Conditions: Influenza A
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 124
Healthy volunteers: no

Brief summary:
This is a Phase 2, randomized, double-blind, placebo-controlled single dose study in otherwise healthy adults with acute uncomplicated seasonal influenza A to assess the safety and tolerability, efficacy, and pharmacokinetics of MHAA4549A.

Detailed description:

Arms:
arm 1: Participants will receive single-dose MHAA4549A, 3600 mg, by intravenous (IV) administration. arm 2: Participants will receive single-dose MHAA4549A, 8400 mg, by IV administration. arm 3: Participants will receive single-dose placebo by IV administration.

Interventions: intervention 1: MHAA4549A intervention 2: Placebo
Intervention descriptions: intervention 1: MHAA4549A will be administered as a single dose by IV administration. intervention 2: Placebo will be administered as a single dose by IV administration.

Protocol document:
Prot_SAP_000.pdf: 
 
Official Title: 
 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled Trial of 
MHAA4549A, a Monoclonal Antibody, Administered as Monotherapy 
for the Treatment of Acute Uncomplicated Seasonal Influenza A 
Infection in Otherwise Healthy Adults 
NCT Number: 
NCT02623322 
Document Dates: 
Protocol Version 3 – dated 13-May-2016 
 
 
 


 
Title
13-May-2016 21:01:46
Date and Time (UTC)
Company Signatory
Approver's Name
 
FINAL PROTOCOL APPROVAL 
 
CONFIDENTIAL 
The information contained in this document, especially any unpublished data, is the property of 
Genentech, Inc. (or under its control) and therefore is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Ethics Committee 
or Institutional Review Board.  It is understood that this information will not be disclosed to others 
without written authorization from Genentech except to the extent necessary to obtain informed 
consent from persons to whom the drug may be administered. 
 
MHAA4549A—Genentech, Inc. 
Protocol GV29893, Version 3 
PROTOCOL 
TITLE: 
A PHASE 2 RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED TRIAL OF MHAA4549A, 
A MONOCLONAL ANTIBODY, ADMINISTERED AS 
MONOTHERAPY FOR THE TREATMENT OF 
ACUTE UNCOMPLICATED SEASONAL 
INFLUENZA A INFECTION IN OTHERWISE 
HEALTHY ADULTS 
PROTOCOL NUMBER: GV29893 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2016-000425-40 
IND NUMBER: 
117,318 
TEST PRODUCT: 
MHAA4549A 
MEDICAL MONITOR: 
 
SPONSOR: 
Genentech, Inc. 
DATE FINAL: 
Version 1:  9 October 2015 
DATE AMENDED: 
Version 2:  22 April 2016 
Version 3:  See electronic date stamp below 


 
MHAA4549A—Genentech, Inc. 
2/Protocol GV29893, Version 3 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 32 
PROTOCOL SYNOPSIS .................................................................................... 33 
1. 
BACKGROUND .......................................................................................... 40 
1.1 
Background on Influenza....................................................... 40 
1.2 
Background on MHAA4549A................................................. 40 
1.2.1 
Nonclinical Background ......................................................... 40 
1.2.2 
Clinical Safety Background.................................................... 41 
1.2.2.1 
Phase 1 Entry-into-Human Study (GV28916)........................ 41 
1.2.2.2 
Phase 1 High-Dose Safety Study (GV29609)........................ 41 
1.2.2.3 
Phase 2a Influenza Nasal Challenge Study 
(GV28985)............................................................................. 42 
1.2.3 
Clinical Pharmacokinetics...................................................... 43 
1.2.4 
Clinical Efficacy Background ................................................. 44 
1.2.4.1 
Virologic Efficacy ................................................................... 44 
1.2.4.2 
Symptomatic Efficacy ............................................................ 44 
1.3 
Study Rationale and Benefit-Risk Assessment...................... 45 
2. 
OBJECTIVES.............................................................................................. 46 
2.1 
Primary Objective .................................................................. 46 
2.2 
Secondary Objectives............................................................ 46 
2.2.1 
Pharmacokinetic Objective .................................................... 47 
2.3 
Exploratory Objectives........................................................... 47 
3. 
STUDY DESIGN ......................................................................................... 47 
3.1 
Description of Study .............................................................. 47 
3.1.1 
Overview of Study Design ..................................................... 47 
3.1.2 
Safety Monitoring Committee ................................................ 49 
3.1.3 
Internal Monitoring Committee and Scientific 
Oversight Committee............................................................. 50 
3.1.4 
Stopping Rules ...................................................................... 50 




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4.5.5 
Physical Examinations........................................................... 63 
4.5.6 
Vital Signs.............................................................................. 63 
4.5.7 
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 64 
4.5.8 
Electrocardiograms................................................................ 65 
4.5.9 
Patient Daily Symptom Diary................................................. 65 
4.6 
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 66 
4.6.1 
Patient Discontinuation.......................................................... 66 
4.6.2 
Study Treatment Discontinuation........................................... 66 
4.6.3 
Study and Site Discontinuation.............................................. 67 
4.6.4 
Study Completion/Early Discontinuation................................ 67 
4.7 
Assay Methods...................................................................... 67 
5. 
ASSESSMENT OF SAFETY....................................................................... 67 
5.1 
Safety Plan ............................................................................ 67 
5.1.1 
Risks Associated with MHAA4549A ...................................... 68 
5.1.1.1 
Immunogenicity ..................................................................... 68 
5.2 
Safety Parameters and Definitions ........................................ 68 
5.2.1 
Adverse Events ..................................................................... 69 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 69 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 70 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 71 
5.3.1 
Adverse Event Reporting Period ........................................... 71 
5.3.2 
Eliciting Adverse Event Information ....................................... 72 
5.3.3 
Assessment of Severity of Adverse Events ........................... 72 
5.3.4 
Assessment of Causality of Adverse Events ......................... 72 
5.3.5 
Procedures for Recording Adverse Events............................ 73 
5.3.5.1 
Infusion-Related Reactions.................................................... 73 
5.3.5.2 
Diagnosis versus Signs and Symptoms................................. 73 
5.3.5.3 
Adverse Events That Are Secondary to Other 
Events.................................................................................... 74 


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5.3.5.4 
Persistent or Recurrent Adverse Events................................ 74 
5.3.5.5 
Abnormal Laboratory Values ................................................. 75 
5.3.5.6 
Abnormal Vital Sign Values ................................................... 75 
5.3.5.7 
Abnormal Liver Function Tests.............................................. 76 
5.3.5.8 
Deaths ................................................................................... 76 
5.3.5.9 
Pre-Existing Medical Conditions............................................ 77 
5.3.5.10 
Lack of Efficacy or Worsening of Influenza A 
Infection................................................................................. 77 
5.3.5.11 
Hospitalization or Prolonged Hospitalization.......................... 77 
5.3.5.12 
Adverse Events Associated with an Overdose or 
Error in Drug Administration .................................................. 78 
5.3.5.13 
Patient-Reported Outcome Data ........................................... 78 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 78 
5.4.1 
Emergency Medical Contacts................................................ 79 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 80 
5.4.2.1 
Events That Occur prior to Study Drug Initiation.................... 80 
5.4.2.2 
Events That Occur after Study Drug Initiation........................ 80 
5.4.3 
Reporting Requirements for Pregnancies.............................. 80 
5.4.3.1 
Pregnancies in Female Patients............................................ 80 
5.4.3.2 
Pregnancies in Female Partners of Male Patients................. 81 
5.4.3.3 
Congenital Anomalies/Birth Defects and 
Abortions ............................................................................... 81 
5.5 
Follow-Up of Patients after Adverse Events .......................... 81 
5.5.1 
Investigator Follow-Up........................................................... 81 
5.5.2 
Sponsor Follow-Up ................................................................ 82 
5.6 
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 82 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 82 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 83 
6.1 
Determination of Sample Size ............................................... 83 
6.2 
Summaries of Conduct of Study............................................ 84 


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6.3 
Summaries of Treatment Group Comparability ..................... 84 
6.4 
Primary Safety Analyses........................................................ 84 
6.5 
Secondary Efficacy Analyses ................................................ 85 
6.5.1 
Secondary Endpoints ............................................................ 85 
6.5.2 
Exploratory Endpoints............................................................ 85 
6.6 
Subgroup Analyses ............................................................... 86 
6.7 
Pharmacokinetic Analyses..................................................... 86 
6.8 
Exploratory Analyses............................................................. 86 
6.8.1 
Biomarker Analyses............................................................... 87 
6.9 
Immunogenicity Analyses...................................................... 87 
6.10 
Interim Analyses.................................................................... 87 
6.10.1 
Optional Interim Analyses...................................................... 87 
7. 
DATA COLLECTION AND MANAGEMENT ............................................... 88 
7.1 
Data Quality Assurance......................................................... 88 
7.2 
Electronic Case Report Forms............................................... 88 
7.3 
Patient-Reported Daily Symptom Data.................................. 88 
7.4 
Source Data Documentation.................................................. 88 
7.5 
Use of Computerized Systems .............................................. 89 
7.6 
Retention of Records............................................................. 89 
8. 
ETHICAL CONSIDERATIONS.................................................................... 90 
8.1 
Compliance with Laws and Regulations ................................ 90 
8.2 
Informed Consent .................................................................. 90 
8.3 
Institutional Review Board or Ethics Committee.................... 91 
8.4 
Confidentiality........................................................................ 91 
8.5 
Financial Disclosure .............................................................. 92 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 92 
9.1 
Study Documentation ............................................................ 92 
9.2 
Protocol Deviations................................................................ 92 
9.3 
Site Inspections ..................................................................... 92 
9.4 
Administrative Structure......................................................... 93 
9.5 
Publication of Data and Protection of Trade 
Secrets .................................................................................. 93 


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9.6 
Protocol Amendments ........................................................... 94 
10. REFERENCES ........................................................................................... 95 
 
 
LIST OF TABLES 
Table 1 
GV28985 Efficacy Results from Intent-to-Treat Infected 
Population................................................................................... 45 
Table 2 
Laboratory, Biomarker, and Other Biological Samples ............... 64 
Table 3 
Adverse Event Grading (Severity) Scale..................................... 72 
Table 4 
Causal Attribution Guidance ....................................................... 73 
Table 5 
Probability of Observing Adverse Events at Different Event 
Rates .......................................................................................... 84 
 
 
LIST OF FIGURES 
Figure 1 
Study Design............................................................................... 49 
Figure 2 
Semi-Quantitative Pharmacokinetic Model of Nasal 
Exposure..................................................................................... 53 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Activities.................................................................. 96 
Appendix 2 
Schedule of Activities for Recurrent Influenza........................... 100 
Appendix 3 
DAIDS Toxicity Grading Tables for Clinical Abnormalities ........ 102 
Appendix 4 
DAIDS Toxicity Grading Tables for Laboratory Abnormalities... 104 
Appendix 5 
Anaphylaxis Precautions and Management.............................. 107 
Appendix 6 
Adult Patient Symptom Diary .................................................... 108 


 
MHAA4549A—Genentech, Inc. 
8/Protocol GV29893, Version 3 
PROTOCOL AMENDMENT, VERSION 3: 
RATIONALE 
This Version 3 amendment revises the study design to address health authority 
feedback:  
• 
Reduces the inclusion criteria enrollment window (from ≤ 120 hours) to “≤ 72 hours 
(3 days) between onset of influenza-like illness (as determined by the investigator) 
and start of study treatment” 
• 
Revision of a typographical error in Section 3.1.3  
 
PROTOCOL AMENDMENT, VERSION 2: 
RATIONALE 
This Version 2 amendment revises the study design to address operational constraints 
associated with patient enrollment and follow up:  
• 
Expands the inclusion criteria enrollment window (from ≤ 72 hours) to “≤ 120 hours 
(5 days) between onset of influenza-like illness (as determined by the investigator) 
and start of study treatment” 
• 
Telephone visits to assess safety (e.g., symptoms, adverse events) at Day 30 and 
Day 100 instead of in-clinic visits 
 
In addition, Version 2 also contains revisions to support the changes discussed above as 
well as updates to sections to be consistent with current company standards 
• 
Update background section with final data for the GV29609 Phase 1 high dose 
study 
• 
Remove the language “Sponsor-approved” from diagnostic inclusion criteria since 
sites can use their local diagnostic tests 
• 
Revised the Stopping Rules (Section 3.1.4) to make the criteria more simple and 
clear 
• 
Updated objectives and outcomes to be consistent with company protocol template 
• 
Added “identification of pro-inflammatory lipid mediators in urine” as an exploratory 
outcome measure 
• 
Updated procedure for reporting persistent or recurrent adverse events 
(Section 5.3.5.4) to be consistent with current company standards 
• 
Updated Emergency Medical Contacts (Section 5.4.1) 
• 
Updated Safety sections (Section 5) to be consistent with current company 
standards 
• 
Update Schedule of Activities to be consistent with changes made to the study 
design 
• 
Addition of question to adult patient symptom diary (Appendix 6) to capture potential 
fevers between time points 


 
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9/Protocol GV29893, Version 3 
• 
Updated language/rearranged sections to be consistent with company protocol 
template standard 


 
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10/Protocol GV29893, Version 3 
PROTOCOL AMENDMENT, VERSION 3: 
SUMMARY OF CHANGES 
PROTOCOL SYNOPSIS  
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
GLOBAL CHANGE 
Changes made to Sections 3.1.1, 3.2, and 4.1.1 and Appendix 1 in Version 2 regarding 
the inclusion criteria enrollment window have been eliminated in Version 3.  That is, the 
inclusion criteria enrollment window has been changed throughout the protocol from 
≤ 120 hours to ≤ 72 hours (3 days) between onset of influenza-like illness (as determined 
by the investigator) and start of study treatment.  This change reverts to the enrollment 
window specified in Version 1. 
SECTION 3.1.3:  Internal Monitoring Committee and Scientific Oversight 
Committee 
Change made to Section 3.1.3 in Version 2 in error has been corrected in Version 3.  
Text remains as it was in Version 1, as follows. 
As a result, the IMC/SOC may recommend stopping further enrollment in the study 
or other protocol modifications. 
 
FIGURE 1:  Study Design 
Figure 1 has been revised to reflect the changes to the protocol. 


 
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11/Protocol GV29893, Version 3 
PROTOCOL AMENDMENT, VERSION 2 & VERSION 3: 
SUMMARY OF CHANGES 
The Summary of Changes below includes all changes made since Version 1 except 
those changes discussed separately in the Summary of Changes for Version 3 above. 
PROTOCOL SYNOPSIS  
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
SECTION 1.1:  BACKGROUND ON INFLUENZA 
However, influenza can also cause serious complications requiring hospitalization such 
as pneumonia leading to acute respiratory failure, secondary bacterial respiratory 
infections, and death.  Annually, seasonal influenza yearly results in approximately 
three to five million cases of severe illness and up to 500,000 deaths worldwide 
(WHO 2014).  Influenza caused an estimated yearly average of 19,100 deaths between 
1997 and 2009 in the United States (Matias et al. 2014).  A comparable mortality and 
morbidity has been reported for European countries (Snacken et al. 2012).  Thus, a 
significant unmet medical need still exists in those at high-risk of developing influenza-
complications, including children, the elderly, pregnant women, and those with 
underlying chronic medical conditions or weakened immune systems.  
SECTION 1.2.1:  Nonclinical Background 
MHAA4549A is a human monoclonal IgG1 antibody that binds to the influenza A virus.  
MHAA4549A was cloned from a single human plasmablast cell isolated from an 
influenza vaccinated donor (Nakamura et al. 2013).  This antibody binds to a highly 
conserved epitope on the influenza A hemagglutinin (HA) stalk region, blocking fusion 
of the viral envelope with the host target cell endosomal membrane and preventing viral 
genome entry into the host cellreplication. 
SECTION 1.2.2:  Clinical Safety Background 
To date, MHAA4549A has been shown to be safe and well tolerated in three completed 
clinical studies, which altogether enrolled 136 healthy volunteers.  In addition, an 
ongoing global Phase 2b Study (GV29216), in 24 countries across North America, 
Europe, Latin America, and Asia-Pacific, is currently enrolling hospitalized patients 
with severe influenza infection and has shown no clinically significant drug-related safety 
signals. 
SECTION 1.2.2.1:  Phase 1 Entry-into-Human Study (GV28916) 
No serious adverse events or dose-limiting toxicities were reported.  Two clinical 
laboratory values were considered TEAEs (an increase in ALT in one subject who 
received 5 mg/kg MHAA4549A and an increase in creatinine phosphokinase [CK] in 
1 subject who received placebo).  Both results returned to normal within 10 days.  No 
serious adverse events or dose limiting toxicities were reported. 


 
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No safety issues were observed with respect to vital signs or ECG measurements.  
Overall, no relevant differences in mean values or deviations from baseline over time 
were observed in subjects receiving MHAA4549A as compared to placebo for all lab 
values.  No drug-emergent anti-therapeutic antibodies (ATAs) were detected in this 
study. 
SECTION 1.2.2.2:  Phase 1 High-Dose Safety Study (GV29609) 
In the Phase 1 high-dose Study (GV29609) 14 healthy volunteers were given single IV 
doses of placebo or MHAA4549A at 8,400 mg (Cohort A) or 10,800 mg (Cohort B) and 
followed for 120 days. 
In a follow up period of 120 days, an unblinded safety data analysis demonstrated that 
these doses of MHAA4549A were safe and well tolerated.  Headache was the most 
commonly reported adverse event in the study  
In subjects who received 8400 mg MHAA4549A (N = 4), 3 subjects reported 14 TEAEs 
• 
Six TEAEs were reported as related to MHAA4549A:  3 headaches, 1 pruritus, 
1 peripheral swelling, and 1 nasal congestion 
In subjects who received 10800 mg MHAA4549A (N = 4), 4 subjects reported 8 TEAEs 
• 
Three TEAEs were reported as related to MHAA4549A:  1 nausea, 1 headache, and 
1 asthenia 
In subjects who received placebo (N = 6), 5 subjects reported 11 TEAEs 
• 
One TEAE was reported as related to placebo:  1 headache 
All TEAEs were reported as mild except for an unrelated moderate TEAE of a > 10x 
upper limit of normal (ULN) increase in creatinine kinase on Day 15 in one subject who 
received 10800 mg MHAA4549A.  There were no serious adverse events and no 
subjects discontinued the study for any reason.  Based on these data in healthy 
volunteers, MHAA4549A is considered safe and well tolerated at doses up to 10800 mg.  
None of the subjects in the study developed treatment induced ATAs.  One subject 
tested positive for ATA at baseline. 
A total of 34 TEAEs were reported by 12 (85.7%) of the 14 subjects who received one 
dose of the study medication or placebo (safety population).  Twenty-four (24) of these 
TEAEs were reported by 7 (87.5%) of the 8 subjects who had received MHAA4549A 
and 10 TEAEs were reported by 5 (83.3%) of the 6 subjects who received placebo.  
TEAEs were reported by 3 of the 4 subjects receiving 8,400 mg MHAA4549A and 4 of 
4 subjects receiving 10,800 mg MHAA4549A.  No notable trends in types of TEAEs or 
laboratory results were observed between dose levels or between subjects who received 
MHAA4549A versus placebo. 
The most commonly reported TEAEs were headache, reported by 4 subjects who 
received MHAA4549A (3 subjects in Cohort A and 1 subject in Cohort B), and 


 
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13/Protocol GV29893, Version 3 
nasopharyngitis, reported by three subjects who received MHAA4549A (1 subject in 
Cohort A and 2 subjects in Cohort B).  All other TEAEs were each reported by no more 
than 1 subject who received MHAA4549A.  The severity of TEAEs was primarily mild, 
with only three moderate TEAEs reported (a bacterial infection, observed in one subject 
who received 8400 mg MHAA4549A, and elevations of blood CK, observed twice in one 
subject who received 10,800 mg MHAA4549A).  No serious adverse events or 
dose-limiting toxicities were reported.  
No safety issues were observed with respect to vital sign results and ECG 
measurements.  Overall, no relevant differences in mean values and changes or shifts 
from baseline over time were observed with respect to dose levels or MHAA4549A 
compared to placebo.  No subjects in the study developed an ATA response following 
study drug administration. 
SECTION 1.2.2.3:  Phase 2a Influenza Nasal Challenge Study (GV28985) 
Adverse events were collected from time of influenza A inoculation (Day 0).  There was 
no evidence of a dose-related pattern of TEAEs in MHAA4549A-treated subjects, an 
observation that is consistent with all of the Phase 1 studies (GV28916 and GV29609) 
conducted to date.   
SECTION 1.2.3:  Clinical Pharmacokinetics 
In the Phase 1 high-dose study (GV29609), MHAA4549A showed linear PK with a 
mean half-life (t1/2) of approximately 21.5 days (range 21.4−21.6 days).  For the 
8,400-mg and 10,800-mg dose groups, the mean apparent clearance (CL) and the mean 
volume of distribution at steady state (Vss) ranged from 151 to 167 mL/day and from 
4590 to 4170 mL, respectively.  PK data from the Phase 1 high dose study (GV29609) 
are consistent with that observed in the Phase 1 study (GV28916) and Phase 2a study 
(GV28985). 
SECTION 1.3:  STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
The primary goal of this exploratory Phase 2 Study (GV29893) is to demonstrate safety 
and tolerability of MHAA4549A in otherwise healthy patients with naturally 
infectedacquired acute uncomplicated seasonal influenza A.  The study will also assess 
the potential ability of MHAA4549A to reduce the severity and/or duration of clinical 
signs and symptoms, and 
 related to acute uncomplicated influenza.  
Other measures, such as influenza reinfection rate, frequency of secondary 
complications, hospital admissions, and mortality, PK, immunogenicity, and biomarkers 
will also be assessed.  
POther potential risks of MHAA4549A include immunogenicity and infusion-related 
reactions.  Theoretically, any biological agent may evoke these responses.  To date, 
MHAA4549A has not been associated with the development of allergic or anaphylactic 
reactions or infusion-related reactions in preclinical or clinical studies.  In the three 
clinical trials conducted so far, none of the subjects dosed with MHAA4549A developed 


 
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an ATA response.  No adverse events have been identified that are specific to 
MHAA4549A. 
Antibody-dependent enhancement (ADE) of infectiondisease has been suggested as a 
potential risk of antiviral antibodies as therapeutic interventions for influenza 
(Khurana et al. 2013).  ADE of viral uptake might occur when non-neutralizing antiviral 
antibodies facilitate virus entry into host cells, leading to enhanced viral shedding and 
replication and shedding (Takada and Kawaoka 2003; Whitehead et al. 2007; 
Dejnirattisai et al. 2010; Crowe 2013). 
SECTION 2.1:  PRIMARY OBJECTIVE 
• 
To evaluate the safety and tolerability of a single IV dose of MHAA4549A as 
compared to placebo when administered in otherwise healthy patients with acute 
uncomplicated seasonal influenza A, focusing on the following: 
Nature, frequency, and severity of serious and non-serious adverse events 
Immunogenicity assessment 
Effects on laboratory values, vital signs, ECG parameters, and other safety 
biomarkers  
 
SECTION 2.2:  Secondary Objectives 
• 
To examine the time to alleviation of clinical signs and symptoms of influenza A 
infection 
• 
To examine the severity of clinical signs and symptoms of influenza A infection 
• 
To measure hospital admission rate  
• 
To measure and lengthduration of hospital stay 
• 
To measure antibiotic usage for secondary bacterial respiratory infections 
• 
To measure the frequency, severity and development of secondary complications of 
influenza (pneumonia, exacerbation of chronic lung disease, myocarditis, acute 
respiratory distress syndrome, acute otitis media, other related complications) 
• 
To measure the incidence of death 
• 
To measure influenza re-infection rate 
 
SECTION 2.3:  EXPLORATORY OBJECTIVES 
• 
  
 
 
 
 
 
 
 
 
 
 
 


 
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• 
 
 
 
 
SECTION 3.1.1:  Overview of Study Design 
Patients who are eligible for enrollment will be randomized in a 1:1:1 ratio into three 
treatment groups:  a single IV dose of 3600 mg MHAA4549A, a single IV dose of 
8400 mg MHAA4549A, or a single IV dose of placebo.  Study drug administration will 
begin within 72 hours (3 days) of onset of influenza-like illness (as defined in the 
inclusion criteria, Section 4.1.1) and all patients will be followed for a minimum of 
100 days from randomization.… 
A Sponsor approved rapid PCR test or rapid antigen test will be used as an aid in the 
diagnosis of influenza A infection and serve as the basis for satisfying study entry 
requirements. 
… A Sponsor approved rapid PCR test or rapid antigen test will be performed as soon 
as possible, preferably within 72 hours of influenza symptom onset.  
 
 
 
  If the patient tests negative by rapid antigen testing, 
the results will be confirmed by PCR.  The patient will follow the assessments in 
Appendix 2, until a negative PCR result for influenza is confirmed.  Such patients will not 
be re-dosed with study treatment, but local standard of care anti-influenza treatments 
including neuraminidase inhibitors will be permitted and recorded.  These patients must 
still complete telephone follow-up visits at Days 30 and 100 from initial randomization. 
A schedule of assessmentsactivities is provided in Appendix 1. 
SECTION 3.1.2:  Safety Monitoring Committee 
The incidence and nature of any adverse events, serious adverse events, and laboratory 
abnormalities will be assessed on an ongoing basis by Investigators in conjunction with 
a Safety Monitoring Committee (SMC)., If an event is identified as a suspected dose
limiting adverse event (DLAE; see Section ), the Sponsor will convene a meeting of the 
Safety Monitoring Committee (SMC) within 24 hours to assess whether the event meets 
the criteria of a confirmed DLAE.  The SMC may also meet to assess the significance of 
other adverse events or safety findings at any time following a request from either an 
Investigator or the Sponsor.   
The SMC will consist of designated Sponsor representatives from clinical science 
(including the Sponsor’s Medical Monitor), safety science, biostatistics, clinical 
pharmacology, as well as the lead Principal Investigator (PI) and any other individuals 
whom the Sponsor requires to assist with such assessments.  When necessary, a SMC 
member may be replaced at any meeting by a designee. 


 
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If an Investigator determines that an event potentially meets Stopping Criteria (see 
Section 3.1.4), the Investigator will immediately contact the Sponsor and a meeting of 
the SMC will be convened within 24 hours.  If, after a review of the blinded study data, 
the SMC unanimously agrees with the Investigator’s original assessment that the event 
potentially meets Stopping Criteria, the patient will be unblinded to the SMC.  If the 
patient actually received active MHAA4549A, then the SMC will consult with the IMC 
and SOC (see Section 3.1.4) to determine the impact upon the study. 
In addition to events that potentially satisfy Stopping Criteria, the SMC may also meet 
to assess the significance of other adverse events or safety findings at any time 
following a request from either an Investigator or the Sponsor.  Regardless of whether 
any specific events require assessment, the SMC will evaluate overall safety at a 
minimum of every 4 weeks. 
SECTION 3.1.3:  Internal Monitoring Committee and Scientific Oversight 
Committee 
To provide additional assurance of patient safety, safety evaluations will also be 
providedconducted by an IMC and SOC, as defined in a separate IMC/SOC agreement.  
In contrast to the SMC, which will rapidlycontinuously evaluate suspected DLAEs and 
other AEs of interestblinded adverse events, the IMC and SOC will periodically evaluate 
all available unblinded study data to assess whether the study data in its entirety 
suggests a significant toxicity or worsening disease associated with MHAA4549A.  As a 
result, theythe IMC/SOC may recommend stopping further enrollment in the study or 
other protocol modifications.  
An IMC and SOC will provide additional assurance of patient safety.  The IMC consists 
of Sponsor representatives from the following functions:  Clinical Science, Drug Safety, 
Biostatistics, and Statistical Programming and Analysis, and may invite representatives 
from other functional areas on an ad-hoc basis when additional expertise is required 
(e.g., Clinical Pharmacology, Research, etc.).  The IMC members will be unblinded to all 
patient treatment and assignment.  The Clinical Science representative on the IMC will 
serve as the IMC Chair and will be a person other than the study Medical Monitor.  The 
IMC Chair and the drug safety scientist on the IMC will not be involved in the conduct of 
the study or have any contact with the study investigators or site staff.  The drug safety 
scientist on the IMC will also not be involved in the conduct of the study or have any 
contact with the study investigators. Although the clinical pharmacologist, biostatistician 
and statistical programmer are the only IMC members of the IMC will be involved in the 
conduct of the study; however, they dowill not have any contact with study investigators, 
and all discussion within the IMC arewill be kept confidential.  All other Sponsor and 
Contract Research Organization personnel involved in the conduct of the study will 
remain blinded to individual treatment assignments. 
The SOC members will consist of at least two external experts in the field who will also 
be unblinded to treatment allocation. , but additional experts may be added to the SOC 


 
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by the IMC during the course of the study if the need arises.  SOC members will also be 
unblinded to study treatment assignments. 
SECTION 3.1.4:  Stopping RulesDefinition of Dose Limiting Adverse Event 
Further dosing in a treatment arm or in the entire study will be suspended if any of the 
following criteria is met: 
• 
If any patient experiences any one of the following adverse events while enrolled in 
the study and the a life-threatening adverse event related to MHAA4549A 
• 
If a single serious adverse event is deemed related to blinded study drug by the 
Investigator, then that MHAA4549A 
• 
If a patient will be considered toexperiences a persistent post-dose QTcF > 500 ms 
and/or > 60 ms longer than the baseline value related to MHAA4549A 
• 
If ≥ 2 patients out of all patients who have experienced a suspected dose limiting 
adverse event (DLAE):received MHAA4549A to date (including this or any other 
study) experience similar adverse events that meet causality criteria (see 
Section 5.3.4): 
Any serious adverse event  
An unexpected worsening of influenza inconsistent with the usual course of 
disease  
Any other intolerable systemic reaction that results in a significant compromise 
in the ability to conduct activities of daily living 
A suspected systemic immunological reaction to study drug  
Adverse events that are graded at least severe and are deemed related to 
MHAB5553A 
 
If a patient in the blinded study experiences any of the above suspected DLAEs (e.i, an 
eventconditions of sufficient severity that risk would exceed benefit if the AE were 
actually the result of treatment by MHAA4549A), the Investigator must immediately 
notify the Sponsor, who will suspend all dosing in the study and convene a meeting of 
the SMC within 24 hours offollowing knowledge of the event.  Further dosing within the 
entire study must be held until the SMC, in consultation with the IMC and SOC, 
determines whether it can be resumed or whether it should be discontinued permanently.   
Once the Sponsor is notified, the SMC will meet to evaluate the suspected DLAE as 
soon as feasible (expected to be within 24 hours of the initial report).  If, after a review of 
the blinded study data, the SMC unanimously agrees with the Investigator’s original 
assessment that the event meets the criteria of a suspected DLAE, the would meet 
Stopping Criteria if the patient had received active drug, the patient’s treatment will be 
unblinded to the SMC.  If the patient actually received active did receive MHAA4549A 
and , further dosing within the DLAE meets causality criteria (Section ) thenentire 
study must be suspended until the DLAE will be considered a confirmed DLAE.  SMC 
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At a minimum, a confirmed DLAE will be considered dose limiting for patient 
experiencing that event, but may also be considered as defining a dose level that 
exceeds the MTD for MHAA4549A.  As a result, the SMC will ask the IMC/SOC to meet 
in an ad hoc session to evaluate all unblinded study data.  Following IMC/SOC input, 
dosing may stop for all patients receiving MHAA4549A at and that dose or for all patients 
within the study (see Stopping Rules in Section ). 
SECTION 3.1.5:  Stopping Rules 
At any meeting of the IMC or SOC, all available clinical and safety data will be evaluated 
and further dosing in a single patient, one or more treatment arms, or the entire study 
will be suspended when any of the following are met: 
• 
If 2 or more patients out of all patients who have received MHAA4549A to date 
(including this and other studies) experience  
Similar confirmed DLAEs   
Adverse events that are graded at least severe and are deemed related to 
MHAA4549A 
• 
If 1 patient experiences a life threatening confirmed DLAE 
• 
If a single serious adverse event that is deemed related to MHAA4549A 
In addition to the above criteria, dosing will also be halted if the IMC and SOC conclude 
there is a clinically significant imbalance in toxicity between armsone or both of the arms 
receiving MHAA4549A and the arm receiving placebo 
Dosing may only resume if the IMC and SOC, in consultation with the SMC, 
unanimously determine, upon that Stopping Criteria have not been met for at least one 
(or for both) of the dose levels in this study.  Any decision on whether Stopping Criteria 
have been met will always be made following a review of all available unblinded data 
from this and allany previous studies examiningstudy that examined MHAA4549A., that 
the events are not causally related to MHAA4549A or do not satisfy severity criteria.  
Furthermore, based upon their interpretation of the data and in consultation with the 
SMC, the IMC and SOC may determine that dosing must stop for all dose levels, only for 
levels at or above the level where the stopping rules were met, or only for the affected 
individuals. 
SECTION 3.2:  END OF STUDY AND LENGTH OF STUDY 
The study will consist of the following study periods 
• 
Screening and Enrollment/Randomization:  ≤ 72 hours (3 days) between onset of 
influenza-like illness (as determined by the investigator) and start of MHAA4549A or 
placebo  
• 
On-Site Follow-Up:  Follow-up study visits at Days 3, 5, and 7, 30, 100 after 
receiving MHAA4549A or placebo 
• 
Telephone Follow-Up:  Telephone follow-up visits at Day 2, 14, 30, and 100 after 
receiving MHAA4549A or placebo 




 
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SECTION 4.1.1:  Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Otherwise healthy adult men or women ≥ 18 years and ≤ 65 years of age on the day 
of signing the informed consent  
• 
Tests positive for influenza A infection using a Sponsor approved rapid PCR test or 
rapid antigen test as an aid in influenza diagnosis during screening 
• 
≤ 72 hours (3 days) between onset of influenza-like illness (as determined by the 
investigator) and start of study treatment.  
• 
Presence of at least 1 moderate or severe constitutional symptom (e.g., headache, 
myalgias, fever, chills, fatigue, anorexia, nausea) and 1 moderate or severe 
respiratory symptom (e.g., cough, sore throat, rhinorrhea) at screening 
• 
All routine laboratory parameters are within normal limits, unless deemed by the 
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• 
Women of childbearing potential, that is women who are not postmenopausal 
(≥ 12 months of non-therapy-induced amenorrhea) or who are surgically sterile 
(absence of ovaries and/or uterus), must have a negative pregnancy test result 
within 2 days prior to study drug 
• 
For women of childbearing potential:  agreement to remain abstinent or use two 
highly effective methods of contraception (failure rate of < 1% per year), including 
vasectomy of a male partner, for at least 120 days after study drug 
 
SECTION 4.1.2:  Exclusion Criteria 
• 
Patients who have been pregnant within 6 months prior to screening, have been 
breastfeeding within 3 months prior to screening,are currently pregnant, 
breastfeeding, or have a positive pregnancy test at screening, or are intending to 
become pregnant during the study 
 
SECTION 4.2:  METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
Randomization will be stratified by onset of influenza-like illness (≤ 36 hours and 
> 36 hours) and the type of influenza test used at enrollment (rapid PCR or rapid antigen 
test).  A dynamic hierarchicalpermuted block randomization method will be used to 
obtain an approximate 1:1:1 ratio of patients in the 3600 mg MHAA4549A, 8400 mg 
MHAA4549A, and placebo strata. 
SECTION 4.3:  STUDY TREATMENT 
The investigational medicinal product (IMP) for this study is MHAA4549A. 
SECTION 4.3.2.1:  MHAA4549A and Placebo 
Administration of MHAA4549A or placebo will be performed in a setting with emergency 
medical equipment and personnel who are trained to monitor for and respond to medical 
emergencies.  A qualified physician or medically qualified designee will be on site during 
study drug administration for all patients.  All patients will be monitored for study drug 
reactions during administration and for at least 30 minutes after completion of study drug 
administration. 
A single dose of MHAA4549A or placebo will be delivered by IV infusion following 
dilution in 0.9% normal saline over approximately 120 minutes.  Study drug should be 
delivered using a 0.20−0.22 μm in-line filter.  Compatibility testing has shown that 
MHAA4549A is stable when diluted in 0.9% normal saline in a polyvinylchloride, 
polyolefin bag, or ethylene vinyl acetate bag (EVA), at or above a combined total 
concentration of 0.24 mg/mL up to 27.0 mg/mL.  Study drug must be administered within 
the treatment window outlined in Section 3.1.1.  Further detailed instructions can be 
found in the Pharmacy Manual. 
Subjects who experience a moderate-to-severe infusion related reaction should have 
their infusion stopped.  The infusion should not be restarted at half of the initial rate.  
The infusion will be discontinued in the event that the subject experiences a serious 
reaction and further dosing of subjects halted until safety of the drug is assessed. 


 
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SECTION 4.4.1:  Permitted Therapy 
Patients with recurrent influenza infection may be given local standard of care 
anti-influenza treatments including neuraminidase inhibitors. 
SECTION 4.4.2:  Prohibited Therapy 
Use of the following therapies is prohibited throughout the patient’s participation in the 
study (from enrollment to end of study): 
• 
Any influenza antiviral therapy (e.g., oseltamivir, zanamivir, peramivir, amantadine, 
rimantadine) from onset of influenza-like illness (except for recurrent influenza as 
described in Section 3.1.1) 
 
SECTION 4.5:  STUDY ASSESSMENTS 
Please see Appendix 1 for the schedule of assessmentsactivities performed during the 
study. 
SECTION 4.5.1:  Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.related procedures.  
Informed Consent Forms for enrolled patients and for patients who are not subsequently 
enrolled will be maintained at the study site. 
SECTION 4.5.2:  Diagnostic Testing for Enrollment 
All patients must be assessed for influenza A disease confirmation prior to enrollment 
into the study.  A Sponsor approved rapid PCR test or rapid antigen test is required for 
diagnosis of influenza A infection.  For the diagnostic test, sample collection may involve 
a nasal swab or a nasopharyngeal swab, depending on the diagnostic platform approved 
at the site.  
It is highly recommended that the rapid PCR test result or the rapid antigen test result be 
available within 2 hours from the time of sample collection. 
SECTION 4.5.4:  
 
 
 
 
 
 
 
 
SECTION 4.5.5:  Physical Examinations 
A complete physical examination should be performed at screening and should include 
an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, 
dermatological, musculoskeletal, respiratory, gastrointestinal, genitourinary, and 




 
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study file at the site.  The following should be recorded in the appropriate eCRF:  heart 
rate, RR interval, QRS interval, PR duration, uncorrected QT interval, and QT interval 
corrected using Fridericia’s formula (QTcF) (or Bazett’s formula [QTcB] if QTcF is not 
available) based on the machine readings of the individual ECG tracings.  Any 
morphologic waveform changes or other ECG abnormalities must be documented on the 
eCRF.  If considered appropriate by the Sponsor, ECGs may be analyzed 
retrospectively at a central laboratory. 
If at a particular postdose timepoint the mean QTcF is > 500 ms and/or > 60 ms 
longer than the baseline value, another ECG must be recorded, ideally within the next 
5 minutes, and ECG monitoring should continue until QTcF has stabilized on two 
successive ECGs.  The Medical Monitor should be notified.  Standard-of-care treatment 
may be instituted per the discretion of the investigator.  If a PK sample is not scheduled 
for that timepoint, an unscheduled PK sample should be obtained.  A decision on study 
drug discontinuation should be made, as described in Section 3.1.4.  The investigator 
should also evaluate the patient for potential concurrent risk factors (e.g., electrolyte 
abnormalities, co-medications known to prolong the QT interval, severe bradycardia). 
SECTION 4.5.9:  Patient Daily Symptom Diary 
Patients will use an electronic device (electronic patient reported outcome [ePRO]) or 
paper diaries (as applicable) to record symptom data (Nicholson et al. 2000; 
Treanor et al. 2000) (Appendix 6).  The investigator staff will provide the paper diary 
PRO device and instructions for completing the symptom diary will be provided by the 
investigator staff.  The purpose of the diary is to record any symptoms of influenza-like 
illness, symptom relief medications and temperature (oral).  The symptom diary card, 
symptom relief medications and temperature should be completed two times daily: when 
a patient first wakes up in the morning (before getting out of bed) and ~12 hours later up 
to Day 14 or until resolution of symptoms (defined as a total symptom score of 0−1 for 
24 hours without use of symptom relief medications).  Temperature should be taken 
before administration of acetaminophen/paracetamol and/or NSAIDs (see Section 4.4.1 
for permitted medications).  Patients should be encouraged to stay consistent with the 
diary schedule and sites should check that patients are able to take their temperature 
properly.  Day 1 entry will be completed within 6 hours prior to start of study infusion.  
The data from electronic diaries will be transmitted to a centralized database at the 
ePRO vendor and can be accessed by appropriate study personnel securely via the 
Internet.  See  for symptom diary.   
SECTION 4.5.9:  Study Completion/Early Discontinuation 
Patients who complete all study visits through Day 100 are considered to have 
completed the study.  All patients who discontinue from the study early will be asked to 
complete all assessments for the early discontinuationcurrent day.  If a patient 
discontinues after Day 7, only a telephone visit is required as the Early Discontinuation 


 
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visit.  Please see Schedule of AssessmentsActivities provided in Appendix 1 for 
assessments performed at the Study Completion and Early Discontinuation visit. 
SECTION 5.1:  SAFETY PLAN 
Administration of MHAA4549A or placebo will be performed in a setting with emergency 
medical equipment and personnel who are trained to monitor for and respond to medical 
emergencies.  A qualified physician or medically qualified designee will be on site during 
study drug administration for all patients.  All patients will be monitored for study drug 
reactions during administration and for at least 30 minutes after completion of study drug 
administration. 
SECTION 5.1.1.1:  Immunogenicity 
MHAA449A is a monoclonal antibody-based therapeutic.  As with any recombinant 
monoclonal antibody, MHAA4549A may elicit an immune response in patients with the 
development of antibodies against MHAA4549A.  Subjects will be closely monitored for 
any potential immune response to MHAA4549A.  Screening, confirmatory, and 
characterization assay with appropriate sensitivity and therapeutic tolerance will be 
employed to assess the prevalence of pre-existing ATAs before, during, and after the 
treatment withto MHAA4549A. 
SECTION 5.3.1:  Adverse Event Reporting Period 
After initiation of study drug, all adverse events will be reported until study 
dischargecompletion at the Day 100 visit or until an Early Discontinuation visit.  After this 
period, the investigator should report any serious adverse events that are believed to be 
related to prior study drug treatment (see Section 5.6). 
SECTION 5.3.5.4:  Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF, unless the severity increases.  The initial severity (intensity or 
grade) of the event will be recorded at the time the event is first reported.  If a persistent 
adverse event becomes more severe, the most extreme severity should also be 
recorded on the Adverse Event eCRF.  Details regarding any increases or decreases in 
severity will be captured on the Adverse Event Intensity or Grade Changes eCRF.  If 
the event becomes serious, it should be reported to the Sponsor immediately (i.e., 
≤ 24 hours after learning that the event became serious; see Section 5.4.2 for reporting 
instructions).as a separate event on the Adverse Event eCRF.  The initial (less severe) 
adverse event report should be updated to indicate that the event resolved on the date 
just prior to the day the even became more severe.  Fluctuations in intensity during 
resolution should not be captured as new events unless they exceed the maximum 
severity previously recorded for that AE  The Adverse Event eCRF should be updated by 
changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events. 


 
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If a persistent adverse event becomes serious, it should be recorded as a separate 
event on the Adverse Event eCRF and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning that the event became serious).  The initial (non
serious) adverse event report should be updated to indicate that the event resolved on 
the date just prior to the day the even became serious. 
SECTION 5.3.5.8:  Deaths 
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6. 
SECTION 5.3.5.11:  Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., in-patient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as addressed 
in Sections 5.3.5.9 and 5.3.5.10 and as outlined below.   
SECTION 5.3.5.11:  Patient-Reported Outcome Data 
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data.  However, if any PRO responses 
suggestive of a possible adverse event are identified during site review of the PRO data, 
the investigator will determine whether the criteria for an adverse event have been met 
and, if so, will report the event on the Adverse Event eCRF. 
SECTION 5.4.1:  Emergency Medical Contacts 
 24-Hour Safety Hotline 
• 
North America:  
 
• 
EMEA/APAC:  
 
 
 Medical Monitor contact information: 
Primary Medical Monitor:  
 
Telephone Nos.:  
US Office 
 
 
US Mobile 
 
Email Address:  
 
Secondary Medical Monitor:  
 
Telephone Nos.:  
US Office 
 
 
US Mobile 
 
Email Address:  
 


 
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SECTION 5.4.2.1:  Events That Occur prior to Study Drug Initiation 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators.below: 
Region 
Fax Number 
Email Address 
North America 
 
 
EMEA 
 
 
Asia Pacific 
 
 
 
SECTION 5.4.2.2:  Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until the patient is discharged fromcompletes the study at Day 
100 or Early Discontinuationdiscontinues early.  Investigators should record all case 
details that can be gathered immediately (i.e., within 24 hours after learning of the event) 
on the Adverse Event eCRF and submit the report via the electronic data capture (EDC) 
system.  A report will be generated and sent to Safety Risk Management by the EDC 
system. 
In the event that the EDC system is unavailable, the paper Clinical Trial Serious 
Adverse Event/Adverse Event of Special Interest Reporting Form provided to 
investigators should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the event), either by faxing or 
by scanning and emailing the form using the fax number or email address provided in 
Section 5.4.2.1to investigators.  Once the EDC system is available, all information will 
need to be entered and submitted via the EDC system. 
SECTION 5.4.3.1:  Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 120 days of study drug 
administration.  A paper Clinical Trial Pregnancy Reporting Form should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 
after learning of the pregnancy), either by faxing or by scanning and emailing the form 
using the fax number or email address provided in Section 5.4.2.1to investigators..  
Pregnancy should not be recorded on the Adverse Event eCRF.  The investigator should 
counsel the patient, discussing the risks of the pregnancy and the possible effects on the 
fetus.  Monitoring of the patient should continue until conclusion of the pregnancy.  Any 
serious adverse events associated with the pregnancy (e.g., an event in the fetus, an 


 
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event in the mother during or after the pregnancy, or a congenital anomaly/birth defect in 
the child) should be reported on the Adverse Event eCRF.  In addition, the Investigator 
will submit a paper Clinical Trial Pregnancy Reporting Form when updated 
information on the course and outcome of the pregnancy becomes available. 
In the event that the EDC system is unavailable, the Clinical Trial Pregnancy Reporting 
Form provided to investigators should be completed and submitted to the Sponsor or its 
designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
either by faxing or by scanning and emailing the form using the fax number or email 
address provided to investigators.  Once the EDC system is available, all information will 
need to be entered and submitted via the EDC system. 
SECTION 5.4.3.3:  Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
30 days of study drug administration.  A paper Clinical Trial Pregnancy Reporting Form 
should be completed and submitted to the Sponsor or its designee immediately (i.e., no 
more than 24 hours after learning of the pregnancy), either by faxing or by scanning and 
emailing the form using the fax number or email address provided in Section 5.4.2.1to 
investigators.  Attempts should be made to collect and report details of the course and 
outcome of any pregnancy in the partner of a male patient exposed to study drug.  In 
order to accomplish this, The pregnant partner will need to sign an Authorization for Use 
and Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy.  
After the authorization has been signed, the investigator will update thesubmit a paper 
Clinical Trial Pregnancy Report eCRF with additionalReporting Form when updated 
information on the course and outcome of the pregnancy becomes available.  An 
investigator who is contacted by the male patient or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the fetus, to 
support an informed decision in cooperation with the treating physician and/or 
obstetrician. 
SECTION 5.6:  POST STUDY ADVERSE EVENTS THAT OCCUR AFTER 
THE ADVERSE EVENT REPORTING PERIOD 
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
100 days after study drug administration), if the event is believed to be related to prior 
study drug treatment.  These events should be reported through the use of the Adverse 
Event eCRF.  However, if the EDC system is not available, the investigator should 
report these events directly to the Sponsor or its designee, either by faxing or by 
scanning and emailing the Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form using the fax number or email address provided to investigators. 


 
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SECTION 6.4:  Primary Safety Analyses 
The prevalence (baseline) of ATA and incidence (treatment emergent) of ATA will be 
reported and correlation with PK, safety, efficacy, and biomarker endpoints will be 
analyzed as data allow. 
SECTION 6.5.2:  Exploratory Endpoints 
• 
 
  
 
 
 
 
SECTION 6.7:  PHARMACOKINETIC ANALYSES 
Individual and mean serum MHAA4549A concentration versus time data will be 
tabulated and plotted.  The serum PK of MHAA4549A will be summarized by estimating 
total serum drug exposure (i.e., AUC), maximum concentration (Cmax), total serum 
clearance, half-life, and volume of distribution, as data allow. 
SECTION 6.8:  EXPLORATORY ANALYSES 
 
 
 
 
 
 
 
 
 
 
 
 
SECTION 6.8.1:  Biomarker Analyses 
 
 
 
 
 
 
  
 
 
 


 
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SECTION 6.9:  IMMUNOGENICITY ANALYSES 
The immunogenicity analyses will be limited to testing of predose samples from all 
patients enrolled in the study.  No post-dose samples will be collected (except for Day 7 
in the case of recurrent influenza). 
The number of ATA-positive patients at baseline will be determined, which will provide 
an estimate of the prevalence of pre-existing ATAs in this patient population. 
 
 
 
No additional immunogenicity assessments are planned for this study. 
SECTION 7.1:  DATA QUALITY ASSURANCE 
If using e PRO devices:  ePRO data will be collected through use of an electronic device 
provided by an ePRO vendor.  The device is designed for entry of data in a way that is 
attributable, secure, and accurate, in compliance with U.S. Food and Drug 
Administration (FDA) regulations for electronic records (21 CFR Part 11).  The ePRO 
device data are available for view access only via secure access.  Only identified and 
trained users may view the data, and their actions become part of the audit trail.  
The Sponsor will have view access only.  System backups for data stored by the 
Sponsor and records retention for the study data will be consistent with the Sponsor’s 
standard procedures. 
SECTION 7.3:  PATIENT-REPORTED DAILY SYMPTOM DATA 
Patients will use an ePRO device use paper diaries to record influenza like symptoms, 
temperature, and acetaminophen/paracetamol and/or NSAIDs use.   
For ePRO devices, the data will be transmitted to a centralized database at the ePRO 
vendor.  The data can be reviewed by site staff via secure access. 
Once the study is complete, the ePRO data, audit trail, and trial and system 
documentation will be archived.  The investigator will receive patient data for the site in 
both human  and machine readable formats on an archival quality compact disc that 
must be kept with the study records as source data.  Acknowledgement of receipt of the 
compact disc is required.  In addition, the Sponsor will receive all patient data in a 
machine readable format on a compact disc. 
SECTION 7.6:  RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, ePRO data/paper diaries (if applicable), Informed Consent Forms, 
laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for at least 15 years after completion or discontinuation of the 


 
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study, or for the length of time required by relevant national or local health authorities, 
whichever is longer.  After that period of time, the documents may be destroyed, subject 
to local regulations.   
SECTION 8.4:  CONFIDENTIALITY 
Given the complexity and exploratory nature of the analyses, data derived from 
exploratory biomarker specimens will generally not be provided to study investigators 
or patients unless required by law.  The aggregate results of any conducted research 
will be available in accordance with the effective Sponsor policy on study data 
publication (see Section 9.5). 
SECTION 9.4:  ADMINISTRATIVE STRUCTURE 
Data reported by patients regarding their symptoms, body temperature, and any use of 
acetaminophen/paracetamol and/or NSAIDs will be captured using paper diaries or 
electronically via ePRO devices (as applicable). 
FIGURE 1:  Study Design 
Figure 1 has been revised to reflect the changes to the protocol. 
TABLE 5:  Probability of Observing Adverse Events at Different Event 
Rates 
Rows for underlying “True Rate” of 2% and 6% have been deleted. 
REFERENCES: 
Matias G, Taylor R, Haguinet F, et al. Estimates of mortality attributable to influenza and 
RSV in the United States during 1997 2009 by influenza type or subtype, age, 
cause of death, and risk status. Influenza Other Respir Viruses 2014;8(5):507 15. 
Snacken R, Quinten C, Devaux I, et al. Surveillance of hospitalized severe cases of 
influenza A (H1N1)pdm09 and related fatalities in nine EU countries in 2010 2011. 
Influenza Other Respir Viruses 2012;6(6):e93 e96. 
APPENDIX 1:  Schedule of Activities 
The Schedule of Assessments has been revised to reflect the changes to the protocol. 
APPENDIX 2:  Schedule of Activities for Recurrent Influenza 
The Schedule of Assessments has been revised to reflect the changes to the protocol. 
APPENDIX 5:  Anaphylaxis Precautions and Management 
The Schedule of Assessments has been revised to reflect the changes to the protocol. 
APPENDIX 6:  Adult Patient Symptom Diary 
The Schedule of Assessments has been revised to reflect the changes to the protocol. 
 


 
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I agree to conduct the study in accordance with the current protocol. 
  
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
 
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by the CRO. 
 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE 2 RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED TRIAL OF MHAA4549A, 
A MONOCLONAL ANTIBODY, ADMINISTERED AS 
MONOTHERAPY FOR THE TREATMENT OF 
ACUTE UNCOMPLICATED SEASONAL 
INFLUENZA A INFECTION IN OTHERWISE 
HEALTHY ADULTS 
PROTOCOL NUMBER: GV29893 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2016-000425-40 
IND NUMBER: 
117,318 
TEST PRODUCT: 
MHAA4549A 
MEDICAL MONITOR: 
 
SPONSOR: 
Genentech, Inc. 






 
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Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Otherwise healthy adult men or women ≥ 18 years and ≤ 65 years of age on the day of 
signing the informed consent  
• 
Tests positive for influenza A infection using a rapid PCR test or rapid antigen test as an aid 
in influenza diagnosis during screening 
• 
≤ 72 hours (3 days) between onset of influenza-like illness (as determined by the 
investigator) and start of study treatment.  
• 
Presence of at least 1 moderate or severe constitutional symptom (e.g., headache, 
myalgias, fever, chills, fatigue, anorexia, nausea) and 1 moderate or severe respiratory 
symptom (e.g., cough, sore throat, rhinorrhea) at screening 
• 
Women of childbearing potential, that is women who are not postmenopausal (≥ 12 months 
of non-therapy-induced amenorrhea) or who are surgically sterile (absence of ovaries 
and/or uterus), must have a negative pregnancy test result within 2 days prior to study drug 
• 
For women of childbearing potential:  agreement to remain abstinent or use two highly 
effective methods of contraception (failure rate of < 1% per year), including vasectomy of a 
male partner, for at least 120 days after study drug 
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of contraception. 
Examples of highly effective contraceptive methods include: bilateral tubal ligation, 
male partner sterilization, combined (estrogen and progestogen) or progestogen-only 
hormonal contraception associated with inhibition of ovulation (oral, intravaginal, 
transdermal), intrauterine device (IUD), and intrauterine hormone releasing system 
(IUS). 
• 
For men:  agreement to remain abstinent or use a condom for at least 30 days after study 
drug administration and agreement to refrain from donating sperm for 90 days after study 
drug administration. 
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of contraception. 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
History of major medical conditions from medical history, physical examination, and/or 
routine laboratory tests that may put the subject at higher risk for influenza related 
complications as determined by the investigator during screening 
• 
Creatinine clearance  ≤ 80 mL/min 
• 
Any abnormal laboratory test or ECG, which is deemed by the investigator to be clinically 
significant 
• 
Patients who have taken any influenza antiviral therapy (e.g. oseltamivir, zanamivir, 
peramivir, amantadine, rimantadine) in the period from onset of influenza-like illness and 
prior to enrollment  
• 
Patients who are currently pregnant, breastfeeding, or have a positive pregnancy test at 
screening, or are intending to become pregnant during the study 
• 
Clinical signs and symptoms consistent with otitis, bronchitis, sinusitis, or pneumonia, or 
active bacterial infection at any site that requires therapy with antibiotics 
• 
Investigational therapy within 30 days prior to initiation of study treatment or within 5 half-
lives of the investigational product, whichever is greater 
• 
Hypersensitivity to any constituents (sodium succinate, sucrose, polysorbate 20) of 
MHAA4549A 


 
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• 
Prior therapy with any anti-influenza monoclonal antibody, including MHAA4549A  
• 
Received nasally administered influenza A vaccine within 14 days prior to screening 
• 
Positive influenza B or influenza A + B infection within 2 weeks prior to study treatment  
• 
Significant history of tobacco use at any time (≥ 10 pack year history, e.g. one pack a day 
for 10 years) 
• 
Patients receiving chronic dose of oral corticosteroids exceeding 10 mg/day of prednisone 
or equivalent steroid dose or inhaled corticosteroids at any dose for a duration of greater 
than 14 days within 30 days prior to screening  
• 
History or evidence of autoimmune disease or known immunodeficiency of any cause 
• 
Patients taking any medications that suppress the immune system (immunosuppressives) 
• 
History of asthma, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, 
reactive airway disease, or chronic lung condition of any etiology. 
A history of childhood asthma before the age of 12 is acceptable provided the subject: 
Has no symptoms consistent with asthma 
Is not receiving chronic or acute treatment for asthma. 
Patients with asthma after age 12 but who has not received treatment for asthma in 
the past 4 years can be included at the investigator’s discretion after consultation with 
the Sponsor.  
• 
Planned medical or surgical procedure during the study 
• 
Known HIV infection with CD4+ T cell count ≤ 200 cells/mL in the past 12 months  
• 
History of illicit drug use or alcohol abuse in the 12 months prior to screening which, in the 
investigator’s judgment, could affect compliance with study requirements 
• 
Serious infection requiring oral or IV antibiotics within 14 days prior to screening 
• 
History or presence of an abnormal ECG that is clinically significant in the investigator’s 
opinion, including complete left bundle branch block, second- or third-degree heart block, or 
evidence of prior myocardial infarction 
End of Study 
The end of the study is defined as the first day when all patients have had a study completion 
visit, early termination visit or have otherwise been discontinued from the study.  
Length of Study 
The total duration of this study for each subject is approximately 14 weeks, including screening, 
enrollment, treatment, and follow-up. 
Investigational Medicinal Products 
MHAA4549A will be supplied by the Sponsor in a sterile, preservative-free liquid solution in a 
single-use 15 mL USP/Ph.  Eur.  Type 1 glass vials filled to deliver 10 mL (500 mg) of 
MHAA4549A solution. 
Test Product (Investigational Drug) 
The randomization of patients will be managed by a central IxRS.  All patients will be randomly 
assigned to receive either a single dose of MHAA4549A at 3600 mg IV, or 8400 mg IV or 
placebo IV at a 1:1:1 ratio. 
Comparator 
MHAA4549A placebo will be provided as a clear, colorless, sterile, preservative-free liquid 
solution and has the same vial configuration as the Drug Product. 
Statistical Methods 
Primary Analysis 
The primary objective of this study is to characterize the safety and tolerability of a single dose 
of MHAA4549A as compared to placebo when administered in otherwise healthy patients with 
acute uncomplicated seasonal influenza A.  Statistical summaries will be descriptive in nature.  


 
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Patients will be grouped according to treatment actually received, and any patients who receive 
any amount of MHAA4549A or placebo will be included in the analyses. 
Determination of Sample Size   
The planned sample size for this study is approximately 47 patients per treatment group.  A total 
of approximately 141 patients will be enrolled in this study in order to obtain 120 evaluable 
patients (an estimated dropout rate of 15%). 
Optional Interim Analyses  
Given the hypothesis-generating nature of this study, the Sponsor may choose to conduct up to 
two interim efficacy analyses.  The decision to conduct an optional interim analysis and the 
timing of the analysis will be documented in the Sponsor’s trial master file prior to the conduct of 
the interim analysis.  The interim analysis will be performed and interpreted by members of the 
Sponsor study team and appropriate senior management personnel who will be unblinded at 
the treatment group level.  Access to treatment assignment information will follow the Sponsor’s 
standard procedures.  If conducted, an interim analysis would be for administrative purposes 
only (i.e., internal planning or decision making) and would not impact the conduct of the current 
study in any way.  A nominal type 1 error penalty of 0.0001 will be taken.  
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
ADE 
antibody-dependent enhancement 
ALT 
alanine aminotransferase 
ALP 
alkaline phosphatase 
aPTT 
activated partial thromboplastin time 
ARDS 
acute respiratory distress syndrome 
AST 
aspartate aminotransferase 
ATA 
anti-therapeutic antibody 
AUC 
area under the curve 
AUC0-infinity 
area under the curve from zero to infinity 
BUN 
blood urea nitrogen 
CK 
creatinine phosphokinase 
Cmax 
maximum observed concentration 
Cmin 
minimum observed concentration 
CRO 
contract research organization 
DAIDS 
Division of Acquired Immunodeficiency Syndrome 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EIH 
entry into humans 
ELISA 
enzyme-linked immunosorbent assay 
E.U. 
European Union 
EVA 
ethylene vinyl acetate 
FDA 
Food and Drug Administration 
GGT 
Gamma-glutamyl transferase 
GLP 
good laboratory practice 
HA 
hemagglutinin 
HAI 
hemagglutinin inhibition 
HED 
human equivalent dose 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Conference on Harmonisation 
IgG 
Immunoglobulin G 
IMC 
Internal Monitoring Committee 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (application) 


 
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Abbreviation 
Definition 
IQR 
interquartile range 
IRB 
Institutional Review Board 
IRR 
infusion related reaction 
ITT 
intent-to-treat 
ITTI 
intent-to-treat infected 
IUD 
intrauterine device 
IUS 
intrauterine system 
IV 
intravenous 
IxRS 
Interactive voice and web response system 
LDH 
lactate dehydrogenase 
LPLV 
last patient, last visit 
NA 
neuraminidase 
NAI 
neuraminidase inhibitor 
NOAEL 
no observed adverse effect level 
NSAID 
non-steroidal anti-inflammatory drug 
PCR 
polymerase chain reaction 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PRO 
patient-reported outcome 
PT  
prothrombin time 
qPCR 
quantitative polymerase chain reaction 
QTcB 
QT interval corrected using Bazett’s formula 
QTcF 
QT interval corrected using Fridericia’s formula 
SAE 
serious adverse event 
SMC 
Safety Monitoring Committee 
SOC 
Scientific Oversight Committee 
TCID50 
50% tissue culture infectious dose 
TEAE 
treatment emergent adverse event 
Tmax 
Time at which the Cmax is observed 
ULN 
upper limit of normal 


 
MHAA4549A—Genentech, Inc. 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON INFLUENZA  
Influenza viruses cause annual epidemics during autumn and winter that are associated 
with significant human disease.  Influenza is a respiratory illness with a broad clinical 
spectrum that typically results in mild symptoms, such as fever and cough, from which 
most people recover without requiring medical attention.  The standard of care therapy 
for patients with acute uncomplicated influenza consists of administration of 
neuraminidase inhibitors (NAI) that include, but are not limited to, oseltamivir, zanamivir, 
and peramivir.   
However, influenza can also cause serious complications requiring hospitalization such 
as pneumonia leading to acute respiratory failure, secondary bacterial respiratory 
infections, and death.  Annually, seasonal influenza results in approximately three to 
five million cases of severe illness and up to 500,000 deaths worldwide (WHO 2014).  
Thus, a significant unmet medical need still exists in those at high-risk of developing 
influenza-complications, including children, the elderly, pregnant women, and those with 
underlying chronic medical conditions or weakened immune systems.  
To address this need, the Sponsor is developing a highly-specific anti-influenza A 
monoclonal antibody therapy (MHAA4549A) for the treatment of hospitalized patients 
with severe influenza.  This study assesses the safety, efficacy, and pharmacokinetics of 
MHAA4549A in otherwise healthy patients with acute uncomplicated seasonal influenza 
A infection. 
1.2 
BACKGROUND ON MHAA4549A 
1.2.1 
Nonclinical Background 
MHAA4549A is a human monoclonal IgG1 antibody that binds to the influenza A virus.  
MHAA4549A was cloned from a single human plasmablast cell isolated from an 
influenza vaccinated donor (Nakamura et al. 2013).  This antibody binds to a highly 
conserved epitope on the influenza A hemagglutinin (HA) stalk region, blocking fusion 
of the viral envelope with the host target cell endosomal membrane and preventing viral 
replication. 
In vitro, MHAA4549A is capable of neutralizing all human seasonal influenza A strains 
tested.  In vivo, efficacy of MHAA4549A has been demonstrated in mouse models of 
influenza A infection, both as a single agent and in combination with oseltamivir.  In the 
absence of influenza infection, the epitope on the human influenza A HA glycoprotein 
targeted by MHAA4549A is not endogenously expressed in human or rat tissues and, 
therefore, is unlikely to be present in the absence of influenza infection.  Ex vivo tissue 
cross-reactivity study data showed no specific binding of MHAA4549A to any of the 
human or rat tissues examined.  Weekly intravenous administration of MHAA4549A 
(total of 5 doses) in Sprague-Dawley rats was well tolerated up to the maximum feasible 
dose of 150 mg/kg.   


 
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1.2.2 
Clinical Safety Background 
To date, MHAA4549A has been shown to be safe and well tolerated in three completed 
clinical studies, which altogether enrolled 136 healthy volunteers.  In addition, an 
ongoing global Phase 2b Study (GV29216), in 24 countries across North America, 
Europe, Latin America, and Asia-Pacific, is currently enrolling hospitalized patients 
with severe influenza infection and has shown no clinically significant drug-related safety 
signals.  
1.2.2.1 
Phase 1 Entry-into-Human Study (GV28916) 
In the Phase 1 entry-into-human (EIH) study (GV28916), 21 healthy volunteers were 
given single IV doses of placebo or MHAA4549A at 1.5 mg/kg, 5 mg/kg, 15 mg/kg, or 
45 mg/kg and followed for 120 days.  
A total of 23 treatment emergent adverse events (TEAEs) were reported by 13 of the 
21 subjects (61.9%) who received one dose of the study medication.  Nineteen of these 
TEAEs were reported by 10 of the 16 subjects (62.5%) who had received MHAA4549A 
and 4 TEAEs were reported by 3 of the 5 subjects (60.0%) who received placebo.  The 
total number of TEAEs reported was similar in all dosing cohorts (4 TEAEs per cohort), 
with the exception of the 5 mg/kg cohort, where seven TEAEs were observed.  Overall, 
no notable trends were observed among dose levels or between subjects who received 
MHAA4549A versus placebo.  
The most commonly reported TEAEs in subjects receiving MHAA4549A were headache 
(4 subjects) and oropharyngeal pain (2 subjects).  The severity of TEAEs was primarily 
mild, with only two moderate TEAEs.  No serious adverse events or dose-limiting 
toxicities were reported.  Two clinical laboratory values were considered TEAEs (an 
increase in ALT in one subject who received 5 mg/kg MHAA4549A and an increase in 
creatinine phosphokinase [CK] in 1 subject who received placebo).  Both results 
returned to normal within 10 days.   
No safety issues were observed with respect to vital signs or ECG measurements.  
Overall, no relevant differences in mean values or deviations from baseline over time 
were observed in subjects receiving MHAA4549A as compared to placebo for all lab 
values.  No drug-emergent anti-therapeutic antibodies (ATAs) were detected in this 
study. 
1.2.2.2 
Phase 1 High-Dose Safety Study (GV29609) 
In the Phase 1 high-dose Study (GV29609) 14 healthy volunteers were given single IV 
doses of placebo or MHAA4549A at 8400 mg (Cohort A) or 10800 mg (Cohort B) and 
followed for 120 days.  
A total of 34 TEAEs were reported by 12 (85.7%) of the 14 subjects who received one 
dose of the study medication or placebo (safety population).  Twenty-four (24) of these 
TEAEs were reported by 7 (87.5%) of the 8 subjects who had received MHAA4549A 


 
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and 10 TEAEs were reported by 5 (83.3%) of the 6 subjects who received placebo.  
TEAEs were reported by 3 of the 4 subjects receiving 8,400 mg MHAA4549A and 4 of 
4 subjects receiving 10,800 mg MHAA4549A.  No notable trends in types of TEAEs or 
laboratory results were observed between dose levels or between subjects who received 
MHAA4549A versus placebo. 
The most commonly reported TEAEs were headache, reported by 4 subjects who 
received MHAA4549A (3 subjects in Cohort A and 1 subject in Cohort B), and 
nasopharyngitis, reported by three subjects who received MHAA4549A (1 subject in 
Cohort A and 2 subjects in Cohort B).  All other TEAEs were each reported by no more 
than 1 subject who received MHAA4549A.  The severity of TEAEs was primarily mild, 
with only three moderate TEAEs reported (a bacterial infection, observed in one subject 
who received 8400 mg MHAA4549A, and elevations of blood CK, observed twice in one 
subject who received 10,800 mg MHAA4549A).  No serious adverse events or 
dose-limiting toxicities were reported.  
No safety issues were observed with respect to vital sign results and ECG 
measurements.  Overall, no relevant differences in mean values and changes or shifts 
from baseline over time were observed with respect to dose levels or MHAA4549A 
compared to placebo.  No subjects in the study developed an ATA response following 
study drug administration.  
1.2.2.3 
Phase 2a Influenza Nasal Challenge Study (GV28985) 
In the Phase 2a challenge Study (GV28985), 101 healthy volunteers were nasally 
inoculated with the H3N2 (A/Wisconsin/67/2005) strain of influenza virus.  
At 24−36 hours after inoculation, 60 subjects received single IV doses of 400 mg, 
1200 mg, or 3600 mg MHAA4549A, 8 subjects received oseltamivir as an active 
comparator, and 32 subjects received placebo.  All subjects, regardless of initial 
treatment, received oseltamivir on Days 7−11 to mitigate risk of late shedding and/or 
further transmission of virus.  
Adverse events were collected from time of influenza A inoculation (Day 0).  There was 
no evidence of a dose-related pattern of TEAEs in MHAA4549A-treated subjects, an 
observation that is consistent with all of the Phase 1 studies (GV28916 and GV29609) 
conducted to date.  Expected influenza-related symptoms and adverse events were 
observed in inoculated subjects; these influenza-related adverse events were similar in 
subjects who received MHAA4549A or placebo.  Of the 101 subjects randomized, 
23 subjects experienced at least 1 adverse event following virus inoculation but prior to 
the first dose of study medication.  The most common adverse events seen prior to the 
administration of study drug were headache (4 subjects), elevated blood pressure 
(4 subjects), dizziness (3 subjects), and procedural hemorrhage (3 subjects). 
Following administration of the study drug, there were 207 TEAEs in 86 of the 100 safety 
evaluable subjects (86%) that occurred in a similar pattern across all treatment groups.  


 
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Thirty-six of the 86 subjects (42%) experienced ≥ 1 study-drug related TEAE.  
Study-drug related TEAEs occurred in a similar proportion and in a similar pattern across 
all treatment groups.  The most common TEAEs were elevations in ALT, AST, and 
amylase which were reported in 15 of 25 TEAEs (60%) in subjects receiving placebo 
(n = 32) or oseltamivir (n = 8) and 26 of 33 TEAEs (79%) in subjects receiving 
MHAA4549A (n = 60).  Similar elevations have been seen previously following influenza 
infection (Polakos et al. 2006; Yingying 2011).  There were no clinically significant 
changes in vital signs, spirometry, or electrocardiograms, and no pattern of study 
drug-related effects in these parameters.  There were no observed adverse events or 
safety events that were considered attributable to interactions between oseltamivir and 
MHAA4549A.  
No subjects experienced a serious adverse event prior to the first dose of study drug.  
Three treatment-unrelated serious adverse events were reported by 2 subjects:  
1 subject, who received placebo, reported symptoms of major depression on Day 15; 
and 1 subject, who received 3600 mg MHAA4549A, reported a lower-limb fracture on 
Day 109 and a post-operative wound infection on Day 133 after study drug 
administration. 
One subject in the placebo group tested positive for ATAs at baseline as well as post-
baseline.  The immunogenicity incidence rate among the 60 subjects who received 
MHAA4549A was 0%.  
1.2.3 
Clinical Pharmacokinetics 
The Phase 1 EIH study (GV28916) demonstrated that MHAA4549A serum 
pharmacokinetics (PK) was dose proportional with a mean half-life of approximately 
23 days (range:  21.9 to 24.6 days).  The PK profile appeared consistent with that of a 
human IgG1 antibody that lacks known endogenous host targets (Ishida et al. 2015). 
In the Phase 2a influenza nasal challenge study (GV28985), serum MHAA4549A 
concentrations exhibited a biphasic disposition with an initial rapid distribution phase 
followed by a slow elimination phase, which was also observed in the Phase 1 EIH study 
(GV28916).  MHAA4549A demonstrated linear serum PK.  The group mean maximum 
observed concentration (Cmax) increased in a dose-proportional manner of 116 μg/mL for 
the 400-mg dose group and 1110 μg/mL for the 3600-mg dose group.  Similarly, the 
group mean area under the curve from zero to infinity (AUC0-infinity) was 1800 and 
18,100 day*μg/mL for the 400- and 3600-mg dose groups, respectively, and is 
approximately dose proportional.  PK data from the Phase 2a study (GV28985) is 
consistent with that observed in the Phase 1 study (GV28916), with MHAA4549A 
demonstrating a mean half-life of approximately 23 days (mean range: 22.5−23.7 days).  
In the Phase 1 high-dose study (GV29609), MHAA4549A showed serum linear PK 
with a mean half-life (t1/2) of approximately 21.5 days (range 21.4−21.6 days).  For the 
8,400-mg and 10,800-mg dose groups, the mean apparent clearance (CL) and the mean 


 
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volume of distribution at steady state (Vss) ranged from 151 to 167 mL/day and from 
4590 to 4170 mL, respectively.  PK data from the Phase 1 high dose study (GV29609) 
are consistent with that observed in the Phase 1 study (GV28916) and Phase 2a study 
(GV28985). 
1.2.4 
Clinical Efficacy Background 
The virologic efficacy analysis for the Phase 2a challenge study (GV28985), presented 
in Table 1, includes the Intent-to-Treat infected (ITTI) population who received 400 mg 
MHAA4549A (N = 11), 1200 mg MHAA4549A (N = 13), 3600 mg MHAA4549A (N = 14), 
oseltamivir alone (N = 2), or placebo (N = 21).  The ITTI population included all subjects 
who were randomized, inoculated with challenge virus, and had laboratory confirmed 
evidence of influenza infection as defined by one or more of the following:  
• 
A positive cell culture assay by 50% tissue culture infectious dose (TCID50) at least 
once during quarantine post-challenge virus inoculation 
Or 
• 
At least two positive detections by any qPCR assay between virus inoculation and 
day of discharge from quarantine 
Or 
• 
Seroconversion ( ≥ 4-fold rise in titer compared to baseline) 
 
1.2.4.1 
Virologic Efficacy 
The 400-mg dose demonstrated a decrease in viral shedding (reduction in median viral 
area under the curve (AUC) by quantitative polymerase chain reaction [qPCR]) by 46% 
(p = 0.05) and peak viral load (reduction in median peak viral load by qPCR) by 20.4% 
(p = 0.02).  The 1200-mg dose showed a decrease in viral shedding by 3.0% (p = 0.90) 
and peak viral load by 0.3% (p = 1.00).  The 3600-mg dose level demonstrated a 
significant decrease in viral shedding by 97.5% (p = 0.01) and peak viral load by 77.3% 
(p = 0.002) (Table 1).  The decreased efficacy observed in the 1200-mg dose group is 
thought to be due to variability from the challenge model and inter-subject differences. 
1.2.4.2 
Symptomatic Efficacy 
The A/Wisconsin/67/2005 virus induced mild symptoms that were predominantly limited 
to the upper respiratory tract, including rhinorrhea, nasal congestion, and sneezing.  
Duration and severity of influenza-related symptoms (rhinorrhea, nasal congestion, 
sneezing, sore throat, earache, malaise, cough, shortness of breath, headache, and 
muscle/joint ache) were collected on a self-reported Symptom Diary Card.  The cards 
grade the symptoms on a scale of 0−3, where Grade 0 is absence, Grade 1 is just 
noticeable, Grade 2 is bothersome but does not prevent participation in activities, and 
Grade 3 is bothersome and interferes with activities.  Composite clinical symptom scores 
for the ITTI population are shown in Table 1.  


 
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Consistent with the virological results, there was a trend toward a decrease in the 
symptoms scores for the 3600-mg dose with a mean reduction of the composite 
symptom score of 82% (Table 1).   
Table 1 
GV28985 Efficacy Results from Intent-to-Treat Infected 
Population 
 
MHAA4549A 
Endpoint 
Placebo
(N = 21) 
400 mg 
(N = 11) 
% Reduction
(p-value) 
1200 mg 
(N = 13) 
% Reduction
(p-value) 
3600 mg 
(N = 14) 
% Reduction 
(p-value) 
Oseltamivir 
(N = 2) 
% Reduction
(p-value) 
Median qPCR AUC 
(log10 vc/mLxhour) 
458.1 
247.2 
46.0% 
(0.0455) 
444.4 
3.0% 
(0.9020) 
11.3 
97.5% 
(0.0051) 
57.4 
87.5% 
(0.0558) 
Median Cell Culture 
AUC 
(log10 TCID50 × hour) 
186.8 
70.3 
62.4% 
(0.0087) 
224.5 
-20.2% 
(0.8742) 
0.0 
100% 
(0.0023) 
28.8 
84.6% 
(0.0558) 
Median qPCR Peak 
(log10 vc/mL) 
6.38 
5.08 
20.4% 
(0.0187) 
6.36 
0.3% 
(1.0000) 
1.45 
77.3% 
(0.0024) 
2.30 
63.9% 
(0.0947) 
Median Cell Culture 
Peak (log10 TCID50) 
4.25 
1.75 
58.8% 
(0.0220) 
4.00 
5.9% 
(0.9578) 
0.00 
100% 
(0.0023) 
1.25 
70.6% 
(0.1150) 
Median Composite 
Symptom Score AUC 
207.7 
87.5 
57.9% 
(0.2000) 
192.1 
7.5% 
(0.8743) 
37.7 
81.8% 
(0.2887) 
8.1 
96.1% 
(0.0855) 
AUC = area under the curve; mg = milligram; mL = milliliter; qPCR = quantitative polymerase chain 
reaction; vc = viral copies; TCID50 = 50% tissue culture infectious dose. 
Note:  Comparison of 400 mg, 1200 mg, 3600 mg and oseltamivir to placebo using 
nonparametric Wilcoxon rank-sum test.  % Reduction is calculated as 100%*[(the median of 
placebo – the median of active)/the median of placebo].  All p-values are unadjusted for multiple 
testing. 
 
The responses observed in the Phase 2a study (GV28985) suggest that higher doses of 
MHAA4549A may improve virological and symptomatic efficacy in a population with 
influenza infection.  Because of this, an 8400-mg dose will be assessed in this study. 
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
Two Phase 1 (GV28916, GV29609) studies have demonstrated that MHAA4549A is safe 
and well tolerated in healthy volunteers at doses up to 10800 mg.  Data from the 
Phase 2a study (GV28985) demonstrated that doses of approximately 3600 mg 
MHAA4549A are safe, well tolerated, and effective in reducing viral titers and influenza 
symptoms as compared to placebo in healthy volunteers inoculated with influenza A 


 
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virus.  No MHAA4549A-specific TEAEs have been identified in any of our clinical studies.  
When combined with nonclinical studies demonstrating that MHAA4549A has a 
well-tolerated safety profile and in vitro and in vivo efficacy against influenza virus, these 
findings support further clinical development of MHAA4549A. 
The primary goal of this exploratory Phase 2 Study (GV29893) is to demonstrate safety 
and tolerability of MHAA4549A in otherwise healthy patients with naturally acquired 
acute uncomplicated seasonal influenza A.  The study will also assess the potential 
ability of MHAA4549A to reduce the severity and/or duration of clinical signs and 
symptoms, 
 related to acute uncomplicated influenza.  Other 
measures, such as influenza reinfection rate, frequency of secondary complications, 
hospital admissions, mortality, PK, immunogenicity, and biomarkers will also be 
assessed.  
Potential risks of MHAA4549A include immunogenicity and infusion-related reactions.  
Theoretically, any biological agent may evoke these responses.  To date, MHAA4549A 
has not been associated with the development of allergic or anaphylactic reactions or 
infusion-related reactions in preclinical or clinical studies.  In the three clinical trials 
conducted so far, none of the subjects dosed with MHAA4549A developed an ATA 
response.  No adverse events have been identified that are specific to MHAA4549A. 
Antibody-dependent enhancement (ADE) of disease has been suggested as a potential 
risk of antiviral antibodies when used as therapeutic interventions for influenza 
(Khurana et al. 2013).  ADE of infection might occur when non-neutralizing antiviral 
antibodies facilitate virus entry into host cells, leading to enhanced viral replication and 
shedding (Takada and Kawaoka 2003; Whitehead et al. 2007; Dejnirattisai et al. 2010; 
Crowe 2013).  In the Phase 2a challenge study (GV28985), no signs or symptoms of 
ADE were observed, including higher viral titers/genomes or increases in clinical 
symptom scores in subjects receiving MHAA4549A as compared to placebo.  
2. 
OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
• 
To evaluate the safety and tolerability of a single IV dose of MHAA4549A as 
compared to placebo when administered in otherwise healthy patients with acute 
uncomplicated seasonal influenza A, focusing on the following: 
Nature, frequency, and severity of serious and non-serious adverse events 
Effects on laboratory values, vital signs, ECG parameters, and other safety 
biomarkers  
 
2.2 
SECONDARY OBJECTIVES 
• 
To examine the time to alleviation of clinical signs and symptoms of influenza A 
infection 
• 
To examine the severity of clinical signs and symptoms of influenza A infection 


 
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• 
To measure hospital admission rate  
• 
To measure duration of hospital stay 
• 
To measure antibiotic usage for secondary bacterial respiratory infections 
• 
To measure the frequency, severity and development of secondary complications of 
influenza (pneumonia, exacerbation of chronic lung disease, myocarditis, acute 
respiratory distress syndrome, acute otitis media, other related complications) 
• 
To measure the incidence of death 
• 
To measure influenza re-infection rate 
 
2.2.1 
Pharmacokinetic Objective  
• 
To characterize the PK profile of a single dose of MHAA4549A in serum 
 
2.3 
EXPLORATORY OBJECTIVES 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
3.1.1 
Overview of Study Design  
This is a randomized, double-blind, placebo-controlled study (GV29893) designed to 
assess the safety and tolerability, efficacy, and pharmacokinetics of MHAA4549A 
compared to placebo when administered to approximately 141 otherwise healthy 
patients with acute uncomplicated seasonal influenza A.  This study will inform the safety 
of MHAA4549A in the natural influenza infection setting. 
Patients who are eligible for enrollment will be randomized in a 1:1:1 ratio into three 
treatment groups:  a single IV dose of 3600 mg MHAA4549A, a single IV dose of 
8400 mg MHAA4549A, or a single IV dose of placebo.  Study drug administration will 
begin within 72 hours (3 days) of onset of influenza-like illness (as defined in the 
inclusion criteria, Section 4.1.1) and all patients will be followed for a minimum of 
100 days from randomization.  After study discharge, all drug-related serious adverse 
events will continue to be reported to the Sponsor.  Randomization will be stratified by 


 
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onset of influenza-like illness (≤ 36 hours and > 36 hours) and type of influenza test used 
for enrollment (rapid PCR or rapid antigen test).  A permuted block randomization 
method will be used to obtain an approximate 1:1:1 ratio of patients in the 3600 mg 
MHAA4549A, 8400 mg MHAA4549A, or placebo groups within each stratum. 
A rapid PCR test or rapid antigen test will be used as an aid in the diagnosis of influenza 
A infection and serve as the basis for satisfying study entry requirements.  The intent-to-
treat (ITT) population will include all patients randomized who received study medication.  
A central quantitative PCR test will be performed on Day 1 virology samples to confirm 
influenza A infection and define the intent-to-treat infected (ITTI) population for analyses.  
If a patient develops new symptoms of influenza (as defined in the inclusion criteria, 
Section 4.1.1) between Days 14 and 100, consistent with recurrent influenza infection 
(reinfection after initial influenza symptoms completely resolved), he/she should 
immediately inform site study personnel.  A rapid PCR test or rapid antigen test will be 
performed as soon as possible, preferably within 72 hours of influenza symptom onset.  
 
 If the patient tests negative by rapid antigen testing, the results 
will be confirmed by PCR.  The patient will follow the assessments in Appendix 2, until a 
negative PCR result for influenza is confirmed.  Such patients will not be re-dosed with 
study treatment, but local standard of care anti-influenza treatments including 
neuraminidase inhibitors will be permitted and recorded.  These patients must still 
complete telephone follow-up visits at Days 30 and 100 from initial randomization.  
Safety evaluations will be provided by an Internal Monitoring Committee (IMC) and 
Scientific Oversight Committee (SOC), as defined in a separate IMC/SOC agreement.  If 
after review of available study data the IMC and SOC conclude that there is a significant 
toxicity or worsening disease associated with MHAA4549A, they may recommend 
stopping further enrollment in the study or other protocol modification. 
A schedule of activities is provided in Appendix 1. 


 
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Figure 1 Study Design 
 
3.1.2 
Safety Monitoring Committee 
The incidence and nature of any adverse events, serious adverse events, and laboratory 
abnormalities will be assessed on an ongoing basis by Investigators in conjunction with 
a Safety Monitoring Committee (SMC).  The SMC will consist of designated Sponsor 
representatives from clinical science (including the Sponsor’s Medical Monitor), safety 
science, biostatistics, clinical pharmacology, as well as the lead Principal Investigator (PI) 
and any other individuals whom the Sponsor requires to assist with such assessments.  
When necessary, a SMC member may be replaced at any meeting by a designee. 
If an Investigator determines that an event potentially meets Stopping Criteria (see 
Section 3.1.4), the Investigator will immediately contact the Sponsor and a meeting of 
the SMC will be convened within 24 hours.  If, after a review of the blinded study data, 
the SMC unanimously agrees with the Investigator’s original assessment that the event 
potentially meets Stopping Criteria, the patient will be unblinded to the SMC.  If the 
patient actually received active MHAA4549A, then the SMC will consult with the IMC 
and SOC (see Section 3.1.4) to determine the impact upon the study. 
In addition to events that potentially satisfy Stopping Criteria, the SMC may also meet 
to assess the significance of other adverse events or safety findings at any time 
following a request from either an Investigator or the Sponsor.  Regardless of whether 


 
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any specific events require assessment, the SMC will evaluate overall safety at a 
minimum of every 4 weeks.   
3.1.3 
Internal Monitoring Committee and Scientific Oversight 
Committee 
To provide additional assurance of patient safety, safety evaluations will also be 
conducted by an IMC and SOC, as defined in a separate IMC/SOC agreement.  In 
contrast to the SMC, which will continuously evaluate blinded adverse events, the IMC 
and SOC will periodically evaluate all available unblinded data to assess whether the 
study data in its entirety suggest a significant toxicity or worsening disease associated 
with MHAA4549A.  As a result, the IMC/SOC may recommend stopping further 
enrollment in the study or other protocol modifications.  
The IMC consists of Sponsor representatives from the following functions:  Clinical 
Science, Drug Safety, Biostatistics, and Statistical Programming and Analysis, and may 
invite representatives from other functional areas on an ad-hoc basis when additional 
expertise is required (e.g., Clinical Pharmacology, Research, etc.).  The IMC members 
will be unblinded to all patient treatment and assignment.  The Clinical Science 
representative on the IMC will serve as the IMC Chair and will be a person other than 
the study Medical Monitor.  The IMC Chair and the drug safety scientist on the IMC will 
not be involved in the conduct of the study or have any contact with the study 
investigators or site staff.  Although the biostatistician and statistical programmer 
members of the IMC will be involved in the conduct of the study, they will not have any 
contact with study investigators, and all discussion within the IMC will be kept 
confidential.  All other Sponsor and Contract Research Organization personnel involved 
in the conduct of the study will remain blinded to individual treatment assignments. 
The SOC members will consist of at least two external experts in the field, and additional 
experts may be added to the SOC by the IMC during the course of the study.  SOC 
members will also be unblinded to study treatment assignments. 
A detailed description of the procedures, data flow, and meeting schedule of the IMC 
and SOC are provided in a separate IMC/SOC agreement. 
3.1.4 
Stopping Rules 
Further dosing in a treatment arm or in the entire study will be suspended if any of the 
following criteria is met: 
• 
If any patient experiences a life-threatening adverse event related to MHAA4549A 
• 
If a single serious adverse event is deemed related to MHAA4549A 
• 
If a patient experiences a persistent post-dose corrected QT interval > 500 ms 
and/or > 60 ms longer than the baseline value related to MHAA4549A 


 
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• 
If ≥ 2 patients out of all patients who have received MHAA4549A to date 
(including this or any other study) experience  similar adverse events that meet 
causality criteria (see Section 5.3.4):  
An unexpected worsening of influenza inconsistent with the usual course of 
disease  
Any intolerable systemic reaction that results in a significant compromise in the 
ability to conduct activities of daily living 
A suspected systemic immunological reaction to study drug  
 
If a patient in the blinded study experiences any of the above (i.e., conditions of 
sufficient severity that risk would exceed benefit), the Investigator must immediately 
notify the Sponsor, who will suspend all dosing in the study and convene a meeting of 
the SMC within 24 hours following knowledge of the event.  If, after a review of the 
blinded study data, the SMC unanimously agrees with the Investigator’s original 
assessment that the event would meet Stopping Criteria if the patient had received 
active drug, the patient’s treatment will be unblinded to the SMC.  If the patient did 
receive MHAA4549A, further dosing within the entire study must be suspended until 
the SMC consults with the IMC and SOC. 
In addition to the above criteria, dosing will also be halted if the IMC and SOC conclude 
there is a clinically significant imbalance in toxicity between one or both of the arms 
receiving MHAA4549A and the arm receiving placebo 
Dosing may only resume if the IMC and SOC, in consultation with the SMC, 
unanimously determine that Stopping Criteria have not been met for at least one (or for 
both) of the dose levels in this study.  Any decision on whether Stopping Criteria have 
been met will always be made following a review of all unblinded data from this and any 
previous study that examined MHAA4549A.  
3.2 
END OF STUDY AND LENGTH OF STUDY 
The study will consist of the following study periods 
• 
Screening and Enrollment/Randomization:  ≤ 72 hours (3 days) between onset of 
influenza-like illness (as determined by the investigator) and start of MHAA4549A or 
placebo  
• 
On-Site Follow-Up:  Follow-up study visits at Days 3, 5, and 7 after receiving 
MHAA4549A or placebo 
• 
Telephone Follow-Up:  Telephone follow-up visits at Day 2, 14, 30, and 100 after 
receiving MHAA4549A or placebo 
 
Patients who are unable to return to the clinic for on-site follow-up visits should be 
contacted by phone to:  1) ascertain health status, 2) record adverse event information, 
and 3) ask that the diary be completed and returned. 


 
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The end of the study is defined as the first day when all patients have had a study 
completion visit, early termination visit or have otherwise been discontinued from the 
study.  
The total duration of this study for each subject is approximately 14 weeks, including 
screening, enrollment, treatment, and follow-up. 
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for MHAA4549A Dose and Schedule 
Single IV doses of 3600 mg and 8400 mg were selected to assess the safety, efficacy, 
and pharmacokinetics of MHAA4549A and to provide data for further clinical 
development.  The selection of dose in this study was based on nonclinical efficacy data 
from the in vivo mouse influenza A infection models, the pharmacokinetics in clinical 
studies (see Section 1.2.3), and the relationship between the pharmacokinetics, 
pharmacodynamics, and efficacy observed in the Phase 2a challenge model in 
influenza A (GV28985). 
The dose of 3600 mg is based on the Phase 2a challenge study (GV28985), which 
demonstrated both a significant decrease in viral shedding in the upper respiratory tract 
and a decrease in the AUC of symptoms scores in patients who received the 3600-mg 
dose of MHAA4549A as compared to patients who received placebo 
(see Section 1.2.4.2).  An MHAA4549A exploratory exposure-response analysis of the 
Phase 2a study demonstrated that subjects with nasal maximum MHAA4549A 
concentration (Cmax) greater than the median nasal Cmax value had shorter time to 
resolution of viral shedding as compared with the placebo group (median:  75.8 hours vs. 
113.7 hours), whereas subjects with nasal Cmax less than the median nasal Cmax value 
had similar time to resolution of viral shedding compared with the placebo group 
(median:  112.1 hours vs. 113.7 hours).  Thus, at higher viral loads, higher doses of 
MHAA4549A are expected to be more efficacious.  
The 8400-mg dose was selected based on the hypothesis that severely ill patients 
hospitalized with influenza infection (the target population of MHAA4549A) are likely to 
have high viral loads and longer durations of viral shedding and require increased doses 
of MHAA4549A.  Simulations from a semi-quantitative pharmacokinetic model 
developed from the Phase 2a challenge study (GV28985) suggest that 8400 mg is the 
minimum dose that will show a separation of nasal exposure from a dose of 3600 mg 
(Figure 2). 
Both the 3600- and 8400-mg doses of MHAA4549A are expected to be safe based on 
data from previous clinical Phase 1 and Phase 2 studies (see Section 1.2.2). 




 
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Patients will be allowed to take over-the-counter medications for symptomatic relief as 
specified in Section 4.4.1.  Site staff will monitor all patients closely for safety and 
severity of disease.   
3.3.4 
  
 
 
 
 
 
3.4 
OUTCOME MEASURES  
3.4.1 
Primary Outcome Measures 
• 
Incidence, nature, and severity of adverse events and clinical laboratory 
abnormalities (graded according to the Division of Acquired Immunodeficiency 
Syndrome [DAIDS] Toxicity Grading Tables for Clinical Abnormalities) associated 
with the administration of MHAA4549A to patients with influenza A as measured by 
changes in vital signs, physical findings, and clinical laboratory results 
 
3.4.2 
Secondary Outcome Measures 
• 
Time to alleviation of all symptoms (nasal congestion, sore throat, cough, aches, 
fatigue, headaches, chills/sweats) with resolution maintained for 24 hours (without 
use of symptom relief medications) as defined by a rating 0 (none) or 1 (mild) for 
each symptom on a 4-point scale of 0−3.  For patients who enroll with mild 
symptoms, the symptom score must be reduced by 1 point during the study duration. 
• 
Incidence of reinfection or relapse with influenza at 100 days after end of treatment 
• 
Incidence of hospitalization for influenza-related complications at 100 days after end 
of treatment and length of stay 
• 
Antibiotic usage for secondary bacterial respiratory infections 
• 
Incidence of complications of influenza (e.g., pneumonia, exacerbations of chronic 
lung disease, myocarditis, acute respiratory distress syndrome (ARDS), otitis media, 
or other influenza related complications) 
• 
Incidence of death 
 
3.4.2.1 
Pharmacokinetic Outcome Measure  
• 
PK measurements in serum (including Cmax, time at which the Cmax is observed 
(Tmax), AUC, systemic clearance, volume of distribution, and half-life as applicable) 
 
3.4.3 
Exploratory Outcome Measures  
 
 


 
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4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
This study aims to enroll approximately 141 patients (47 per treatment arm) and is 
designed to assess the safety, efficacy, and pharmacokinetics of a single IV infusion at 
two dose levels of MHAA4549A in otherwise healthy adult patients with acute 
uncomplicated seasonal influenza A versus a comparator arm of placebo.  Patients who 
withdraw/discontinue/are lost to follow-up may not be replaced.  
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Otherwise healthy adult men or women ≥ 18 years and ≤ 65 years of age on the day 
of signing the informed consent  


 
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• 
Tests positive for influenza A infection using a rapid PCR test or rapid antigen test 
as an aid in influenza diagnosis during screening 
• 
≤ 72 hours (3 days) between onset of influenza-like illness (as determined by the 
investigator) and start of study treatment.  
• 
Presence of at least 1 moderate or severe constitutional symptom (e.g., headache, 
myalgias, fever, chills, fatigue, anorexia, nausea) and 1 moderate or severe 
respiratory symptom (e.g., cough, sore throat, rhinorrhea) at screening 
• 
Women of childbearing potential, that is women who are not postmenopausal 
(≥ 12 months of non-therapy-induced amenorrhea) or who are surgically sterile 
(absence of ovaries and/or uterus), must have a negative pregnancy test result 
within 2 days prior to study drug 
• 
For women of childbearing potential:  agreement to remain abstinent or use two 
highly effective methods of contraception (failure rate of < 1% per year), including 
vasectomy of a male partner, for at least 120 days after study drug 
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle 
of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of 
contraception. 
Examples of highly effective contraceptive methods include: bilateral tubal 
ligation, male partner sterilization, combined (estrogen and progestogen) or 
progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, intravaginal, transdermal), intrauterine device (IUD), and intrauterine 
hormone releasing system (IUS). 
• 
For men: agreement to remain abstinent or use a condom for at least 30 days after 
study drug administration and agreement to refrain from donating sperm for 90 days 
after study drug administration. 
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle 
of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of 
contraception. 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
History of major medical conditions from medical history, physical examination, 
and/or routine laboratory tests that may put the subject at higher risk for influenza 
related complications as determined by the investigator during screening 
• 
Creatinine clearance ≤ 80 mL/min 
• 
Any abnormal laboratory test or ECG, which is deemed by the investigator to be 
clinically significant 
• 
Patients who have taken any influenza antiviral therapy (e.g. oseltamivir, zanamivir, 
peramivir, amantadine, rimantadine) in the period from onset of influenza-like illness 
and prior to enrollment  


 
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• 
Patients who are currently pregnant, breastfeeding, or have a positive pregnancy 
test at screening, or are intending to become pregnant during the study 
• 
Clinical signs and symptoms consistent with otitis, bronchitis, sinusitis, or 
pneumonia, or active bacterial infection at any site that requires therapy with 
antibiotics 
• 
Investigational therapy within 30 days prior to initiation of study treatment or within 
5 half-lives of the investigational product, whichever is greater 
• 
Hypersensitivity to any constituents (sodium succinate, sucrose, polysorbate 20) of 
MHAA4549A 
• 
Prior therapy with any anti-influenza monoclonal antibody, including MHAA4549A  
• 
Received nasally administered influenza A vaccine within 14 days prior to screening 
• 
Positive influenza B or influenza A+B infection within 2 weeks prior to study 
treatment  
• 
Significant history of tobacco use at any time (≥ 10 pack year history, e.g. one pack 
a day for 10 years) 
• 
Patients receiving chronic dose of oral corticosteroids exceeding 10 mg/day of 
prednisone or equivalent steroid dose or inhaled corticosteroids at any dose for a 
duration of greater than 14 days within 30 days prior to screening  
• 
History or evidence of autoimmune disease or known immunodeficiency of any 
cause 
• 
Patients taking any medications that suppress the immune system 
(immunosuppressives) 
• 
History of asthma, chronic obstructive pulmonary disease (COPD), pulmonary 
hypertension, reactive airway disease, or chronic lung condition of any etiology. 
A history of childhood asthma before the age of 12 is acceptable provided the 
subject: 
Has no symptoms consistent with asthma 
Is not receiving chronic or acute treatment for asthma. 
Patients with asthma after age 12 but who has not received treatment for 
asthma in the past 4 years can be included at the investigator’s discretion 
after consultation with the Sponsor.  
• 
Planned medical or surgical procedure during the study 
• 
Known HIV infection with CD4+ T cell count ≤ 200 cells/mL in the past 12 months  
• 
History of illicit drug use or alcohol abuse in the 12 months prior to screening which, 
in the investigator’s judgment, could affect compliance with study requirements 
• 
Serious infection requiring oral or IV antibiotics within 14 days prior to screening 
• 
History or presence of an abnormal ECG that is clinically significant in the 
investigator’s opinion, including complete left bundle branch block, second- or 
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4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
The randomization of patients will be managed by a central Interactive Voice and/or Web 
Response System (IxRS) through use of a permuted block randomization that includes a 
random component.  
Randomization will be stratified by onset of influenza-like illness (≤ 36 hours and 
> 36 hours) and the type of influenza test used at enrollment (rapid PCR or rapid antigen 
test).  A permuted block randomization method will be used to obtain an approximate 
1:1:1 ratio of patients in the 3600 mg MHAA4549A, 8400 mg MHAA4549A, and placebo 
strata. 
An unblinded review of safety will be performed on a regular basis by the IMC and SOC 
as described in the IMC/SOC agreement. 
Due to the slight yellow color of MHAA4549A, unblinded personnel (i.e., unblinded site 
pharmacist or other designated, qualified unblinded study personnel) at each study site 
will prepare the IV infusions of study drug.  The Sponsor will provide masking bags and 
blinded study personnel will administer the study drug.  The other parties who are 
involved in the conduct of the study (i.e., patients and blinded site personnel) will remain 
blinded to patient-specific treatment assignments until the final database lock after the 
completion of the study. 
While PK samples must be collected from patients assigned to the comparator arm to 
maintain the blinding of treatment assignment, PK assay results for these patients are 
generally not needed for the safe conduct or proper interpretation of this trial.  Personnel 
responsible for performing PK assays will be unblinded to patients’ treatment 
assignments to identify appropriate PK samples to be analyzed.  Samples from patients 
assigned to the comparator arm will not be analyzed except by request (i.e., to evaluate 
a possible error in dosing). 
If unblinding is necessary for patient management (e.g., in the case of a serious adverse 
event for which patient management might be affected by knowledge of treatment 
assignment), the investigator will be able to break the treatment code by contacting the 
IxRS.  Treatment codes should not be broken except in emergency situations.  If a 
treatment code is broken by a site for any other reason, the investigator must contact the 
Medical Monitor directly.  The investigator should document and provide an explanation 
for any premature unblinding (e.g., accidental unblinding, unblinding due to a serious 
adverse event). 
For regulatory reporting purposes, and if required by local health authorities, the 
Sponsor will break the treatment code for all serious, unexpected suspected adverse 
reactions (see Section 5.7) that are considered by the investigator or Sponsor to be 
related to study drug. 


 
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4.3 
STUDY TREATMENT  
The investigational medicinal product (IMP) for this study is MHAA4549A. 
4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
MHAA4549A and Placebo 
MHAA4549A will be supplied by the Sponsor in a sterile, preservative-free liquid solution 
in a single-use 15 mL USP/Ph.  Eur.  Type 1 glass vials filled to deliver 10 mL (500 mg) 
of MHAA4549A solution. 
MHAA4549A placebo will be provided as a clear, colorless, sterile, preservative-free 
liquid solution and has the same vial configuration as the Drug Product. 
For information on the formulation and handling of MHAA4549A, see the pharmacy 
manual and the Investigator’s Brochure. 
4.3.2 
Dosage, Administration, and Compliance 
4.3.2.1 
MHAA4549A and Placebo 
The randomization of patients will be managed by a central IxRS.  All patients will be 
randomly assigned to receive either a single dose of MHAA4549A at 3600 mg IV, or 
8400 mg IV or placebo IV at a 1:1:1 ratio.  
Administration of MHAA4549A or placebo will be performed in a setting with emergency 
medical equipment and personnel who are trained to monitor for and respond to medical 
emergencies.  A qualified physician or medically qualified designee will be on site during 
study drug administration for all patients.  All patients will be monitored for study drug 
reactions during administration and for at least 30 minutes after completion of study drug 
administration. 
A single dose of MHAA4549A or placebo will be delivered by IV infusion following 
dilution in 0.9% normal saline over approximately 120 minutes.  Study drug should be 
delivered using a 0.20−0.22 μm in-line filter.  Compatibility testing has shown that 
MHAA4549A is stable when diluted in 0.9% normal saline in a polyvinylchloride, 
polyolefin bag, or ethylene vinyl acetate bag (EVA), at or above a combined total 
concentration of 0.24 mg/mL up to 27.0 mg/mL.  Study drug must be administered within 
the treatment window outlined in Section 3.1.1.  Further detailed instructions can be 
found in the Pharmacy Manual. 
Subjects who experience a moderate-to-severe infusion related reaction should have 
their infusion stopped.  The infusion should not be restarted.  The infusion will be 
discontinued in the event that the subject experiences a serious reaction and further 
dosing of subjects halted until safety of the drug is assessed. 
There are no recommended dosage modifications for MHAA4549A because it is a single 
infusion.  Any overdose or incorrect administration of study drug should be noted on the 


 
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Study Drug Administration electronic Case Report Form (eCRF).  Adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.  General supportive measures will be taken to 
manage any adverse events associated with overdose.  Patients experiencing such 
adverse events will be followed up clinically until the event has resolved. 
Trained clinical site staff responsible for adequate and accurate study drug 
administration, accounting, and management will administer study drugs to patients.  
Study drug preparation and dosing instructions will be provided to each site.  The exact 
times of study drug administration will be recorded in the relevant 
dispensing/administration logs and patient’s source notes.  Any noncompliance or 
problems with study drug administration will be recorded in the patient’s source notes 
and reported to the Sponsor if appropriate. 
4.3.3 
Investigational Medicinal Product Accountability 
IMPs required for completion of this study (MHAA4549A) will be provided by the 
Sponsor.  The study site will acknowledge receipt of IMPs and confirm the shipment 
condition and content.  Any damaged shipments will be replaced.  
The IMP will be stored in a secure pharmacy or locked area, with access limited to 
authorized personnel, in accordance with the details provided in the Investigator’s 
Brochure and Pharmacy Manual.  Upon receipt, MHAA4549A and placebo vials must be 
refrigerated at 2°C−8°C until use.  MHAA4549A does not contain antimicrobial 
preservatives; therefore, care must be taken to ensure that the solution for infusion is not 
microbiologically compromised during preparation.  Dilute under appropriate aseptic 
conditions using 0.9% normal saline.  The solution for infusion should be used 
immediately.  If not used immediately, in-use storage times and conditions prior to use 
should not exceed 24 hours at 2°C−8°C and/or 4 hours at ambient temperature 
(18°C−24°C). If the dose solution is stored at 2°C−8°C, it should be removed from 
refrigeration and allowed to reach room temperature prior to administration.  If the 
infusion is interrupted and the combined ambient temperature storage and interruption 
time exceeds 4 hours, prepare a new dose solution to resume the infusion (see the 
Pharmacy Manual).  Protect dose solutions from heat and intense light.  Vials are 
intended for single use only; therefore, any remaining solution should be discarded.  
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation.  The site's method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log. 


 
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4.3.4 
Post-Trial Access to MHAA4549A 
As this is single dose administration, the Sponsor does not intend to provide 
MHAA4549A to patients after the conclusion of the study or any earlier withdrawal.  
Patients may or may not be eligible for any potential subsequent trials of MHAA4549A 
under a separate protocol. 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
4.4 
CONCOMITANT THERAPY AND FOOD 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal or homeopathic remedies, nutritional supplements) used by a patient from 
30 days prior to screening to the study completion/discontinuation visit.  All such 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF.  
4.4.1 
Permitted Therapy  
Patients who use oral contraceptives, hormone-replacement therapy, or other 
maintenance therapy should continue their use. 
Acetaminophen/paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) are 
allowed for relief of severe influenza symptoms.  The patient must record the use of 
these medications as directed in the patient diary. 
Patients with recurrent influenza infection may be given local standard of care 
anti-influenza treatments including neuraminidase inhibitors. 
4.4.2 
Prohibited Therapy 
Use of the following therapies is prohibited throughout the patient’s participation in the 
study (from enrollment to end of study): 
• 
Any influenza antiviral therapy (e.g., oseltamivir, zanamivir, peramivir, amantadine, 
rimantadine) from onset of influenza-like illness (except for recurrent influenza as 
described in Section 3.1.1) 
• 
Investigational therapy  
• 
Oral/inhaled corticosteroids 
• 
Antitussives or expectorants  
• 
Combination cold or influenza remedies  
• 
Antihistamines 
• 
Herbal medicines for influenza virus infection 
 


 
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4.4.3 
Prohibited Food  
There are no prohibited foods for this study. 
4.5 
STUDY ASSESSMENTS  
Please see Appendix 1 for the schedule of activities performed during the study. 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures.  Informed Consent Forms for enrolled patients 
and for patients who are not subsequently enrolled will be maintained at the study site. 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before randomization.  The investigator will maintain a screening log 
to record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
4.5.2 
Diagnostic Testing for Enrollment 
All patients must be assessed for influenza A disease confirmation prior to enrollment 
into the study.  A rapid PCR test or rapid antigen test is required for diagnosis of 
influenza A infection.  For the diagnostic test, sample collection may involve a nasal 
swab or a nasopharyngeal swab, depending on the diagnostic platform at the site.  
4.5.3 
Medical History and Demographic Data 
Medical history includes clinically significant diseases and procedures, including chronic 
respiratory disease, infections, surgeries, cancer history (including prior cancer therapies 
and procedures), reproductive status, smoking history, use of alcohol and drugs of 
abuse, and all medications (e.g., prescription drugs, over-the-counter drugs, herbal or 
homeopathic remedies, nutritional supplements) used by the patient within 30 days prior 
to the screening visit. 
Demographic data will include age, sex, and self-reported race/ethnicity. 
4.5.4 
 
 
 
 
 
 
 
 


 
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4.5.5 
Physical Examinations 
A complete physical examination should be performed at screening and should include 
an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, 
dermatological, musculoskeletal, respiratory, gastrointestinal, genitourinary, and 
neurological systems.  Any abnormality identified at baseline should be recorded on the 
General Medical History and Baseline Conditions eCRF. 
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed.  Changes from baseline abnormalities should be 
recorded in patient notes.  New or worsened clinically significant abnormalities should be 
recorded as adverse events on the Adverse Event eCRF.   
4.5.6 
Vital Signs  
Vital signs will include measurements of respiratory rate, pulse rate, temperature (oral), 
and systolic and diastolic blood pressures while the patient is in a seated or supine 
position for at least 5 minutes. 




 
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For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
4.5.8 
Electrocardiograms 
Single ECG recordings will be obtained at specified timepoints, as outlined in the 
schedule of activities (see Appendix 1), and may be obtained at unscheduled timepoints 
as indicated.  
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements.  
Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the patient has been resting in a supine position for at least 10 minutes.  
All ECGs are to be obtained prior to other procedures scheduled at that same time 
(e.g., vital sign measurements, blood draws) and if possible, should not be obtained 
within 3 hours after any meal.  Circumstances that may induce changes in heart rate, 
including environmental distractions (e.g., television, radio, conversation) should be 
avoided during the pre-ECG resting period and during ECG recording. 
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  The following should be recorded in the appropriate eCRF:  heart 
rate, RR interval, QRS interval, PR duration, uncorrected QT interval, and QT interval 
corrected using Fridericia’s formula (QTcF) (or Bazett’s formula [QTcB] if QTcF is not 
available) based on the machine readings of the individual ECG tracings.  Any 
morphologic waveform changes or other ECG abnormalities must be documented on the 
eCRF.  If considered appropriate by the Sponsor, ECGs may be analyzed 
retrospectively at a central laboratory. 
If at a particular postdose timepoint the mean corrected QT interval is > 500 ms and/or 
> 60 ms longer than the baseline value, another ECG must be recorded, ideally within 
the next 5 minutes, and ECG monitoring should continue until the corrected QT 
interval has stabilized on two successive ECGs.  The Medical Monitor should be 
notified.  Standard-of-care treatment may be instituted per the discretion of the 
investigator.  If a PK sample is not scheduled for that timepoint, an unscheduled PK 
sample should be obtained.  A decision on study drug discontinuation should be made, 
as described in Section 3.1.4.  The investigator should also evaluate the patient for 
potential concurrent risk factors (e.g., electrolyte abnormalities, co-medications known 
to prolong the QT interval, severe bradycardia). 
4.5.9 
Patient Daily Symptom Diary  
Patients will use  paper diaries to record symptom data (Nicholson et al. 2000; 
Treanor et al. 2000) (Appendix 6).  The investigator staff will provide the paper diary 
and instructions for completing the symptom diary.  The purpose of the diary is to record 


 
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any symptoms of influenza-like illness, symptom relief medications and temperature 
(oral).  The symptom diary card, symptom relief medications and temperature should be 
completed two times daily: when a patient first wakes up in the morning (before getting 
out of bed) and ~12 hours later up to Day 14 or until resolution of symptoms (defined as 
a total symptom score of 0−1 for 24 hours without use of symptom relief medications).  
Temperature should be taken before administration of acetaminophen/paracetamol 
and/or NSAIDs (see Section 4.4.1 for permitted medications).  Patients should be 
encouraged to stay consistent with the diary schedule and sites should check that 
patients are able to take their temperature properly.  Day 1 entry will be completed within 
6 hours prior to start of study infusion.  
Data from paper diaries will be entered into the EDC system by site staff. 
4.6 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Patient Discontinuation 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following: 
• 
Patient withdrawal of consent at any time 
• 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he/she continues in the study 
• 
Investigator or Sponsor determines it is in the best interest of the patient 
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn.  Patients who withdraw/discontinue/are lost to follow-up may not be 
replaced. 
4.6.2 
Study Treatment Discontinuation 
Patients must discontinue study treatment during infusion if they experience any of the 
following: 
• 
Life-threatening infusion-related reactions 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.   
The IMC and SOC may recommend to permanently discontinue further dosing for all 
patients within one or all study arms in the event of a general safety concern. 


 
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4.6.3 
Study and Site Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
• 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients. 
• 
Patient enrollment is unsatisfactory. 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.   
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
• 
Excessively slow recruitment 
• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 
• 
Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice 
• 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 
 
4.6.4 
Study Completion/Early Discontinuation 
Patients who complete all study visits through Day 100 are considered to have 
completed the study.  All patients who discontinue from the study early will be asked to 
complete all assessments for the current day.  If a patient discontinues after Day 7, 
only a telephone visit is required as the Early Discontinuation visit.  Please see 
Schedule of Activities provided in Appendix 1 for assessments performed at the Study 
Completion and Early Discontinuation visit. 
4.7 
ASSAY METHODS 
Serum concentrations of MHAA4549A (pharmacokinetics) will be measured using 
validated quantitative immunoassays.  ATA in serum will be measured using a validated 
bridging enzyme-linked immunosorbent assay (ELISA).  Samples that are positive for 
ATA may be further characterized, depending on the safety profile and clinical data. 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
MHAA4549A is not approved and is currently in clinical development.  Thus, the entire 
safety profile is not known at this time.  The safety plan for this study is based upon 
preclinical data and the previous Phase 1 and Phase 2a studies.  In addition, the safety 
plan is designed to ensure patient safety and will include specific eligibility criteria and 
monitoring assessments as detailed below. 


 
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The investigator, in consultation with the Sponsor, is responsible for assuring the safety 
of study participants who have entered this study and for taking appropriate action 
concerning any event that seems unusual, even if this event may be considered to be an 
unanticipated benefit to the study participant.  The investigator will be responsible for a 
clinical assessment of the study participants before discharge from the study, and for the 
establishment of a discharge plan, if needed. 
Administration of MHAA4549A or placebo will be performed in a setting with emergency 
medical equipment and personnel who are trained to monitor for and respond to medical 
emergencies.  A qualified physician or medically qualified designee will be on site during 
study drug administration for all patients.  All patients will be monitored for study drug 
reactions during administration and for at least 30 minutes after completion of study drug 
administration. 
During the study, the incidence and nature of adverse events, serious adverse events, 
and laboratory abnormalities will be assessed.  An ongoing, blinded review of safety will 
be carried out by the Medical Monitor and a drug safety scientist.  An unblinded review 
of safety will be performed on an ongoing regular basis by the IMC and SOC as 
described in the IMC/SOC agreement. 
5.1.1 
Risks Associated with MHAA4549A 
There are no known risks associated with MHAA4549A based on completed Phase 1 
(GV28916, GV29609) and Phase 2 (GV28985) studies. 
5.1.1.1 
Immunogenicity 
MHAA449A is a monoclonal antibody-based therapeutic.  As with any recombinant 
monoclonal antibody, MHAA4549A may elicit an immune response in patients with the 
development of antibodies against MHAA4549A.  Screening, confirmatory, and 
characterization assay with appropriate sensitivity and therapeutic tolerance will be 
employed to assess the prevalence of pre-existing ATAs to MHAA4549A in all study 
participants.  Post-dosing ATAs to MHAA4549A will be measured in subjects with 
recurrent influenza infections.  
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 


 
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5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.10 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
• 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies) 
 
Adverse events will be monitored throughout the entire study (enrollment through 
Day 100 or Early Discontinuation). 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
• 
Is fatal (i.e., the adverse event actually causes or leads to death) 
• 
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
This does not include any adverse event that had it occurred in a more severe 
form or was allowed to continue might have caused death. 
• 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.11) 
• 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions) 
• 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
• 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
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The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to DAIDS Table 
for Grading the Severity of Adult and Pediatric Adverse Events; see Section 5.3.3 and 
Appendix 4); the event itself may be of relatively minor medical significance (such as 
severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
include the following: 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s 
law (see Section 5.3.5.7) 
• 
Suspected transmission of an infectious agent by the study drug, as defined below 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only 
when a contamination of the study drug is suspected. 
• 
Adverse events associated with suspected cases of infusion-related reactions (IRR) 
which occur within 24 hours of study drug administration and may show the 
following signs and symptoms (for guidance on reporting adverse events associated 
with IRR, see Section 5.3.5.1) 
Fever and/or shaking chills 
Flushing and/or itching 
Alterations in heart rate and blood pressure 
Dyspnea or chest discomfort 
Back or abdominal pain 
Nausea, vomiting, and/or diarrhea 
Various types of skin rashes 
Anaphylaxis  


 
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• 
Anaphylaxis due to IV drugs most often presents with the following signs and 
symptoms: 
Cutaneous symptoms:  flushing, itching, urticarial, and/or angioedema (usually 
of face, eyelids, or lips) 
Respiratory symptoms:  repetitive cough, sudden nasal congestion, shortness 
of breath, chest tightness, wheeze, sensation of throat closure or choking, 
and/or change in voice quality due to laryngeal edema 
Cardiovascular symptoms:  faintness, tachycardia (or less often bradycardia), 
tunnel vision, chest pain, hypotension, sense of impending doom, and/or loss of 
consciousness 
Gastrointestinal symptoms:  nausea, vomiting, abdominal cramping, and 
diarrhea 
 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.4, 5.5, and 5.6. 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).   
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events). 
After initiation of study drug, all adverse events will be reported until study completion 
at the Day 100 visit or until an Early Discontinuation visit.  After this period, the 
investigator should report any serious adverse events that are believed to be related to 
prior study drug treatment (see Section 5.6). 


 
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5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?"  
 
5.3.3 
Assessment of Severity of Adverse Events 
Investigators will seek information on adverse events and serious adverse events at 
each patient contact.  All adverse events, and serious adverse events, whether reported 
by the patient or noted by authorized study personnel, will be recorded. 
The adverse event grading (severity) scale in the DAIDS v1.0 will be used for assessing 
adverse event severity (see Table 3). 
Table 3 
Adverse Event Grading (Severity) Scale 
Parameter 
Grade 1  
Mild 
Grade 2 
Moderate 
Grade 3  
Severe 
Grade 4 
Potentially 
Life-Threatening 
Estimating Severity Grade 
Clinical adverse 
events NOT 
identified 
elsewhere in this 
DAIDS Adverse 
Event Grading 
Table 
Symptoms 
causing no or 
minimal 
interference with 
usual social and 
functional 
activities 
Symptoms 
causing greater 
than minimal 
interference with 
usual social and 
functional 
activities 
Symptoms 
causing inability 
to perform usual 
social and 
functional 
activities 
Symptoms 
causing inability 
to perform basic 
self-care 
functions OR 
Medical or 
operative 
intervention 
indicated to 
prevent 
permanent 
impairment, 
persistent 
disability, or 
death 
DAIDS= Division of Acquired Immunodeficiency Syndrome. 
 
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration (see also  
Table 4): 
• 
Temporal relationship of event onset to the initiation of study drug 


 
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• 
Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
• 
Known association of the event with the study drug or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
• 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 
Table 4 
 Causal Attribution Guidance 
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge. 
NO 
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., pre-existing medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug). 
 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
Infusion-Related Reactions 
Adverse events that occur during or within 24 hours after study drug administration 
should be captured as individual signs and symptoms on the Adverse Event eCRF 
rather than an overall diagnosis (e.g., record dyspnea and hypotension as separate 
events rather than a diagnosis of infusion-related reaction or anaphylactic reaction). 
5.3.5.2 
Diagnosis versus Signs and Symptoms 
For adverse events other than infusion-related reactions (see Section 5.3.5.1), a 
diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 


 
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and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 
5.3.5.3 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
• 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
• 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
• 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
• 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
5.3.5.4 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  Details regarding any increases or decreases in severity will be captured on the 
Adverse Event Intensity or Grade Changes eCRF.  If the event becomes serious, it 
should be reported to the Sponsor immediately (i.e., ≤ 24 hours after learning that the 
event became serious; see Section 5.4.2 for reporting instructions).  The Adverse Event 
eCRF should be updated by changing the event from "non-serious" to "serious," 
providing the date that the event became serious, and completing all data fields related 
to serious adverse events. 


 
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A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 
5.3.5.5 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it is verified by a repeat assessment and meets 
any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
• 
Is clinically significant in the investigator’s judgment  
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.  Investigators should promptly 
repeat any abnormal assessment or clinically significant laboratory result.  Only those 
findings that remain clinically significant upon a repeat assessment will be considered 
adverse events. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5  × ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 
potassium," as opposed to "abnormal potassium").  If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the adverse event.  For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.6 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it is verified by a repeat assessment and meets any 
of the following criteria: 
• 
Is accompanied by clinical symptoms 


 
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• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Is clinically significant in the investigator’s judgment  
 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.7 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × ULN) in combination with either an elevated 
total bilirubin (> 2 × ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with total bilirubin 
> 2 × ULN 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with clinical jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest 
(see Section 5.4.2). 
5.3.5.8 
Deaths 
Deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1) that are attributed by the investigator solely to progression of influenza or 
any related co-morbidities should be recorded only on the Study Completion/Early 
Discontinuation eCRF.  All other on-study deaths, regardless of relationship to study 
drug, must be recorded on the Adverse Event eCRF and immediately reported to the 
Sponsor (see Section 5.4.2). 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 


 
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reported.  The term "sudden death" should be used only for the occurrence of an 
abrupt and unexpected death due to presumed cardiac causes in a patient with or 
without pre-existing heart disease, within 1 hour after the onset of acute symptoms or, in 
the case of an unwitnessed death, within 24 hours after the patient was last seen alive 
and stable.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death. 
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6. 
5.3.5.9 
Pre-Existing Medical Conditions 
A pre-existing medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A pre-existing medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study beyond that 
anticipated for the natural course of the condition.  When recording such events on 
the Adverse Event eCRF, it is important to convey the concept that the pre-existing 
condition has changed by including applicable descriptors (e.g., "more frequent 
headaches"). 
5.3.5.10 
Lack of Efficacy or Worsening of Influenza A Infection 
Medical occurrences or symptoms of deterioration that are anticipated as part of 
influenza A should be recorded as an adverse event if judged by the investigator to have 
unexpectedly worsened in severity or frequency or changed in nature at any time during 
the study.  When recording an unanticipated worsening of influenza A on the Adverse 
Event eCRF, it is important to convey the concept that the condition has changed by 
including applicable descriptors (e.g., "accelerated influenza A"). 
5.3.5.11 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., in-patient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.   
The following hospitalization scenarios are not considered to be adverse events: 
• 
Hospitalization for respite care 
• 
Planned hospitalization required by the protocol (e.g., for study drug administration 
or insertion of access device for study drug administration) 


 
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• 
Hospitalization for a pre-existing condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease 
The patient has not experienced an adverse event 
 
The following hospitalization scenarios are not considered to be serious adverse events, 
but should be reported as adverse events instead: 
• 
Hospitalization for an adverse event that would ordinarily have been treated in an 
outpatient setting had an outpatient clinic been available (e.g., requirement for 
outpatient care outside of normal outpatient clinical operating hours)  
 
5.3.5.12 
Adverse Events Associated with an Overdose or Error in Drug 
Administration 
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  All adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2). 
No safety data related to overdosing of MHAA4549A are available; however, overdoses 
with a monoclonal antibody theoretically could cause volume overload that can result in 
edema and/or heart failure. 
5.3.5.13 
Patient-Reported Outcome Data  
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data.  However, if any PRO responses 
suggestive of a possible adverse event are identified during site review of the PRO data, 
the investigator will determine whether the criteria for an adverse event have been met 
and, if so, will report the event on the Adverse Event eCRF. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
• 
Serious adverse events (see Section 5.4.2 for further details) 


 
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• 
Adverse events of special interest (see Section 5.4.2 for further details) 
• 
Pregnancies (see Section 5.4.3 for further details) 
 
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and Institutional Review Board (IRB)/Ethics 
Committee (EC). 
5.4.1 
Emergency Medical Contacts 
 24-Hour Safety Hotline 
• 
North America:  
 
 
• 
EMEA/APAC:  
 
 
Genentech Medical Monitor contact information: 
Primary Medical Monitor: 
  
Telephone Nos.: 
US Office:  
 
 
US Mobile:  
 
Email Address:  
 
 
Secondary Medical Monitor: 
 
Telephone Nos.:  
U.S. Office:  
 
 
U.S. Mobile:  
 
Email Address:  
 
 


 
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5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1 
Events That Occur prior to Study Drug Initiation 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided below: 
Region 
Fax Number 
Email Address 
North America 
 
 
EMEA 
 
 
Asia Pacific 
 
 
 
5.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until the patient completes the study at Day 100 or discontinues 
early.  Investigators should record all case details that can be gathered immediately (i.e., 
within 24 hours after learning of the event) on the Adverse Event eCRF and submit the 
report via the electronic data capture (EDC) system.  A report will be generated and sent 
to Safety Risk Management by the EDC system. 
In the event that the EDC system is unavailable, the paper Clinical Trial Serious 
Adverse Event/Adverse Event of Special Interest Reporting Form provided to 
investigators should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the event), either by faxing or 
by scanning and emailing the form using the fax number or email address provided in 
Section 5.4.2.1.  Once the EDC system is available, all information will need to be 
entered and submitted via the EDC system.   
Instructions for reporting post-study adverse events are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 120 days of study drug 
administration.  A paper Clinical Trial Pregnancy Reporting Form should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 
after learning of the pregnancy), either by faxing or by scanning and emailing the form 
using the fax number or email address provided in Section 5.4.2.1.  Pregnancy should 


 
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not be recorded on the Adverse Event eCRF.  The investigator should counsel the 
patient, discussing the risks of the pregnancy and the possible effects on the fetus.  
Monitoring of the patient should continue until conclusion of the pregnancy.  Any serious 
adverse events associated with the pregnancy (e.g., an event in the fetus, an event in 
the mother during or after the pregnancy, or a congenital anomaly/birth defect in the 
child) should be reported on the Adverse Event eCRF.  In addition, the Investigator 
will submit a paper Clinical Trial Pregnancy Reporting Form when updated 
information on the course and outcome of the pregnancy becomes available. 
5.4.3.2 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
30 days of study drug administration.  A paper Clinical Trial Pregnancy Reporting Form 
should be completed and submitted to the Sponsor or its designee immediately (i.e., no 
more than 24 hours after learning of the pregnancy), either by faxing or by scanning and 
emailing the form using the fax number or email address provided in Section 5.4.2.1.  
Attempts should be made to collect and report details of the course and outcome of any 
pregnancy in the partner of a male patient exposed to study drug.  The pregnant partner 
will need to sign an Authorization for Use and Disclosure of Pregnancy Health 
Information to allow for follow-up on her pregnancy.  After the authorization has been 
signed, the investigator will submit a paper Clinical Trial Pregnancy Reporting Form 
when updated information on the course and outcome of the pregnancy becomes 
available.  An investigator who is contacted by the male patient or his pregnant partner 
may provide information on the risks of the pregnancy and the possible effects on the 
fetus, to support an informed decision in cooperation with the treating physician and/or 
obstetrician. 
5.4.3.3 
Congenital Anomalies/Birth Defects and Abortions 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2).  Any abortion should be reported in the same fashion (as the Sponsor 
considers abortions to be medically significant). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported. 


 
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During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification. 
All pregnancies reported during the study should be followed until pregnancy outcome.   
5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details and outcome information (e.g., from 
hospital discharge summaries, consultant reports, autopsy reports) in order to perform 
an independent medical assessment of the reported case. 
5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD 
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
100 days after study drug administration), if the event is believed to be related to prior 
study drug treatment.  These events should be reported through the use of the Adverse 
Event eCRF.  However, if the EDC system is not available, the investigator should 
report these events directly to the Sponsor or its designee, either by faxing or by 
scanning and emailing the Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form using the fax number or email address provided to investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document: 
• 
MHAA4549A Investigator's Brochure 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 


 
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Certain adverse events are anticipated to occur in the study population at some 
frequency independent of study drug exposure and will be excluded from expedited 
reporting.  These anticipated events include, but are not limited to, the following: 
• 
Asymptomatic elevations of ALT, AST, and/or amylase without corresponding 
elevations of bilirubin have been shown to be increased during influenza A infection 
(Polakos et al. 2006; Yingying 2011). 
• 
Influenza associated disease and/or complications of influenza 
 
An IMC and SOC will monitor the incidence of the above-listed anticipated events during 
the study.  An aggregate report of any clinically relevant imbalances that do not favor the 
test product will be submitted to health authorities. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
The database will be cleaned and locked when all patients have completed the study 
(Day 100) or discontinued. 
The primary objective of this study is to characterize the safety and tolerability of a single 
dose of MHAA4549A as compared to placebo when administered in otherwise healthy 
patients with acute uncomplicated seasonal influenza A.  Statistical summaries will be 
descriptive in nature (e.g., means, standard deviations, and percentiles).  Patients will be 
grouped according to treatment actually received, and any patients who receive any 
amount of MHAA4549A or placebo will be included in the analyses. 
All secondary efficacy analyses will be conducted according to the intent-to-treat 
principle and will include all patients who meet the following condition with patients 
allocated to the treatment arm to which they were randomized: 
• 
Confirmation of influenza A from Day 1 pre-dose samples using a central PCR (to 
exclude false positives from local tests) 
No formal hypothesis testing will be done in this study.  As a result, no adjustment for 
type 1 error will be made to account for the multiplicity of analyses. 
6.1 
DETERMINATION OF SAMPLE SIZE 
The planned sample size for this study is approximately 47 patients per treatment group.  
A total of approximately 141 patients will be enrolled in this study in order to obtain 
120 evaluable patients (an estimated dropout rate of 15%). 
The table below gives the probability of seeing an adverse event with a sample size of 
40 per group.  If the event occurs at a rate of ≥ 5%, the study has a ≥ 87% chance of 
seeing at least 1 event in the dose group. 


 
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Table 5 
Probability of Observing Adverse Events at Different Event Rates 
Underlying “True Rate” 
Probability of Seeing at Least 
1 Event 
Probability of Seeing at Least 
2  Events 
1% 
33% 
6% 
5% 
87% 
60% 
10% 
99% 
92% 
15% 
99% 
98% 
Note:  Assumes that event rate follows a binomial distribution with p = AE rate and 
n = 40 patients/arm. 
 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
The number of patients who enroll, discontinue (early discontinuation of treatment or 
early termination from the study), and complete the study will be tabulated by treatment 
group using descriptive statistics.  Reasons for early discontinuation of treatment or early 
termination from the study will be listed and summarized by treatment group.  Any 
eligibility criteria exceptions and other protocol deviations will also be summarized by 
treatment group. 
6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
Demographic and baseline characteristics of the patient will be summarized for all 
randomized patients by treatment group by use of descriptive statistics.  Baseline is 
defined as the last available value prior to study drug administration.  During the study 
patient disposition, concurrent treatment, and compliance with study treatment and visits 
will be summarized on the safety analysis population using descriptive statistics. 
6.4 
PRIMARY SAFETY ANALYSES 
The safety analyses will include all randomized patients who received study drug, with 
patients grouped according to the treatment actually received.  Safety parameters to be 
evaluated include adverse events (including deaths, serious adverse events, 
discontinuations due to adverse events, and the incidence and severity of adverse 
events), clinical laboratory tests, vital signs, and ECGs.  All collected adverse event data 
will be listed by study site and patient number.  All adverse events that occur on or after 
treatment on Day 1 will be summarized for each treatment group by mapped term, 
appropriate thesaurus levels, body system, and event within each body system, and 
toxicity grade.  In addition, all serious adverse events, including deaths, will be listed 
separately and summarized.  Serious adverse events caused by a protocol-mandated 
intervention (e.g., invasive procedures such as biopsies, discontinuation of medications) 
that occur between consent and first dose of study medication will be listed separately. 


 
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Laboratory data with values outside of the normal ranges will be identified.  In addition, 
select laboratory data will be summarized by treatment group using descriptive summary 
statistics. 
The absolute and percentage changes from baseline in vital sign parameters will be 
computed, and changes deemed clinically significant by the Investigator will be noted. 
Appropriate descriptive summary statistics will be provided for all vital sign parameters. 
The prevalence (baseline) of ATA will be reported and correlation with PK, safety, 
efficacy, and biomarker endpoints will be analyzed as data allow. 
6.5 
SECONDARY EFFICACY ANALYSES  
The efficacy analyses will include all randomized patients who are confirmed to be 
influenza A infected, with patients grouped according to the treatment assigned at 
randomization.  Efficacy parameters to be evaluated include duration and severity of 
influenza symptoms, hospitalization, and influenza-related complications.  
Time to event data will be analyzed using Kaplan-Meier methodology and will be 
summarized using n, median when estimable, hazard ratios, and 95% confidence 
intervals.  Patients who are lost to follow-up (while event free) will be censored at the 
time that they are last known to be event free. 
Estimation of the treatment difference of proportions and its 95% confidence interval will 
be calculated using stratum-adjusted Mantel-Haenszel methodology (Koch et al. 1989).  
For continuous endpoints, Analysis of Covariance methods (after appropriate 
transformation of data) will be used to estimate treatment differences and 
95% confidence intervals.  
Other than censoring in the time to event analyses, no other imputation for missing data 
will be performed. 
6.5.1 
Secondary Endpoints  
• 
Median time to alleviation of clinical signs and symptoms of influenza A infection 
• 
Proportion of patients requiring hospitalization  
• 
Median duration of hospitalization 
• 
Proportion of patients with influenza-related deaths 
• 
Proportion of patients requiring antibiotics for respiratory infection 
• 
Proportion of patients with influenza secondary complications 
• 
Proportion of patients with influenza re-infection 
 
6.5.2 
Exploratory Endpoints 
• 
 
 


 
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6.6 
SUBGROUP ANALYSES 
Subgroup analyses will be performed to examine the consistency of the treatment 
estimates with use of the endpoints.  Subgroups will include the stratification factors.  
Additional subgroups may be added following assessment of baseline characteristics as 
exploratory analyses.  
6.7 
PHARMACOKINETIC ANALYSES  
Individual and mean serum MHAA4549A concentration versus time data will be 
tabulated and plotted.  The serum PK of MHAA4549A will be summarized by estimating 
total serum drug exposure (i.e., AUC), maximum concentration (Cmax), total serum 
clearance, half-life, and volume of distribution, as data allow.  Estimates for these 
parameters will be tabulated and summarized (e.g., mean, standard deviation, 
coefficient of variation).  Inter-patient variability will be evaluated.  MHAA4549A serum 
concentration-time data may be compared with available data from other MHAA4549A 
clinical studies.  
Additional PK analyses, such as population PK, may be conducted as appropriate and 
reported separately.  Potential correlations between relevant PK parameters and safety 
or efficacy outcomes, as well as other covariates, may also be explored and reported 
separately.  
6.8 
EXPLORATORY ANALYSES  
 
 
 
 


 
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6.8.1 
Biomarker Analyses  
 
 
 
 
 
 
  
 
 
 
 
 
6.9 
IMMUNOGENICITY ANALYSES  
The immunogenicity analyses will be limited to testing of predose samples from all 
patients enrolled in the study.  No post-dose samples will be collected (except for Day 7 
in the case of recurrent influenza). 
The number of ATA-positive patients at baseline will be determined, which will provide 
an estimate of the prevalence of pre-existing ATAs in this patient population. 
 
 
 
No additional immunogenicity assessments are planned for this study. 
6.10 
INTERIM ANALYSES 
6.10.1 
Optional Interim Analyses 
Given the hypothesis-generating nature of this study, the Sponsor may choose to 
conduct up to two interim efficacy analyses.  The decision to conduct an optional interim 
analysis and the timing of the analysis will be documented in the Sponsor’s trial master 
file prior to the conduct of the interim analysis.  The interim analysis will be performed 
and interpreted by members of the Sponsor study team and appropriate senior 
management personnel who will be unblinded at the treatment group level.  Access to 
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conducted, an interim analysis would be for administrative purposes only (i.e., internal 
planning or decision making) and would not impact the conduct of the current study in 
any way.  A nominal type 1 error penalty of 0.0001 will be taken.  
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system. 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data will be sent 
directly to the Sponsor, using the Sponsor’s standard procedures to handle and process 
the electronic transfer of these data. 
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures. 
Data from paper diaries will be entered into the EDC system by site staff.  
7.2 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required. 
7.3 
PATIENT-REPORTED DAILY SYMPTOM DATA  
Data from paper diaries will be entered into the EDC system by site staff. 
7.4 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents.  


 
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Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6. 
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities. 
7.5 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change. 
7.6 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, paper diaries, Informed Consent Forms, laboratory test results, 
and medication inventory records, must be retained by the Principal Investigator for at 
least 15 years after completion or discontinuation of the study, or for the length of time 
required by relevant national or local health authorities, whichever is longer.  After that 
period of time, the documents may be destroyed, subject to local regulations.   
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 


 
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8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union (E.U.) 
or European Economic Area will comply with the E.U. Clinical Trial Directive 
(2001/20/EC). 
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form will be provided to each site.  If 
applicable, it will be provided in a certified translation of the local language.  The 
Sponsor or its designee must review and approve any proposed deviations from the 
Sponsor's sample Informed Consent Forms or any alternate consent forms proposed by 
the site (collectively, the "Consent Forms") before IRB/EC submission.  The final 
IRB/EC−approved Consent Forms must be provided to the Sponsor for health authority 
submission purposes according to local requirements. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 


 
MHAA4549A—Genentech, Inc. 
91/Protocol GV29893, Version 3 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time. 
Each Consent Form may also include patient authorization to allow use and disclosure 
of personal health information in compliance with the U.S.  Health Insurance Portability 
and Accountability Act of 1996 (HIPAA).  If the site utilizes a separate Authorization 
Form for patient authorization for use and disclosure of personal health information 
under the HIPAA regulations, the review, approval, and other processes outlined above 
apply except that IRB review and approval may not be required per study site policies. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file.  
8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 


 
MHAA4549A—Genentech, Inc. 
92/Protocol GV29893, Version 3 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes. 
Given the complexity and exploratory nature of the analyses, data derived from 
exploratory biomarker specimens will generally not be provided to study investigators 
or patients unless required by law.  The aggregate results of any conducted research 
will be available in accordance with the effective Sponsor policy on study data 
publication (see Section 9.5). 
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA and other national and local health authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate. 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., last patient, last visit 
[LPLV]). 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures. 
9.3 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study. 


 
MHAA4549A—Genentech, Inc. 
93/Protocol GV29893, Version 3 
9.4 
ADMINISTRATIVE STRUCTURE 
Genentech, Inc, a member of the Roche group, is the Sponsor of this study.  A clinical 
research organization (CRO) may provide clinical operations oversight, including but not 
limited to project management, medical monitoring, site management, data quality 
support, safety reporting, and regulatory activities as specified in the study management 
plans.  Genentech will provide CRO oversight, develop the database and randomization 
scheme, and conduct statistical programming and analysis.  An IMC and SOC will 
provide safety monitoring for the study in addition to the ongoing review of safety by the 
Medical Monitor and safety scientist. 
EDC will be utilized for this study.  An IxRS will be used to assign patient numbers, 
randomize patients into study through use of a permuted block algorithm, and manage 
site drug supply.  A central laboratory will be used for sample management and storage 
until shipment to specialty laboratories or Genentech for analysis. 
Data reported by patients regarding their symptoms, body temperature, and any use of 
acetaminophen/paracetamol and/or NSAIDs will be captured using paper diaries. 
9.5 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals.  The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site: 
http://www.rochetrials.com/pdf/RocheGlobalDataSharingPolicy.pdf 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective clinical study report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 


 
MHAA4549A—Genentech, Inc. 
94/Protocol GV29893, Version 3 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 


 
MHAA4549A—Genentech, Inc. 
95/Protocol GV29893, Version 3 
10. 
REFERENCES 
Crowe JE. Universal Flu Vaccines: Primum non nocere. Sci Transl Med 2013;5(200):1-3. 
Dejnirattisai W, Jumnainsong A, Onsirisakul N, et al. Cross reacting antibodies enhance 
dengue virus infection in humans. Science 2010;328(5979):745-8. 
Ishida JH, Burgess T, Derby M, et al. Phase 1 randomized, double-blind, placebo-
controlled study of RG7667, an Anti-Cytomegalovirus combination monoclonal 
antibody therapy, in healthy adults. Antimicrob Agents Chemother 2015; 
59(8):4919-4929. 
Koch GG, Carr GJ, Amara IA, et al. Categorical data analysis. In: Berry DA, editor. 
Statistical methodology in the pharmaceutical sciences. New York: Marcel Dekker 
1989:291-475. 
Khurana S, Loving CL, Manischewitz J, et al. Vaccine-induced anti-HA2 antibodies 
promote virus fusion and enhance influenza virus respiratory disease. Sci Transl 
Med 2013;5(200):1-10. 
Nakamura G, Ning C, Park S, et al. An in vivo human-plasmablast enrichment technique 
allows rapid identification of therapeutic influenza A antibodies. Cell Host Microbe 
2013;14(1):93-103. 
Nicholson KG, Aoki FY, Osterhaus AD, et al. Efficacy and safety of oseltamivir in 
treatment of acute influenza: a randomized controlled trial. Lancet 
2000;355:1845-50.  
Polakos NK, Cornejo JC, Murray DA, et al. Kupffer cell-dependent hepatitis occurs 
during influenza infection. Am J Pathol 2006;168(4):1169-78. 
Takada A, Kawaoka Y. Antibody-dependent enhancement of viral infection: molecular 
mechanisms and in vivo implications. Rev Med Virol 2003;13:387-98. 
Treanor JJ, Haydon FG, Vrooman PS, et al. Efficacy and safety of the oral 
neuraminidase inhibitor oseltamivir in treating acute influenza. JAMA 
2000;238(8):1016-24. 
Whitehead SS, Blaney JE, Durbin AP, et al. Prospects for a dengue virus vaccine. Nat 
Rev Microbiol 2007;5(7):518-28. 
World Health Organization (WHO). Influenza (Seasonal). Updated March 2014. 
Available at http://www.who.int/mediacentre/factsheets/fs211/en/ 
Yingying C. Abnormal liver chemistry in patients with influenza A H1N1. Liver Int 
2011;31(6):902. 
 






Appendix 1 (cont’d) 
 
Schedule of Activities 
MHAA4549A—Genentech, Inc. 
98/Protocol GV29893, Version 3 
f Vital signs will be collected within 1 hour before MHAA4549A infusion and within 1 hour after completion of MHAA4549A infusion and include 
temperature (oral), respiratory rate, heart rate, systolic blood pressure, and diastolic blood pressure.  Temperature should be measured using 
the same methodology throughout the study and should be measured prior to administration of any antipyretic drugs.  Temperature, blood 
pressure, respiratory rate, and heart rate will be completed after the patient has been in a seated or supine position for at least 5 minutes.  
g Patient should rest in a supine position for 10 minutes prior.  If screening ECG is taken within 1-3 hours pre-dose, Day 1 pre-dose ECG does 
not need to be taken. 
h On Day 1, ECG must be taken within 1-3 hours pre-dose and 1-3 hours post-dose. 
i All patients will be monitored for study drug reactions during administration and for at least 30 minutes after completion of study drug 
administration. 
j Complete physical examination includes evaluations of general appearance of head, eye, ear, nose, and throat, cardiovascular, 
dermatological, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurological systems .  Changes from any prior examination 
should be recorded.  New or worsened abnormalities should be recorded as AEs, if appropriate.  
k Limited, symptom-directed physical examination includes, at a minimum, evaluation of general appearance, dermatological examination of the 
injection sites, evaluations directed by patient-reported symptoms, and any other evaluations that the investigator deems clinically relevant.  
Changes from any prior examination should be recorded.  New or worsened abnormalities should be recorded as AEs.  
l Height will be obtained at screening only.  Weight will be obtained at all indicated visits (pre-infusion on Day 1).  Height and weight will be 
recorded in centimeters and kilograms, respectively 
m Local laboratory measurements should be utilized.  Hematology and chemistry panel at screening must be collected within 36 hours prior to 
study drug administration.  Lipase will be reflexively assessed on all samples with amylase > ULN. 
n Urinalysis at screening must be collected within 36 hours prior to study drug administration.  Urinalysis includes pH, specific gravity, 
glucose, protein, ketones, blood, bilirubin, nitrite, and leukocyte esterase.  Microscopic examination (e.g., sediment, RBCs, WBCs, casts, 
crystals, epithelial cells, bacteria) will be performed if clinically indicated.  Screening sample will be collected locally.  Day 3, 7 and 
unscheduled samples will be collected locally and centrally.  
 
 
  
  
 
 
q Day 1 serum PK samples are to be drawn within 30 (± 5) minutes pre-dose of MHAA4549A, and 60 (± 15) minutes after the end of infusion.  
On Days 3, 5, 7 PK samples will be drawn from the contralateral arm from that used for drug infusion and must be labeled with the exact time 
of draw.  


Appendix 1 (cont’d) 
 
Schedule of Activities 
MHAA4549A—Genentech, Inc. 
99/Protocol GV29893, Version 3 
r The symptom diary and temperature (oral) should be completed two times daily: when the study subject first wakes up in the morning (before 
getting out of bed) and about 12 hours later, up to Day 14 or until resolution of symptoms (defined as a total symptom score of 0-1 for 24 
hours without use of symptom relief medications).  Temperature should be taken before administration of acetaminophen/paracetamol and/or 
NSAIDs.  Day 1 entry will be completed within 6 hours prior to start of study infusion. 
 






 
MHAA4549A—Genentech, Inc. 
102/Protocol GV29893, Version 3 
Appendix 3  
DAIDS Toxicity Grading Tables for Clinical Abnormalities 
From the FDA Guidance document ‘Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventative Vaccine Clinical Trials’ (September 2007) 
Vital Signs a 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Fever (°C) b 
(°F)* 
38.0−38.4 
100.4−101.1 
38.5−38.9 
101.2−102.0 
39.0−40.0 
102.1−104.0 
> 40 
> 104 
Tachycardia – 
beats per minute 
101−115 
116−130 
> 130 
ER visit or hospitalization 
for arrhythmia 
Bradycardia – 
beats per minute c 
50−54  
45−49 
< 45 
ER visit or hospitalization 
for arrhythmia 
Hypertension 
(systolic) – mmHg  
141−150  
151−155 
> 155 
ER visit or hospitalization 
for malignant 
hypertension 
Hypertension 
(diastolic) – mmHg  
91−95 
96−100 
> 100 
ER visit or hospitalization 
for malignant 
hypertension 
Hypotension 
(systolic) – mmHg 
85−89  
80−84 
< 80 
ER visit or hospitalization 
for hypotensive shock 
Respiratory Rate – 
breaths per minute 
17−20 
21−25  
> 25 
Intubation 
a Subject should be at rest for all vital sign measurements. 
b Oral/tympanic temperature; no recent hot or cold beverages or smoking. 
c When resting heart rate is between 60−100 beats per minute.  Use clinical judgment when 
characterizing bradycardia among some healthy subject populations, for example, conditioned 
athletes. 
 


Appendix 3 (cont’d) 
DAIDS Toxicity Grading Tables for Clinical Abnormalities 
MHAA4549A—Genentech, Inc. 
103/Protocol GV29893, Version 3 
Systemic 
(General) 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Nausea/ 
vomiting 
No interference 
with activity or 
1 − 2 episodes/ 
24 hours 
Some interference 
with activity or 
> 2 episodes/ 
24 hours 
Prevents daily 
activity, requires 
outpatient IV 
hydration 
ER visit or 
hospitalization for 
hypotensive shock
Diarrhea 
2 − 3 loose stools 
or < 400 g/ 
24 hours 
4 − 5 stools or 
400 − 800 g/ 
24 hours 
5 or more watery 
stools or > 800 g/ 
24 hours or 
requires 
outpatient IV 
hydration 
ER visit or 
hospitalization 
Headache 
No interference 
with activity 
Repeated use of 
non-narcotic pain 
reliever > 24 hours 
or some 
interference with 
activity 
Significant; any 
use of narcotic 
pain reliever or 
prevents daily 
activity 
ER visit or 
hospitalization 
Fatigue 
No interference 
with activity 
Some interference 
with activity 
Significant; 
prevents daily 
activity 
ER visit or 
hospitalization 
Myalgia 
No interference 
with activity 
Some interference 
with activity 
Significant; 
prevents daily 
activity 
ER visit or 
hospitalization 
 
g = gram; IV = intravenous. 
 
Systemic 
Illness 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Illness or 
clinical 
adverse 
event (as 
defined 
according to 
applicable 
regulations) 
No interference 
with activity 
Some interference 
with activity no 
requiring medical 
intervention 
Prevents daily 
activity and 
requires medical 
intervention 
ER visit or 
hospitalization 
 
 


 
MHAA4549A—Genentech, Inc. 
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Appendix 4  
DAIDS Toxicity Grading Tables for Laboratory Abnormalities a 
HEMATOLOGY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin 
9.5−10.5 g/dL 
8.0−9.4 g/dL 
6.5−7.9 g/dL 
< 6.5 g/dL 
Absolute 
Neutrophil 
Count 
1,000−1,500/mm3 
750−999/mm3 
500−749/mm3 
< 500/mm3 
*Platelets 
125,000−140,000/mm3 100,000−124,999/mm3 25,000−99,999/mm3 
< 25,000/mm3 
WBCs 
11,000−13,000/mm3 
13,000−15,000/mm3 
15,000−30,000/mm3 
> 30,000 or 
< 1,000/mm3 
*Lymphocytes 
Decrease – 
cell/mm3 
750−1,000 
500−749  
250−499 
< 250 
*Eosinophils – 
cell/mm3 
650−1500 
1501−5000 
> 5000 
Hypereosinophilic
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 × ULN 
1.26−1.50 × ULN 
1.51−3.0 × ULN 
> 3 × ULN 
Activated 
Partial 
Thromboplastin 
Time (APTT) 
1.01−1.66 × ULN 
1.67−2.33 × ULN 
2.34−3 × ULN 
> 3 × ULN 
Methemoglobin 
5.0−9.9% 
10.0−14.9% 
15.0−19.9% 
> 20.0% 
ADL = Activities of Daily Living; CPK = creatine phosphokinase; Dec = Decreased; dl = deciliter; g = gram; 
IV = Intravenous; LLN = Lower limit of normal; mcg = microgram; mm = millimeter; Mod = Moderate; 
Req = Required; Rx = Therapy; SGOT = serum glutamic oxaloacetic transaminase; SGPT = serum 
glutamic pyruvic transaminase; ULN = Upper limit of normal. 
a Adapted from Division of Microbiology and Infectious Diseases (DMID) Adult Toxicity Table November 
2007 DRAFT and FDA Guidance document ‘Toxicity Grading Scale from Healthy Adult and 
Adolescent Volunteers Enrolled in Preventative Vaccine Clinical Trials 
 


Appendix 4 (cont’d) 
DAID Toxicity Grading Tables for Laboratory Abnormalities 
MHAA4549A—Genentech, Inc. 
105/Protocol GV29893, Version 3 
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 
Hypercalcemia 
(corrected 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  


Appendix 4 (cont’d) 
DAID Toxicity Grading Tables for Laboratory Abnormalities 
MHAA4549A—Genentech, Inc. 
106/Protocol GV29893, Version 3 
CHEMISTRIES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hyperbilirubinemia 
(when accompanied 
by any increase in 
other liver function 
test) 
1.1− < 1.25 × ULN1.25− < 1.5 × ULN 1.5−1.75 × ULN 
> 1.75 × 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 × ULN 
> 3.0 × ULN 
dL = deciliter; L = liter; mEq = milliequivalent; mg = milligram; ULN = upper limit of normal. 
 
ENZYMES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
AST (SGOT) 
1.1− < 2.0 × ULN 
2.0− < 3.0 × ULN 
3.0−8.0 × ULN 
> 8.0 × ULN 
ALT (SGPT) 
1.1− < 2.0 × ULN 
2.0− < 3.0 × ULN 
3.0−8.0 × ULN 
> 8.0 × ULN 
GGT 
1.1− < 2.0 × ULN 
2.0− < 3.0 × ULN 
3.0−8.0 × ULN 
> 8.0 × ULN 
Alkaline 
Phosphatase 
1.1− < 2.0 × ULN 
2.0− < 3.0 × ULN 
3.0−8.0 × ULN 
> 8.0 × ULN 
Amylase 
1.1−1.5 × ULN 
1.6−2.0 × ULN 
2.1−5.0 × ULN 
> 5.1 × ULN 
Lipase 
1.1−1.5 × ULN 
1.6−2.0 × ULN 
2.1−5.0 × ULN 
> 5.1 × ULN 
*CPK – mg/dL 
1.25−1.5 × ULN 
1.6−3.0 × ULN 
3.1−10.0 × ULN 
> 10 × ULN 
ALT = alanine transaminase; AST = aspartase transaminase; CPK = creatine phosphokinase; 
dl = deciliter; GGT = Gamma-glutamyl transferase; mg = milligram; SGOT = serum glutamic 
oxaloacetic transaminase; SGPT = serum glutamic pyruvic transaminase; ULN = upper limit of 
normal. 
 
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 casts 
Obstructive or 
required 
transfusion 
*Glucose 
Trace 
1+ 
2+ 
Hospitalization for 
hyperglycemia 
g = gram; hpf = high power field; mg = milligram; RBC = red blood cell. 


 
MHAA4549A—Genentech, Inc. 
107/Protocol GV29893, Version 3 
Appendix 5  
Anaphylaxis Precautions and Management 
Administration of MHAA4549A will be performed in a setting with emergency medical 
equipment and personnel who are trained to monitor for and respond to medical 
emergencies.  A qualified physician or medically qualified designee will be on site during 
study drug administration for all patients. 
The following equipment is needed in the event of a suspected anaphylactic reaction 
during study drug infusion: 
• 
Airway management equipment 
• 
O2 
• 
Epinephrine for subcutaneous, intravenous, and/or endotracheal use in accordance 
with standard practice  
• 
Antihistamines 
• 
Corticosteroids 
• 
IV infusion solutions, tubing, catheters, and tape 
 
The following are the procedures to follow in the event of a suspected anaphylactic 
reaction during study drug infusion: 
• 
Stop the study drug infusion. 
• 
Maintain an adequate airway. 
• 
Administer antihistamines, epinephrine, or other medications as required by patient 
status and directed by the physician in charge. 
• 
Continue to observe the patient and document observations. 


 
MHAA4549A—Genentech, Inc. 
108/Protocol GV29893, Version 3 
Appendix 6  
Adult Patient Symptom Diary 
This diary will keep track of your flu symptoms and temperature during the study.  You 
should complete it 2 times a day: when you first wake up in the morning (before getting 
out of bed) and about 12 hours later. Remember to take your temperature before you 
take any medicines to help your flu symptoms.  
Please rate each symptom based on how you feel right now. 
Symptom 
None 
0 
Mild 
1 
Moderate 
2 
Severe 
3 
1. Nasal 
Congestion 
 
 
 
 
2. Sore Throat 
 
 
 
 
3. Cough 
 
 
 
 
4. Aches and 
Pains 
 
 
 
 
5. Fatigue 
(tiredness) 
 
 
 
 
6. Headache 
 
 
 
 
7. Chills/sweats 
(feverish) 
 
 
 
 
 


Appendix 6 (cont’d) 
 
Adult Patient Symptom Diary 
MHAA4549A—Genentech, Inc. 
109/Protocol GV29893, Version 3 
Temperature: 
Please take your temperature now.  
What is your temperature right now? (Measure before taking fever medication): _______ 
(Choose °C or °F) 
Did you measure a temperature > 38.0°C (100.4°F) in the past 12 hours? 
____Yes 
____No 
 
What was the time and temperature?:_________ 
Medications for relief: 
Please look at your “allowed medication” wallet card.  It shows the most common names 
of these medications (i.e., acetaminophen/paracetamol, ibuprofen, other NSAIDs) 
Have you taken any of these “allowed medications” to help your flu symptoms in the past 
12 hours? 
____Yes 
____No