.
VIS410-203 Clinical Study Report
CONFIDENTIAL
Page 182 of 183

Visterra, Inc. 
 
VIS410-203 
3 July 2017 
 
VIS410-203 
Confidential  
Page 15 of 15 
Location in 
Protocol 
Changes 
Rationale 
mixed effects modeling as implemented in NONMEM or 
equivalent software. If necessary, the data may be pooled 
with data from previous studies. Additional analyses and 
summaries may be generated as appropriate. 
Results of population PK or PK/PD analyses may be 
reported outside the clinical study report. 
Section 10.11 
Immunological 
Analyses 
Immunological assessments will be summarized for the 
MITT population by parameter, treatment group, and time 
point using descriptive statistics: 
• 
Anti-influenza A antibodies by HAI in serum 
• 
ADA titers 
• 
Concentrations of cytokines in serum 
Updated language to more 
accurately describe all 
immunological analyses in 
one section. 
Section 10.12 
Viral Resistance 
Viral sensitivity to VIS410 and oseltamivir will be assessed 
over time during the study. This evaluation will be 
performed using the safety population 
Clarified that viral resistance 
will be assessed. Analysis 
population will be defined in 
the SAP. 
Appendix 14.1 
Footnote to Questionnaire 
Copyright© 2014, 2015, 2016 Leidos Biomedical Research, 
Inc. 
All rights reserved. 
Research Tool in Development: Do NOT copy or distribute 
Added appropriate copyright 
information. 
Schedule of 
Assessments 
Visit window of ± 1 day added to Day 5 and Day 7 
Visit window added to allow 
flexibility for subjects 
discharged from the hospital 
prior to Day 5. 
 
Visterra, Inc.
VIS410-203 Clinical Study Report
CONFIDENTIAL
Page 183 of 183

Protocol History 
Visterra, Inc. – VIS410-203 
Document  
Issue Date 
Amendment Type 
Comments 
Clinical Study Protocol 
21 October 2016 
(Version 1) 
- 
This document 
Revised Clinical Study Protocol 
25 October 2016 
(Version 1.1) 
Country-specific: 
South Africa 
Inclusion of HIV testing at 
baseline