Conditions: Influenza
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 168
Healthy volunteers: no

Brief summary:
This is a randomized, double-blind, placebo-controlled study that will investigate the safety and clinical activity of a single intravenous (IV) dose of MHAA4549A in adult participants hospitalized with severe influenza A in combination with oseltamivir versus a comparator arm of placebo with oseltamivir.

Detailed description:

Arms:
arm 1: Participants will receive a single low IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days. arm 2: Participants will receive a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days. arm 3: Participants will receive a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy (75 or 150 mg BID) for minimum of 5 days.

Interventions: intervention 1: MHAA4549A intervention 2: Oseltamivir intervention 3: Placebo
Intervention descriptions: intervention 1: Participants will receive a single dose of MHAA4549A by IV infusion on Day 1 intervention 2: Participants will receive oseltamivir capsule either 75 mg or 150 mg BID orally for minimum of 5 days. Dosage and administration should follow local prescribing information for oseltamivir. intervention 3: Participants will receive a single IV dose of placebo matched to MHAA4549A on Day 1

Protocol document:
Prot_SAP_000.pdf: 
 
Official Title: 
A Phase 2 Randomized, Double-Blind Placebo-Controlled Trial of 
MHAA4549A, a Monoclonal Antibody, in Combination with 
Oseltamivir Versus Oseltamivir for Treatment of Severe Influenza 
Infection 
NCT Number: 
NCT02293863 
Document Date: 
Protocol Version 1: 30-May-2014 
Protocol Version 2: 14-Aug-2014 
Protocol Version 3: 25-Sep-2014 
Protocol Version 5: 20-Mar-2015 
Protocol Version 7: 16-May-2016 
 
 
 
 
 
 


 
Title
30-May-2014 23:24:25
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The information contained in this document, especially any unpublished data, is the property of 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 GV29216, Version 1 
 
PROTOCOL 
TITLE: 
A PHASE 2 RANDOMIZED, DOUBLE-BLIND 
PLACEBO-CONTROLLED TRIAL OF MHAA4549A, 
A MONOCLONAL ANTIBODY, IN COMBINATION WITH 
OSELTAMIVIR VERSUS OSELTAMIVIR FOR 
TREATMENT OF SEVERE INFLUENZA A INFECTION 
PROTOCOL NUMBER: GV29216 
VERSION NUMBER: 
1 
EUDRACT NUMBER: 
2014-000461-43 
IND NUMBER: 
117,318 
TEST PRODUCT: 
MHAA4549A 
MEDICAL MONITOR: 
, M.D., Ph.D. 
SPONSOR: 
Genentech, Inc./Roche Registration Ltd. 
DATE FINAL: 
See electronic date stamp below 
 


MHAA4549A—Genentech, Inc. 
Protocol GV29216, Version 1                                                                                                           2 
 
TABLE OF CONTENTS 
PROTOCOL ACCEPTANCE FORM .................................................................... 8 
PROTOCOL SYNOPSIS ...................................................................................... 9 
1. 
BACKGROUND .......................................................................................... 18 
1.1 
Background on Influenza....................................................... 18 
1.2 
Background on MHAA4549A................................................. 18 
1.3 
Study Rationale and Benefit-Risk Assessment...................... 20 
1.3.1 
Study Rationale ..................................................................... 20 
1.3.2 
Benefit-Risk Assessment....................................................... 21 
1.3.2.1 
Treatment in Combination with Oseltamivir ........................... 21 
1.3.2.2 
Drug Mechanism and Preclinical Studies .............................. 21 
1.3.2.3 
Rationale for Selection of Phase 2b Study 
Population.............................................................................. 21 
1.3.2.4 
Patient Monitoring and Supervision ....................................... 22 
2. 
OBJECTIVES.............................................................................................. 22 
2.1 
Safety Objectives................................................................... 22 
2.2 
Primary Efficacy Objectives................................................... 23 
2.3 
Secondary Efficacy Objectives .............................................. 23 
2.4 
Pharmacokinetic Objectives .................................................. 23 
2.5 
Exploratory Objectives........................................................... 24 
3. 
STUDY DESIGN ......................................................................................... 24 
3.1 
Description of the Study......................................................... 24 
3.1.1 
Overview of Study Design ..................................................... 24 
3.1.2 
Independent Data Monitoring Committee .............................. 26 
3.1.3 
End of Study.......................................................................... 26 
3.2 
Rationale for Study Design.................................................... 26 
3.2.1 
Rationale for Study Design.................................................... 26 
3.2.2 
Rationale for Patient Population and Primary 
Endpoint ................................................................................ 27 
3.2.3 
Rationale for Control Group and Treatment 
Window.................................................................................. 27 


3.2.4 
Rationale for MHAA4549A Dosage ....................................... 29 
3.2.5 
Rationale for Biomarker Assessments................................... 29 
3.3 
Outcome Measures ............................................................... 30 
3.3.1 
Safety Outcome Measures .................................................... 30 
3.3.2 
Primary Efficacy Outcome Measure ...................................... 30 
3.3.3 
Secondary Efficacy Outcome Measures................................ 30 
3.3.4 
Pharmacokinetic Outcome Measures.................................... 31 
3.3.5 
Exploratory Outcome Measures ............................................ 31 
4. 
MATERIALS AND METHODS .................................................................... 32 
4.1 
Patients.................................................................................. 32 
4.1.1 
Inclusion Criteria.................................................................... 32 
4.1.2 
Exclusion Criteria................................................................... 33 
4.2 
Method of Treatment Assignment and Blinding..................... 34 
4.3 
Study Treatment.................................................................... 35 
4.3.1 
Formulation, Packaging, and Handling.................................. 35 
4.3.1.1 
MHAA4549A and Placebo..................................................... 35 
4.3.1.2 
Oseltamivir (Tamiflu).............................................................. 36 
4.3.2 
Dosage, Administration, and Compliance.............................. 36 
4.3.2.1 
MHAA4549A and Placebo..................................................... 36 
4.3.2.2 
Oseltamivir-Neuraminidase Inhibitor (NAI) ............................ 37 
4.3.3 
Investigational Medicinal Product Accountability ................... 37 
4.4 
Post-Trial Access to MHAA4549A......................................... 38 
4.5 
Concomitant Therapy and Food ............................................ 38 
4.5.1 
Permitted Therapy ................................................................. 38 
4.5.2 
Prohibited Therapy ................................................................ 38 
4.5.3 
Prohibited Food ..................................................................... 38 
4.6 
Study Assessments ............................................................... 38 
4.6.1 
Informed Consent Forms and Screening Log........................ 39 
4.6.2 
Diagnostic Testing for Enrollment.......................................... 39 
4.6.3 
Medical History and Demographic Data ................................ 39 
4.6.4 
Priority of Assessments ......................................................... 39 
4.6.5 
Physical Examinations........................................................... 39 
4.6.6 
Vital Signs.............................................................................. 40 
MHAA4549A—Genentech, Inc. 
Protocol GV29216, Version 1 
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5.3.5.3 
Persistent or Recurrent Adverse Events................................ 53 
5.3.5.4 
Abnormal Laboratory Values ................................................. 54 
5.3.5.5 
Abnormal Vital Sign Values ................................................... 54 
5.3.5.6 
Abnormal Liver Function Tests.............................................. 55 
5.3.5.7 
Deaths ................................................................................... 55 
5.3.5.8 
Pre-existing Medical Conditions ............................................ 56 
5.3.5.9 
Lack of Efficacy or Worsening of Influenza A 
Infection................................................................................. 56 
5.3.5.10 
Hospitalization or Prolonged Hospitalization.......................... 56 
5.3.5.11 
Adverse Events Associated with an Overdose ...................... 57 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 57 
5.4.1 
Emergency Medical Contacts................................................ 58 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest...................................................................... 58 
5.4.2.1 
Events That Occur prior to Study Drug Initiation.................... 58 
5.4.2.2 
Events That Occur after Study Drug Initiation........................ 59 
5.4.3 
Reporting Requirements for Pregnancies.............................. 59 
5.4.3.1 
Pregnancies in Female Patients............................................ 59 
5.4.3.2 
Pregnancies in Female Partners of Male Patients................. 60 
5.4.3.3 
Congenital Anomalies/Birth Defects and 
Abortions ............................................................................... 60 
5.4.4 
Investigator Follow-Up........................................................... 60 
5.4.5 
Sponsor Follow-Up ................................................................ 61 
5.5 
Poststudy Adverse Events..................................................... 61 
5.6 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 61 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 62 
6.1 
Determination of Sample Size ............................................... 62 
6.2 
Summaries of Conduct of Study............................................ 63 
6.3 
Summaries of Treatment Group Comparability ..................... 63 
6.4 
Efficacy Analyses .................................................................. 64 
6.4.1 
Primary Efficacy Endpoint...................................................... 64 
MHAA4549A—Genentech, Inc. 
Protocol GV29216, Version 1 
5 


6.4.2 
Secondary Efficacy Endpoints............................................... 64 
6.4.3 
Subgroup Analyses ............................................................... 64 
6.5 
Safety Analyses..................................................................... 65 
6.6 
Pharmacokinetic Analyses..................................................... 65 
6.7 
Optional Interim Analysis....................................................... 66 
7. 
DATA COLLECTION AND MANAGEMENT ............................................... 67 
7.1 
Data Quality Assurance......................................................... 67 
7.2 
Electronic Case Report Forms............................................... 67 
7.3 
Source Data Documentation.................................................. 67 
7.4 
Use of Computerized Systems .............................................. 68 
7.5 
Retention of Records............................................................. 68 
8. 
ETHICAL CONSIDERATIONS.................................................................... 68 
8.1 
Compliance with Laws and Regulations ................................ 68 
8.2 
Informed Consent .................................................................. 69 
8.3 
Institutional Review Board or Ethics Committee.................... 70 
8.4 
Confidentiality........................................................................ 70 
8.5 
Financial Disclosure .............................................................. 70 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 71 
9.1 
Study Documentation ............................................................ 71 
9.2 
Protocol Deviations................................................................ 71 
9.3 
Site Inspections ..................................................................... 71 
9.4 
Administrative Structure......................................................... 71 
9.5 
Protocol Amendments ........................................................... 71 
10. REFERENCES ........................................................................................... 73 
 
MHAA4549A—Genentech, Inc. 
Protocol GV29216, Version 1 
6 




PROTOCOL ACCEPTANCE FORM 
TITLE: 
A PHASE 2 RANDOMIZED, DOUBLE-BLIND 
PLACEBO-CONTROLLED TRIAL OF MHAA4549A, 
A MONOCLONAL ANTIBODY, IN COMBINATION WITH 
OSELTAMIVIR VERSUS OSELTAMIVIR FOR 
TREATMENT OF SEVERE INFLUENZA A INFECTION 
PROTOCOL NUMBER: GV29216 
VERSION NUMBER: 
1 
EUDRACT NUMBER: 
2014-000461-43 
IND NUMBER: 
117,318 
TEST PRODUCT: 
MHAA4549A 
MEDICAL MONITOR: 
, M.D., Ph.D. 
SPONSOR: 
Genentech, Inc./Roche Registration Ltd. 
 
I agree to conduct the study in accordance with the current protocol. 
  
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please return a copy of the signed form as instructed by the CRO.  Please retain 
the original for your study files. 
 
MHAA4549A—Genentech, Inc. 
Protocol GV29216, Version 1 
8 


PROTOCOL SYNOPSIS 
A PHASE 2 RANDOMIZED, DOUBLE-BLIND TRIAL OF 
MHAA4549A, A MONOCLONAL ANTIBODY IN 
COMBINATION WITH OSELTAMIVIR VERSUS 
OSELTAMIVIR FOR TREATMENT OF SEVERE INFLUENZA 
A INFECTION 
TITLE: 
GV29216 
PROTOCOL NUMBER: 
VERSION NUMBER: 
1 
2014-000461-43 
EUDRACT NUMBER: 
117,318 
IND NUMBER: 
MHAA4549A 
TEST PRODUCT: 
INFLUENZA A 
INDICATION: 
Genentech, Inc./Roche Registration Ltd. 
SPONSOR: 
 
Objectives 
Safety Objectives 
The safety objectives for this study are as follows: 
• 
To evaluate the safety of MHAA4549A in combination with oseltamivir compared with 
placebo and oseltamivir in patients with severe influenza A, focusing on the nature, 
frequency, and severity of serious and non-serious adverse events, as well as effects on 
laboratory values, vital signs, electrocardiogram (ECG) parameters, anti-therapeutic 
antibodies (ATA), or other safety biomarkers 
Efficacy Objectives 
The primary efficacy objective for this study is as follows: 
• 
To determine the time to normalization of respiratory function of patients dosed with 
MHAA4549A in combination with oseltamivir compared to patients dosed with placebo and 
oseltamivir 
The secondary efficacy objectives for this study are as follows: 
• 
To measure clinical failure after 24 hours post-infusion of study drug  
• 
To determine the time to clinical resolution of vital signs 
• 
To measure mortality in patients 
• 
To determine changes in the extent and duration of viral shedding in upper respiratory 
samples 
• 
To measure the duration of hospital and/or intensive care unit (ICU) stay  
• 
To measure antibiotic usage for respiratory indications  
• 
To measure the frequency and severity of the following secondary complications of 
influenza: 
− 
Pneumonia (hospital acquired pneumonia [HAP]/ ventilator acquired pneumonia [VAP]) 
− 
Exacerbations of chronic lung disease 
− 
Myocarditis 
− 
Acute respiratory distress syndrome (ARDS) 
MHAA4549A—Genentech, Inc. 
Protocol GV29216, Version 1 
9 




window.  All patients will receive oseltamivir for a minimum of 5 days (10 doses), starting on 
Day 1 beginning no later than 8 hours after study drug administration.  All patients will be 
followed for 30 days from the time of study drug administration. 
Number of Patients 
The study has a planned enrollment of approximately 334 patients (adult men and women) 
globally.  Patients will receive MHAA4549A or placebo in 1:1 ratio.  The number of patients on 
PPV should not exceed 45% of the total enrolled patients. 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Men or women  ≥ 18 years of age on day of signing informed consent or obtaining surrogate 
consent from an authorized representative 
• 
Diagnosis of influenza A as determined by the Sponsor-supplied rapid influenza test 
− 
If negative rapid influenza A test, a positive local molecular test (PCR) is required 
• 
One of the following markers of severity within 24 hours of hospital admission: 
− 
Requirement for PPV, OR 
− 
Requirement for O2 supplementation to maintain SpO2 > 92% 
• 
A negative urine or serum pregnancy test for women of childbearing potential 
• 
Patients of reproductive potential must agree to use reliable means of contraception as 
described below as a minimum (adherence to more stringent local requirements may be 
required): 
− 
For female patients:  Use of two acceptable methods of contraception throughout the 
trial, including the active treatment phase AND for 24 weeks after the last dose of 
MHAA4549A.  Acceptable methods of contraception include:  intrauterine device, 
systemic hormonal contraception (oral or depot), vaginal ring, tubal ligation of the female 
partner, vasectomy of the male partner, use of latex condoms plus spermicide by the 
male partner, or cervical cap plus spermicide (where the spermicide could be foam, 
vaginal suppository, gel, cream, etc.). 
− 
For male patients:  Use of condoms for 30 days after dosing when circulating drug levels 
remain high. 
− 
Non-reproductive potential is defined below (but could be superseded by local definitions, 
if they are more stringent): 
Women who are postmenopausal (i.e., spontaneous amenorrhea for the past year 
confirmed by an follicle stimulating hormone [FSH] level greater than 40 mIU/mL 
unless the patient is receiving a hormonal therapy for their menopause)  
Women who are surgically sterile (i.e., hysterectomy, complete bilateral 
oophorectomy) 
Men who are surgically sterile (castration) 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Pregnant or lactating, or intending to become pregnant during the study 
− 
Women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) 
or who are not surgically sterile must have a negative urine or serum pregnancy test 
result within 2 days prior to study treatment 
• 
Hypersensitivity to monoclonal antibodies or any constituents of study drug 
• 
Investigational therapy within the 30 days prior to study treatment  
• 
Received prior therapy with any anti-influenza monoclonal antibody therapy including 
MHAA4549A 8 months prior to study treatment 
MHAA4549A—Genentech, Inc. 
Protocol GV29216, Version 1 
11 


• 
Current treatment (within 7 days of dosing) with amantadine or rimantidine 
• 
Patients who have taken more than a total of 3 days (6 doses) of approved anti-influenza 
therapy (i.e., oral oseltamivir, inhaled zanamivir, or oral ribavirin) in the period from onset of 
symptoms and prior to enrollment 
• 
Admission > 48 hours prior to study treatment 
• 
Onset of influenza symptoms > 5 days prior to study treatment 
• 
Positive influenza B or influenza A + B infection within 2 weeks prior to study treatment 
• 
High probability of mortality in the next 48 hours as determined by the investigator  
• 
Patient requiring home or baseline oxygenation therapy 
• 
Patient with history of chronic lung disease resulting in baseline SpO2 < 95%  
• 
Patient on chronic dose of corticosteroids exceeding 10 mg/day of prednisone or equivalent 
steroid dose for a duration of greater than 14 days within 30 days of entry into study 
• 
Patients with the following significant immune suppression: 
− 
Bone marrow or solid organ transplant in the previous 12 months 
− 
Cancer chemotherapy in the previous 12 month 
− 
HIV infection with most recent CD4 < 200 cells/mL 
− 
Other significant immune suppression as determined by the investigator in discussion 
with the Sponsor Medical Monitor or representative 
• 
Patient on extracorporeal membrane oxygenation (ECMO) at time of randomization 
• 
Any disease or condition that would, in the opinion of the site investigator or Sponsor, place 
the subject at an unacceptable risk of injury or render the subject unable to meet the 
requirements of the protocol 
Length of Study 
This study will consist of the following study periods: 
• 
A screening period of 48 hours, beginning at time of hospital submission 
• 
A treatment period of 1 day, during which patients will receive a single dose of MHAA4549A 
or placebo and up to 10 days of oseltamivir. 
• 
A follow-up period beginning at hospital discharge through 30 days post study drug 
(MHAA4594A/placebo) administration 
End of Study 
The end of the study is defined as the first day when all patients have had a study completion 
visit or early termination visit or have otherwise been discontinued from the study. 
Outcome Measures 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
Adverse events and clinical laboratory abnormalities 
• 
Vital signs, physical findings, ATAs, and clinical laboratory results during and following 
administration of MHAA4549A 
Efficacy Outcome Measures 
The primary outcome measure for this study is as follows: 
• 
Time to normalization of respiratory function defined as: 
− 
The time to cessation of O2 support resulting in a stable SpO2 >95% for at least 24 hours 
The secondary efficacy outcome measures for this study are as follows: 
• 
Clinical failure 24 hours post-infusion of study drug defined as: 
− 
Progression to increased O2 requirement defined by an increase in oxygen 
supplementation from low flow oxygen (2 − 6 L/min) to high flow oxygen ( > 6 L/min) or 
from oxygen supplementation alone to any PPV 
MHAA4549A—Genentech, Inc. 
Protocol GV29216, Version 1 
12 






Interim Analyses 
In order to adapt to information that may emerge during the course of this study (e.g., additional 
results of competitor studies) the Sponsor may choose to conduct one interim efficacy 
analysis.  Section 6.7 contains the specifications in place to ensure the study continues to meet 
the highest standards of integrity when such an optional IA is executed. 
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 I error penalty of 0.0001 will be taken. 
Determination of Sample Size   
A total of 334 patients will be enrolled in this study in order to obtain approximately 
300 evaluable patients (an estimated dropout rate of 10%).  It is assumed that the median time 
to normalization of respiratory function in the control arm is 5 days 
 
MHAA4549A—Genentech, Inc. 
Protocol GV29216, Version 1 
15 


 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
 
 
Adverse event 
AE 
Adverse events of special interest 
AESI 
Alanine aminotransferase 
ALT 
Acute respiratory distress syndrome 
ARDS 
Aspartate aminotransferase 
AST 
Anti-therapeutic antibody 
ATA 
Area under serum concentration−time curve  
AUC 
AUEC 
Area under viral load−time curve  
Twice a day 
BID 
Celsius 
°C 
Maximum observed concentration 
Cmax 
Minimum observed concentration 
Cmin 
Creatine phosphokinase 
CPK 
Contract (or Clinical) Research Organization 
CRO 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAIDS 
Division of Acquired Immunodeficiency Syndrome 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ECMO 
Extracorporeal membrane oxygenation 
EDC 
Electronic data capture 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
HA 
Hemagglutinin  
HAI 
Hemagglutinin inhibition 
HAP 
Hospital Acquired Pneumonia 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HR 
Heart rate 
 
 
ICH 
International Conference on Harmonisation 
ICU 
Intensive Care Unit 
IDCC 
Independent Data Coordinating Center 
iDMC 
Independent Data Monitoring Committee 
Anti-Influenza A (MHAA4549A)—Genentech, Inc. 
Protocol GV29216, Version 1 
16 


 
Abbreviation 
Definition 
IEC 
Independent Ethics Committee 
IMP 
Investigational medicinal product 
IND 
Investigational New Drug (application) 
IRB 
Institutional Review Board 
IRR 
Infusion-related reactions 
IV 
Intravenous 
LFTs 
Liver function tests 
mAB 
Monoclonal antibody 
NAI 
Neuraminidase inhibitor 
NP 
Nasopharyngeal 
PCR 
Polymerase Chain Reaction 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PPV 
Positive pressure ventilation 
qPCR 
Quantitative Polymerase Chain Reaction 
QTcF 
QT interval corrected using Fridericia’s formula 
RBC 
Red blood cell 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SOC 
Standard of care 
SpO2 
Oxygen saturation 
SUSAR 
Suspected unexpected serious adverse reactions 
TCID50 
50% tissue culture infection dose 
ULN 
Upper limit of normal 
VAP 
Ventilation Acquired Pneumonia 
WBC 
White blood cell 
w/v 
Weight/volume 
 
MHAA4549A—Genentech, Inc. 
Protocol GV29216, Version 1 
17 


 
1. 
BACKGROUND 
1.1 
BACKGROUND ON INFLUENZA 
Influenza A is a membrane-enveloped RNA virus that causes significant morbidity and 
mortality.  Currently, there is a great need in hospitalized influenza patients for a 
parenteral therapeutic option that is well tolerated, can rapidly resolve influenza-related 
signs and symptoms, decrease mortality, reduce hospital and intensive care unit (ICU) 
stays, as well as have a prolonged window for initiation of treatment beyond the current 
standard of care (SOC) (i.e., within 48 hours of the onset of flu symptoms). 
Approximately 200,000 to 278,000 patients are hospitalized with severe influenza 
infections annually in the United States (U.S.) (Thompson et al. 2004; Zhou et al. 2012), 
and assuming the same rate reported in the U.S., an estimated 319,000 to 
445,000 patients are hospitalized in the European Union (E.U.).  Hospitalization due to 
severe influenza is associated with high mortality (4%−8%), ICU admission (5%−17%; 
Lee and Ison 2012), mechanical ventilation support in an ICU setting (7%−11%; 
Doshi et al. 2011), and prolonged hospital stays (5−9 days; Lee and Ison 2012).  During 
a pandemic season, the outcomes may be more serious, with up to 34% of patients 
requiring ICU care and a mortality rate as high as 15% (Lee and Ison 2012). 
Influenza infection is an upper and lower respiratory disease with a broad spectrum of 
presentations that can result in fever, shortness-of-breath, pneumonia, respiratory failure, 
secondary respiratory infections, and even death.  The SOC therapy for patients 
hospitalized with influenza consists of supportive measures and administration of 
available antiviral agents, primarily neuraminidase inhibitors (NAI) that include but are 
not limited to oseltamivir, zanamivir, and peramivir.  However, a significant unmet 
medical need still exists in the severely ill patient population, as evidenced by the 
considerable degree of morbidity and mortality in this setting.  To address this need, 
Genentech Inc. /F.Hoffmann-La Roche Ltd. (Genentech) is developing a highly-specific, 
anti-influenza A (MHAA4549A) antibody therapy for treatment of hospitalized patients 
with severe influenza. 
1.2 
BACKGROUND ON MHAA4549A 
MHAA4549A is a human monoclonal IgG1 antibody (mAb) that binds to the influenza A 
virus and is 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 stalk region, which allows broad neutralization 
of the influenza A virus by blocking the hemagglutinin-mediated, membrane-fusion event 
in the late endosome. 
In vitro, MHAA4549A is capable of neutralizing all current clinically relevant influenza A 
strains.  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.  
MHAA4549A specifically targets an epitope on the human influenza A hemagglutinin 
Anti-Influenza A (MHAA4549A)—Genentech, Inc. 
Protocol GV29216, Version 1 
18 


 
glycoprotein, which does not appear to be endogenously expressed on human or rat 
tissues and, therefore, is unlikely to be present in the absence of viral infection.  Weekly 
administration of MHAA4549A (total of 5 doses) in Sprague-Dawley rats was well 
tolerated up to the maximum feasible dose of 150 mg/kg.  The results of the ex vivo 
tissue cross-reactivity study indicates no specific binding of MHAA4549A to any of the 
human or rat tissues examined. 
Clinical experience with MHAA4549A has consisted of two studies in 122 healthy 
volunteers, and has been shown to be safe and well tolerated to date.  The first study 
was a Phase 1 study (GV28916) in 21 healthy volunteers where single doses of 
1.5 mg/kg, 5 mg/kg, 15 mg/kg, and 45 mg/kg were tested with an extended follow-up 
period of 120 days.  MHAA4549A was safe and well tolerated with no serious adverse 
events (SAEs).  All adverse events (AEs) were mild or mild-to-moderate and resolved 
fully.  In addition, the observed pharmacokinetics were generally dose proportional, 
appeared to have a pharmacokinetic (PK) profile consistent with that of a IgG1 human 
antibody that lack known endogenous host targets, and no anti-therapeutic antibodies 
(ATAs) were detected with available samples.  
The second study was a Phase 2a (GV28985) challenge study in 101 healthy volunteers 
infected with a H3N2 strain of influenza virus.  Fixed dosing was selected for this study 
and is further described in Section 1.3.2.3.  Three doses were tested: 400 mg, 1200 mg, 
and 3600 mg.  All subjects have completed dosing, and interim PK and efficacy data are 
available for the 1200-mg and 3600-mg dose groups.  During the Phase 2a (GV28985) 
study, the related AEs that were observed included elevated liver function tests (LFTs) 
and amylase levels.  No dose relationship was observed for LFTs (i.e., placebo 30.8%, 
1200 mg 40%, 3600 mg 35%), and no SAEs were observed that were related to 
MHAA4549A.  Based on this data, MHAA4549A is considered generally safe and well 
tolerated to date at all doses tested including the 3600 mg dose.  Analysis of efficacy 
from the 3600-mg dose level demonstrated a statistically significant decrease in viral 
shedding from upper respiratory tract as measured by area under the curve (97% 
reduction by quantitative polymerase chain reaction [qPCR]) and peak viral load (77% 
reduction by qPCR) as outlined in Table 1.  In this study, oseltamivir was started on 
Day 7 for a 5-day course, and there were no observed AEs or imbalances in safety 
events that were considered attributable to interactions between oseltamivir and 
MHAA4549A.  The PK profile of MHAA4549A and oseltamivir are being analyzed in 
GV28985 to exclude potential drug-drug interactions and will be available before the 
start of this study.  Testing for ATAs in the Phase 2a has not been concluded. 
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Table 1 Interim Efficacy Results from Phase 2a Challenge Study (GV28985) 
MHAA4549A 
Endpoint 
Placebo 
1200 mg 
% reduction 
(p-value)a 
3600 mg 
% reduction 
(p-value)a 
Median qPCR Viral AUEC 
(log10 vc/mL x hour) 
458.1 
444.4 
3.0% 
(0.9174) 
11.3 
97.5% 
(0.0092) 
Median qPCR Peak Viral Load 
(log10 vc/mL) 
6.38 
6.36 
0.3% 
(1.0000) 
1.45 
77.3% 
(0.0054) 
Median Total Clinical Symptom
AUEC 
207.7 
192.1 
7.5% 
(0.8846) 
37.7 
81.8% 
(0.2922) 
AUEC = area under viral load−time curve; qPCR = quantitative polymerase chain reaction. 
a Comparison of 3600 mg to placebo using nonparametric Wilcoxon rank-sum test.  All p-values 
are unadjusted for multiple testing. 
 
See the MHAA4549A Investigator’s Brochure for additional details on nonclinical and 
clinical studies. 
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
1.3.1 
Study Rationale 
The Phase 1 and Phase 2a studies have demonstrated that MHAA4549A is safe and 
well tolerated to date in healthy volunteers including those who were inoculated with 
influenza A virus.  Preliminary data from the Phase 2a study also provides evidence that 
the 3600 mg dose of MHAA4549A is effective in reducing viral titers in healthy 
volunteers inoculated with influenza A virus.  These findings, when combined with 
previous nonclinical studies showing MHAA4549A to have in vitro and in vivo efficacy, a 
well-tolerated safety profile, and anti-viral activity, support further clinical development of 
MHAA4549A. 
In this Phase 2b study (GV29216), MHAA4549A is being evaluated in combination with 
the current SOC (oseltamivir), to decrease the severity and duration of viral infection with 
influenza A virus with the ultimate goal of reducing the clinical symptoms of infection as 
compared to oseltamivir with placebo.  There are three primary goals for this Phase 2b 
study:  
• 
Demonstrate the safety and efficacy of MHAA4549A in combination with oseltamivir 
in hospitalized influenza A patients  
• 
 
 
  
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• 
Demonstrate and evaluate the optimal endpoints for study in hospitalized patients 
with influenza A, given the lack of precedence for approval in patients hospitalized 
with influenza infection, an area of high unmet medical need 
 
This Phase 2b study has been designed to estimate the improvement in outcome of a 
combination therapy of MHAA4549A 3600 mg with oseltamivir versus placebo with 
oseltamivir.  All patients will be on oseltamivir which is part of the recommended SOC.  
In addition, and as discussed above, MHAA4549A is a human monoclonal antibody that 
has, to date, shown an acceptable safety profile, a PK profile consistent with that of a 
IgG1 human antibody that lacks known endogenous host targets, and a demonstrated 
antiviral activity at the planned dose level of 3600 mg. 
1.3.2 
Benefit-Risk Assessment 
1.3.2.1 
Treatment in Combination with Oseltamivir 
All patients in the study will receive the current SOC treatment of oseltamivir either with 
or without MHAA4549A.  Therefore, all patients at minimum will be treated with SOC for 
influenza.  Given that MHAA4549A is an antibody, the potential for interaction with 
oseltamivir is very low.  In the ongoing Phase 2a challenge study (GV28985), several 
study subjects received MHAA4549A followed by oseltamivir with no AEs attributable to 
the combination therapy noted to date.  In addition, the PK profile of oseltamivir in 
concomitantly treated subjects will be assessed. 
1.3.2.2 
Drug Mechanism and Preclinical Studies 
The available pre-clinical data suggest that there is low risk for drug target-related safety 
events in healthy humans since MHAA4549A specifically targets an epitope on a viral 
protein (i.e., the human influenza A virus hemagglutinin glycoprotein), which is not 
endogenously expressed in human tissues.  Furthermore, there were no adverse 
MHAA4549A-related findings demonstrated in nonclinical studies at doses up to 
150 mg/kg administered weekly for 5 weeks and no evidence of target present in host 
tissues.   
1.3.2.3 
Rationale for Selection of Phase 2b Study Population 
The target patient population of hospitalized patients with severe influenza A requiring 
oxygen (O2) or positive pressure ventilation (PPV) is considered an appropriate 
population to test MHAA4549A for the following reasons: 
• 
Nonclinical safety data does not show any expected or unexpected toxicity. 
• 
Clinical safety data for MHAA4549A demonstrates a well-tolerated safety profile.  
There were mild, related AEs observed in the Phase 1 study (GV28916) and 
MHAA4549A was well tolerated.  No ATAs were detected.  Safety data from the 
ongoing Phase 2a challenge study (GV28985) was observed to have mild and 
moderate transient elevations in alanine transaminase (ALT), aspartate 
transaminase (AST), and amylase that may be related to either MHAA4549A or to 
influenza infection.  There was no dose-dependent relationship of LFT elevations 
with MHAA4549A and the overall event rate was in line with that of previous 
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challenge studies (27/100 [27%] in the study vs. approximately 26%) (Polakos 2006).  
No SAEs that were related to study drug were observed.  Testing for ATAs in 
Study GV28985 has not yet been concluded. 
• 
The Phase 2a challenge study (GV28985) interim efficacy data demonstrated a 
significant decrease in viral shedding in the upper respiratory tract at the 3600 mg 
dose.  There was a 97.5% (p = 0.0092) decrease in the area under viral load−time 
curve  (AUEC) and a 77% (p = 0.0054) decrease in peak viral load by qPCR 
measurement in comparison to the placebo group, thus confirming proof of antiviral 
activity at the 3600 mg dose level.  
 
1.3.2.4 
Patient Monitoring and Supervision 
MHAA4549A will be administered to enrolled patients in a hospital environment under 
close medical supervision by physician investigators.  Medical staff will be available for 
prompt evaluation and treatment of any adverse events.  Emergency resuscitation 
equipment and emergency facilities will be readily available.  Patients will undergo 
screening assessments to confirm eligibility, will be closely monitored during the 
administration of MHAA4549A, and will be resident for at least 24 hours following the 
administration of MHAA4549A.  Furthermore, safety laboratory tests relating to the blood 
chemistries, including liver function tests, will be conducted. 
An independent Data Monitoring Committee (iDMC) will evaluate the safety of 
MHAA4549A at a timepoint to be specified in the iDMC charter.  
The 120-day follow-up period in the Phase 1 and 2a studies allowed for monitoring of 
subjects for approximately 5 half-lives of the study drug.  No ATAs were detected in the 
Phase 1 study, and the ATA testing for the Phase 2a study is ongoing.  The Phase 2b 
study will also include an appropriate safety follow-up period of up to 30 days and an 
unlimited collection of all SAEs believed related to MHAA4549A.   
Based on the above data and design of this study, the Sponsor concludes that the 
benefit−risk profile of MHAA4549A in the population with severe influenza is favorable.  
2. 
OBJECTIVES 
2.1 
SAFETY OBJECTIVES 
The safety objectives for this study are as follows: 
• 
To evaluate the safety of MHAA4549A in combination with oseltamivir compared 
with placebo and oseltamivir in patients with severe influenza A, focusing on the 
nature, frequency, and severity of serious and non-serious adverse events as well 
as effects on laboratory values, vital signs, electrocardiogram (ECG) parameters, 
ATAs, or other safety biomarkers 
 
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2.2 
PRIMARY EFFICACY OBJECTIVES 
The primary efficacy objective for this study is as follows: 
• 
To determine the time to normalization of respiratory function of patients dosed with 
MHAA4549A in combination with oseltamivir compared to patients dosed with 
placebo and oseltamivir. 
 
2.3 
SECONDARY EFFICACY OBJECTIVES 
The secondary efficacy objectives for this study are as follows: 
• 
To measure clinical failure, as defined in Section 3.3.3, after 24 hours post-infusion 
of study drug  
• 
To determine the time to clinical resolution of vital signs  
• 
To measure mortality in patients  
• 
To determine changes in the extent and duration of viral shedding in upper 
respiratory samples  
• 
To measure the duration of hospital and/or ICU stay 
• 
To measure antibiotic usage for respiratory indications  
• 
To measure the frequency and severity of the following secondary complications of 
influenza:  
o Pneumonia (hospital acquired pneumonia [HAP]/ ventilator acquired pneumonia 
[VAP]) 
o Exacerbations of chronic lung disease 
o Myocarditis 
o Acute respiratory distress syndrome (ARDS) 
o Otitis media 
o Other related complications 
o Readmission rates at 30 days after study treatment 
• 
To measure duration of PPV 
• 
To measure readmission rates 
 
2.4 
PHARMACOKINETIC OBJECTIVES  
The major PK objective for this study is as follows: 
• 
To characterize the PK profile of MHAA4549A in serum 
 
The exploratory PK objectives for this study are as follows: 
 
 
 
 
 
 
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2.5 
EXPLORATORY OBJECTIVES 
The exploratory objectives of this study are as follows: 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
3. 
STUDY DESIGN  
3.1 
DESCRIPTION OF THE STUDY 
3.1.1 
Overview of Study Design 
This is a Phase 2b, randomized, double-blind, placebo-controlled study designed to 
assess the safety and clinical activity of a single intravenous (IV) dose of MHAA4549A in 
hospitalized patients with severe influenza A in combination with oseltamivir versus a 
comparator arm of placebo with oseltamivir.  This study is planned to take place in 
approximately 170 study centers globally. 
Patients will be randomized 1:1 into two treatment groups:  a single IV dose of 3600 mg 
of MHAA4549A with oseltamivir or a single IV dose of placebo with oseltamivir.  All 
patients will receive oseltamivir, a NAI, as standard therapy for a minimum of 5 days 
after study drug administration.  Oseltamivir at doses of 75 BID or 150 mg BID is 
permitted in order to be consistent with local SOC practice.  Treatment for longer than 
5 days is permitted based on local investigator discretion.  The patient must start 
Sponsor-supplied oseltamivir within 8 hours of study drug administration.  The study has 
a planned enrollment of approximately 334 patients globally. 
Hospitalized patients with an O2 or PPV requirement will be evaluated for influenza A 
infection.  Enrollment in this study requires ongoing treatment within 24 hours of hospital 
admission with one of the following:  
• 
any PPV or  
• 
any supplemental O2 to maintain oxygen saturation (SpO2) >92% (see Section 3.3.2)   
 
Patients on PPV should not exceed 45% of the total patients enrolled. 
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A Sponsor-supplied rapid influenza test and/or a local polymerase chain reaction (PCR) 
test must be used as an aid in the diagnosis of influenza A infection.   
 
 
 
 
 
 
 
  
At the time of randomization, patients who are eligible for enrollment as described above, 
will be randomized to receive MHAA4549A at a dose of 3600 mg or placebo. Patients 
will be stratified by country, PPV versus supplemental O2 on the day of admission, and 
suspected or confirmed bacterial pneumonia versus no bacterial pneumonia based on 
the status on the day of admission. 
Eligible patients who are enrolled into the study will receive either a single IV infusion of 
MHAA4549A or a single IV infusion of placebo on Day 1.  All patients must have the 
study drug infused within 48 hours of hospital admission or sooner if possible.  All 
patients will receive oseltamivir for a minimum of 5 days (10 doses), starting on Day 1, 
beginning no later than 8 hours after study drug administration.   
All patients will be followed and evaluated at minimum on a daily basis for the duration of 
their hospital stay consistent with the planned schedule of assessments.  Any suspicion 
of bacterial superinfection should be thoroughly evaluated including microbiological 
confirmation, if possible.  A follow-up study visit should occur on Day 14 ± 1 (if 
discharged before Day 14) and Day 30 ± 4 days, if discharged before Day 30. 
A schedule of assessments is provided in Appendix 1a and Appendix 1b.  A diagram of 
the study design is presented in Figure 1.  
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Figure 1 
Phase 2b Study Design (GV29216) 
 
  
3.1.2 
Independent Data Monitoring Committee 
An iDMC, which consists of two independent physicians and one independent 
biostatistician, will review safety data of the trial to ensure the safety of the patients 
enrolled.  This should allow early detection of any potential safety concern and, thus, 
ensure the best possible protection of patients’ safety.  In addition, it includes a 
non-voting biostatistician from an independent data coordinating center (IDCC) who 
prepares the safety reports, including information on patient accrual and SAEs from the 
study.  The iDMC reviews the safety reports, addresses any safety concerns, and 
informs the Sponsor whether or not to continue the study.   
A detailed description of the procedures, data flow, and meeting schedule of the iDMC 
will be provided in a separate iDMC charter. 
3.1.3 
End of Study 
The end of study is defined as the first day when all patients have had a study 
completion visit or early termination visit or have otherwise been discontinued from the 
study. 
3.2 
RATIONALE FOR STUDY DESIGN 
3.2.1 
Rationale for Study Design 
Hospitalized influenza A infection represents a high unmet need, which, when left 
untreated, may progress to a more serious disease that may result in significant 
morbidity and mortality in otherwise healthy adults as well as in vulnerable populations.   
This study is designed to estimate the improvement in outcome of a combination 
regimen of MHAA4549A with oseltamivir compared to a SOC arm of placebo with 
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oseltamivir.  The study population will include hospitalized patients with influenza A 
requiring O2 support and/or PPV support within 24 hours of hospital admission.  
Study GV29216 will be a Phase 2b study involving approximately 334 patients.  The 
sample size was determined based on an expected clinically meaningful difference of 
1 − 2 days improvement in time to normalization of respiratory function between the 
control and treatment arms, assuming a 5-day median time to the time to normalization 
of respiratory function in the SOC arm (Blackwood 2011; PREMIER® database).   
This design ensures that all patients in the trial will receive the current NAI treatment, 
oseltamivir, as SOC at a minimum, and will evaluate the clinical benefit of combining 
MHAA4549A with this SOC regimen.  Therefore, this study aims to identify a regimen 
that could deliver maximum benefit in this high unmet need disease, while still treating all 
enrolled patients with the currently accepted SOC. 
3.2.2 
Rationale for Patient Population and Primary Endpoint 
Severe influenza, for the purpose of this study, is defined as requiring one of the 
following treatments: PPV or any supplemental O2 to maintain an SpO2 > 92%.  PPV is 
defined as any mechanical positive pressure device to maintain oxygenation; this can 
include mask ventilation and intubation.  A Sponsor-supplied rapid influenza test and/or 
a local PCR must be used as an aid in the diagnosis of influenza A infection. 
This patient population was chosen based on the rationale that respiratory failure is a 
hallmark of influenza and a major driver of morbidity and mortality, as well as 
hospitalization.  The recovery from ventilator support has been shown to be directly 
proportional to time spent in the ICU (Blackwood 2011; PREMIER® database).  Based 
upon an analysis of morbidity and mortality, the patient population that requires 
supplemental O2 or ventilation on their first day of admission was determined to have a 
high unmet medical need as they have an estimated mortality of 9%−32%, and 27% 
require admission to the ICU, according to analysis of a database of over 70,000 
hospitalized patients in the US from 2005−2012 (PREMIER® database).   
Support for use of the respiratory endpoint in this population comes from recently 
published data demonstrating that a composite endpoint that captured respiratory rate, 
fever, heart rate, and blood pressure resolution was primarily driven by the respiratory 
component of the endpoint (Marty et al. 2014).   
3.2.3 
Rationale for Control Group and Treatment Window  
In this study, the SOC regimen for the control or comparator group is oseltamivir, an NAI.  
In the treatment groups, MHAA4549A will be dosed in addition to an oseltamivir SOC 
regimen.  The oseltamivir dose will be consistent with the local investigator practice at 
each site where the study will be conducted.  Either 75 mg or 150 mg orally BID 
oseltamivir for a minimum of 5 days is permitted following treatment with MHAA4549A.  
Treatment for longer than 5 days is permitted based on local investigator discretion.  The 
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oseltamivir dosing regimen, including the renal dosing adjustment, is listed in Table 2.  
This control treatment was based on consideration of safety, ethics, and efficacy for 
treatment of severe influenza and is consistent with guidelines for antiviral treatment of 
hospitalized patients with influenza (Harper et al. 2009, Fiore 2011). 
Table 2 
Oseltamivir Dosing Regimen 
Neuraminidase Inhibitor 
Dosing Regimen 
Duration of 
Therapy 
Oseltamivir  
75 mg or 150 mg orally BID a 
75 mg oral once daily for adult patients with 
creatinine clearance (CrCL) between  
10 and 30 mL/minb 
5 days c 
a 75 mg or 150 mg dose at the discretion of the investigator, and dose must be documented.  
Capsules can be opened and the granules administered via nasogastric tube, if required. 
b No recommended dosing regimens are available for patients with end-stage renal disease 
undergoing routine hemodialysis or continuous peritoneal dialysis treatment. 
c Longer treatment times are at the discretion of the investigator. 
  
From a safety standpoint there are no expected drug interactions between MHAA4549A, 
a monoclonal antibody, and any NAI, which are small molecule drugs that bind to a 
different viral protein than MHAA4549A.  In the Phase 2a challenge study, all subjects 
that were dosed with MHAA4549A also received a 5-day course of oseltamivir starting 
on Day 7.  There were no safety effects attributable to the combination when the drugs 
were present concurrently.  The pharmacokinetics of oseltamivir and its potential 
interaction with MHAA4549A are being assessed from this Phase 2a. 
For this Phase 2b study, a combination of MHAA4549A and oseltamivir was determined 
to be the most clinically feasible treatment regimen, both from an ethical as well as a 
practical perspective.  The treatment of all patients with oseltamivir ensures that all 
patients will receive SOC given the high morbidity and mortality of hospitalized patients 
with influenza A along with guidelines from Centers for Disease Control and Prevention 
(CDC) and Infectious Diseases Society of America (IDSA) stating NAIs are the SOC for 
hospitalized patients with influenza A (Harper et al. 2009 and CDC Website).  Further, 
pre-clinical efficacy data from a study using MHAA4549A and oseltamivir in combination, 
showed a potential synergistic effect of both compounds which may be due to the 
different and potentially complementary mechanisms of action, i.e. targeting viral 
hemagglutinin and neuramindase. 
Dosing of MHAA4549A is confined to a treatment window designed for best expected 
treatment success and to ensure that any observed effects can be attributed to the study 
drug with high confidence.  MHAA4549A shall only be dosed within 5 days of symptom 
onset, within 3 days of initial treatment with a NAI, and no later than 48 hours after 
admission to the hospital.  This proposed window is supported by data demonstrating 
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that hospitalized influenza patients benefit from NAI treatment even at 5 days from 
symptom onset (Louie et al. 2012).  
3.2.4 
Rationale for MHAA4549A Dosage 
A single IV dose of 3600 mg of MHAA4549A was selected to assess the efficacy of 
MHAA4549A and to provide data for further clinical development.  The selection of dose 
in this study for severely ill patients was based on the observed human 
pharmacokinetics in Phase 1 and the relationship between the pharmacokinetics, 
pharmacodynamics, and efficacy observed in a Phase 2a human challenge model of 
influenza.  The dose is adequately supported by safety data from the completed Phase 1 
study and ongoing Phase 2a study in healthy volunteers, which has completed dosing.  
MHAA4549A was shown to be safe and well-tolerated at all dose levels (ranging from 
1.5 mg/kg to 45 mg/kg for Phase 1 and 400-3600 mg for Phase 2a) through a follow-up 
period of 120 days post-dose in the Phase 1 study.  The dose level used in this study 
was determined following an interim analysis of the 1200-mg and 3600-mg doses in the 
Phase 2a study, GV28985, which demonstrated the following: 
• 
The 3600-mg dose demonstrated a significant decrease in viral shedding in upper 
respiratory samples.  Based on current interim analysis data, there was a 97.5% 
(p = 0.0092) decrease in AUEC and a 77.3% decrease in peak viral load by qPCR 
measurement compared to the placebo group.   
• 
The 1200-mg dose level was not efficacious. 
• 
There are no safety concerns at the 3600-mg dose level to date. 
• 
Hospitalized patients generally have a longer duration of viral shedding and 
significantly more viral burden in the lower lung compartments; therefore, high 
concentrations of mAb are likely needed to achieve sufficient occupancy of the virus 
binding sites in the upper and lower respiratory compartments.  Furthermore, higher 
concentrations of mAb are necessary to mitigate the risk of resistance for 
MHAA4549A and neuramindase inhibitors such as oseltamivir. 
 
The Phase 1 study was conducted using body-weight based dosing followed by a fixed 
dosing strategy that was used in the Phase 2 study.  Thus, the fixed dosing regimen that 
was used in the Phase 2a study will be used for this study, given the practical 
advantages and positive safety profile of MHAA4549A to date.  Further, fixed dosing is 
generally recommended with monoclonal antibodies, due to their minimal PK variability 
(Bai et al. 2012).  The PK variability introduced by different dosing regimens (i.e., 
body-weight based dosing versus fixed dosing) is moderate relative to the variability 
generally observed in pharmacodynamics, efficacy, and safety and would not be 
expected to be clinically meaningful.   
3.2.5 
Rationale for Biomarker Assessments  
 
 
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3.3 
OUTCOME MEASURES  
3.3.1 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
Adverse events and clinical laboratory abnormalities  
• 
Vital signs, physical findings, ATAs, and clinical laboratory results during 
and following administration of MHAA4549A 
 
3.3.2 
Primary Efficacy Outcome Measure 
The primary outcome measure for this study is as follows: 
• 
Time to normalization of respiratory function defined as: 
− 
The time to cessation of O2 support resulting in a stable SpO2 >95% for at least 
24 hours (see Appendix 2 for details) 
 
3.3.3 
Secondary Efficacy Outcome Measures 
The secondary efficacy outcome measures for this study are as follows: 
• 
Clinical failure 24 hours post-infusion of study drug; defined as: 
− 
Progression to increased O2 requirement defined by an increase in oxygen 
supplementation from low flow oxygen (2 − 6 L/min) to high flow oxygen 
( > 6 L/min) or from oxygen supplementation alone to any PPV 
− 
Progression to ICU 
− 
Prolonged ventilation or O2 support defined by  > 2 weeks, or 
− 
Death 
• 
Time to clinical normalization of vital signs (3/5 criteria must be met): 
− 
SpO2 > 95% without supplemental O2 for at least 24 hours  
− 
Respiratory rate < 24 without supplemental O2 for at least 24 hours 
− 
Core temperature < 37.2°C immediately prior to receipt of any antipyretic drug, 
and at least 6-8 hours from the last dose of antipyretic or core temperature 
> 36°C in patients who are initially hypothermic 
− 
Heart rate (HR) < 100/minute 
− 
Systolic blood pressure (SBP) > 90 mmHg 
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• 
All-cause mortality at Day 14 and Day 30 
• 
Influenza A viral load in nasopharyngeal samples   
− 
AUEC 
− 
Peak viral load 
− 
Time to resolution of infection  
• 
Duration of hospitalization 
• 
Duration of ICU stay 
• 
Antibiotic usage for respiratory infections 
• 
Complications of influenza: 
− 
Pneumonia (HAP/VAP) 
− 
Exacerbations of chronic lung disease 
− 
Myocarditis 
− 
ARDS 
− 
Otitis media 
− 
Other related complications 
• 
All-cause readmission at Day 30 
• 
Duration of ventilation 
 
3.3.4 
Pharmacokinetic Outcome Measures  
The primary PK outcome measures for this study are as follows: 
• 
PK parameters for MHAA4549A in serum including total exposure (i.e., AUC), 
maximum observed concentration (Cmax), clearance, half-life, and volume of 
distribution, when appropriate, as data allow   
The exploratory PK outcome measures for this study are as follows: 
 
 
 
 
 
 
 
 
3.3.5 
Exploratory Outcome Measures  
 
 
 
 
 
 
 
  
 
 
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4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
This study aims to enroll approximately 334 men and women and is designed to assess 
the safety and clinical activity of a single IV administration of MHAA4549A in adult 
patients hospitalized with severe influenza A.   
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Hospitalized men or women ≥ 18 years of age on the day of signing the informed 
consent or obtaining surrogate consent from an authorized representative 
• 
Diagnosis of influenza A as determined by the Sponsored-supplied rapid influenza 
test 
− 
If negative rapid influenza A test, a positive local molecular test (PCR) is 
required  
• 
One of the following markers of severity within 24 hours of hospital admission: 
− 
Requirement for PPV  − or −  
− 
Requirement for O2 supplementation to maintain SpO2 > 92% 
• 
A negative urine or serum pregnancy test for women of child-bearing potential 
• 
Patients of reproductive potential must agree to use reliable means of contraception 
as described below as a minimum (adherence to more stringent local requirements 
may be required): 
− 
For female patients:  Use of two acceptable methods of contraception 
throughout the trial, including the active treatment phase AND for 24 weeks after 
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the last dose of MHAA4549A.  Acceptable methods of contraception 
include:  intrauterine device, systemic hormonal contraception (oral or depot), 
vaginal ring, tubal ligation of the female partner, vasectomy of the male partner, 
use of latex condoms plus spermicide by the male partner, or cervical cap plus 
spermicide (where the spermicide could be foam, vaginal suppository, gel, 
cream, etc.). 
− 
For male patients:  Use of condoms for 30 days after dosing when circulating 
drug levels remain high. 
− 
Non-reproductive potential is defined below (but could be superseded by local 
definitions, if they are more stringent): 
Women who are postmenopausal (i.e., spontaneous amenorrhea for the past 
year confirmed by an FSH level greater than 40 mIU/mL unless the patient is 
receiving a hormonal therapy for their menopause)  
Women who are surgically sterile (i.e., hysterectomy, complete bilateral 
oophorectomy) 
Men who are surgically sterile (castration) 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Pregnant or lactating or intending to become pregnant during the study 
− 
Women who are not postmenopausal (≥ 12 months of non-therapy-induced 
amenorrhea) or who are not surgically sterile must have a negative urine or 
serum pregnancy test result within 2 days prior to study treatment. 
• 
Hypersensitivity to mABs or any constituents of study drug 
• 
Investigational therapy within the 30 days prior to study treatment  
• 
Received prior therapy with any anti-influenza monoclonal antibody therapy 
including MHAA4549A 8 months prior to study treatment 
• 
Current treatment (within 7 days of dosing) with amantadine or rimantidine 
• 
Patients who have taken more than a total of 3 days (6 doses) of approved 
anti-influenza therapy (e.g., oral oseltamivir, inhaled zanamivir, or oral ribavirin) in 
the period from onset of symptoms and prior to enrollment 
• 
Admission > 48 hours prior to study treatment 
• 
Onset of influenza symptoms > 5 days prior to study treatment 
• 
Positive influenza B or influenza A + B infection within 2 weeks prior to study 
treatment 
• 
High probability of mortality in the next 48 hours as determined by the investigator  
• 
Patient requiring home or baseline oxygenation therapy 
• 
Patient with history of chronic lung disease resulting in baseline SpO2 < 95%  
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• 
Patient on a chronic dose of corticosteroids exceeding 10 mg/day of prednisone or 
equivalent steroid dose for a duration of greater than 14 days within 30 days of entry 
into study 
• 
Patients with the following significant immune suppression:  
− 
Bone marrow or solid organ transplant in the previous 12 months 
− 
Cancer chemotherapy in the previous 12 month 
− 
HIV infection with most recent CD4 < 200 cells/mL 
− 
Other significant immune suppression as determined by the investigator in 
discussion with the Sponsor Medical Monitor or representative 
• 
Patient on extracorporeal membrane oxygenation (ECMO) at time of randomization 
• 
Any disease or condition that would, in the opinion of the site investigator or 
Sponsor, place the subject at an unacceptable risk of injury or render the subject 
unable to meet the requirements of the protocol 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
The randomization of patients will be managed by a central Interactive Voice and Web 
Response System (IxRS).  All patients will be randomly assigned to receive either 
MHAA4549A 3600 mg or placebo at a 1:1 ratio stratified by country, whether patient is 
on PPV vs supplemental O2 on the day of admission, and whether the patient has 
suspected or confirmed bacterial pneumonia vs no bacterial pneumonia on the day of 
admission.  All patients will receive oseltamivir (75 mg or 150 mg BID) for a minimum of 
5 days.  Treatment for longer than 5 days is permitted based on local investigator 
discretion. 
The treatment assignments will be unblinded to an external IDCC to facilitate the iDMC 
assessment of safety.  
Blinded personnel at each study site will make appropriate preparations and perform the 
IV infusions of study drug, as described in Section 4.3.3.  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.  
Bioanalytical laboratory 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 (e.g., to evaluate a possible error in study drug administration). 
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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 in IxRS.  
Treatment codes should not be broken except in emergency situations.  If the 
investigator wishes to know the identity of the study drug for any other reason, they 
should 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 suspected unexpected serious adverse 
reactions (SUSAR)(see Section 5.6) that are considered by the investigator or Sponsor 
to be related to study drug. 
4.3 
STUDY TREATMENT  
4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
MHAA4549A and Placebo 
MHAA4549A, matching placebo, and up to 10-day supply of oseltamivir (Tamiflu®) will 
be supplied by the Sponsor.  For information on the formulation, packaging, and 
handling of MHAA4549A and placebo; see the Pharmacy Manual and the 
MHAA4549A Investigator's Brochure. 
The MHAA4549A vial delivers 10 mL (500 mg) of drug product solution, but may contain 
more (approximately 10.3 mL) than the stated volume to enable delivery of the entire 
10 mL volume.  MHAA4549A is formulated as 50 mg/mL in 10 mM sodium succinate, 
240 mM sucrose, and 0.02% (w/v) polysorbate 20 at pH 5.5 and is contained in a 15 mL 
forma vitrum (USP/PH. Eur. Type 1) glass vial.  The drug product is suitable for single 
use only and contains no preservatives. 
Placebo for MHAA4549A has the same composition as the drug product (without 
MHAA4549A) and is supplied in an identical vial configuration.  The placebo contains no 
preservatives and is suitable for single-use only.  Placebo is formulated as 10 mM 
sodium succinate, 240 mM sucrose, and 0.02% polysorbate 20 at pH 5.5 in a total 
volume of 10 mL in a 15 mL forma vitrum (USP/PH. Eur. Type 1) glass vial. 
MHAA4549A and placebo are supplied in identical blinded vials labeled with unique kit 
numbers.  IxRS will assign kit numbers for each treatment arm; all treatment arms will be 
assigned the same total number of vials for each treatment, and the same preparation 
instructions.  Placebo is identical to active MHAA4549A in formulation and appearance 
but does not contain active drug substance. 
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4.3.1.2 
Oseltamivir (Tamiflu) 
Oseltamivir (Tamiflu) is an influenza NAI indicated for treatment of acute, uncomplicated 
influenza.  For information on the formulation, packaging, and handling of oseltamivir; 
see the local prescribing information for oseltamivir. 
Storage: Capsules should be stored at 25°C (77.7°F); excursions permitted to 15° to 
30°C (59° to 86°F). 
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 3600 mg IV 
or placebo IV at a 1:1 ratio.  Oseltamivir will be dispensed via IxRS.  Oseltamivir dosing 
is described in Table 2.  
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 will be on site during study drug administration for all 
patients. 
A single dose of MHAA4549A or placebo will be delivered by IV infusion following 
dilution in 0.9% normal saline over approximately 60 minutes.  Study drug should be 
delivered using a 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 for 
preparation of study drug can be found in the Pharmacy Manual.   
There are no recommended dosage modifications for MHAA4549A since it is a single 
infusion.  Any overdose or incorrect administration of study drug should be noted on the 
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 AEs associated with overdose.  Patients experiencing such AEs 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.  
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4.3.2.2 
Oseltamivir-Neuraminidase Inhibitor (NAI)  
The Sponsor will be providing oseltamivir (Tamiflu®) for this study for up to a 10-day 
course.  Dosage and administration should follow local prescribing information for 
oseltamivir.  Either 75 mg or 150 mg of oseltamivir will be administered twice daily as 
described in Table 2.  Capsules can be opened and the granules administered via 
nasogastric tube, if required.  
Guidelines for dosage modification for renal dosing are presented in Table 2 . 
Any overdose or incorrect administration of oseltamivir should be noted on the 
oseltamivir Administration eCRF.  Adverse events associated with an overdose or 
incorrect administration of oseltamivir should be recorded on the Adverse Event eCRF. 
4.3.3 
Investigational Medicinal Product Accountability 
Investigational medicinal products (IMPs) required for completion of this study (i.e., 
MHAA4549A and oseltamivir) 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 to 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 to 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. 
The total duration from the preparation of dose solutions to the end of infusion should 
not exceed 24 hours.  Vials are intended for single use only; therefore, any remaining 
solution should be discarded (see the Pharmacy Manual).  
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 or their delegate 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. 
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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. 
4.4 
POST-TRIAL ACCESS TO MHAA4549A 
As this is single dose administration, Genentech 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. 
4.5 
CONCOMITANT THERAPY AND FOOD 
4.5.1 
Permitted Therapy  
Concomitant medication 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 concomitant medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF.  For any NAIs (e.g., oseltamivir, peramivir, zanamivir, 
laninimavir) that have been taken prior to study drug therapy, the number of doses and 
duration of therapy must be recorded. 
Patients who use oral contraceptives, hormone-replacement therapy, or other 
maintenance therapy should continue their use. 
All therapies required for management of the patient’s acute illness are permitted except 
for those listed below in Section 4.5.2. 
4.5.2 
Prohibited Therapy 
Use of the following therapies is prohibited during the study and for at least 7 days prior 
to study treatment, unless otherwise specified below:  probenecid, amantadine, or 
rimantidine 
Use of other NAIs, including but not limited to oral oseltamivir, inhaled zanamivir, oral 
ribavirin, laninimivir, and peramivir, are prohibited during the study, but allowed up to 
3 days (6 doses) prior to study treatment as outlined in the exclusion criteria.  If 
oseltamivir resistance is highly suspected or identified during treatment then, following 
discussion with the sponsor medical representative, an alternative NAI to oseltamivir 
may be used. 
4.5.3 
Prohibited Food  
There are no prohibited foods for this study.  
4.6 
STUDY ASSESSMENTS  
Please see Appendix 1a and Appendix 1b for the schedule of assessments performed 
during the study. 
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4.6.1 
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.  Informed consent by 
authorized representatives may be obtained only if allowed by and in accordance with 
local regulations and Independent Review Board (IRB)/Independent Ethics Committee 
(IEC) policies and procedures.  Informed Consent Forms (ICF) 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. 
4.6.2 
Diagnostic Testing for Enrollment 
All hospitalized patients with severe influenza A will be assessed for disease 
confirmation and enrollment into the study.  A Sponsor-supplied rapid influenza test is 
required for the diagnosis of influenza A infection and uses an nasopharyngeal swab.  
When the Sponsor-supplied rapid influenza test is negative, the study inclusion criteria 
can be satisfied with a positive local molecular test (PCR) if the result is within the 
48-hour screening window.  Other tests may not be used for enrollment in the study 
unless the Sponsor has reviewed and approved the use of the diagnostic. 
4.6.3 
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.  A careful assessment of the patient’s baseline SpO2 should be 
made especially if the patient has a history of severe chronic lung disease. 
Demographic data will include age, sex, and self-reported race/ethnicity. 
4.6.4 
Priority of Assessments 
When events warrant, or in the opinion of the investigator, safety issues become 
paramount, safety assessments will always have priority over all other measurements 
and procedures.  Under routine circumstances, however, PK, nasal virological, and 
biomarker serum/plasma samples have priority over other measurements.  The timing 
and number of safety measurements may be modified based on clinical evaluations. 
4.6.5 
Physical Examinations 
A complete physical examination should include an evaluation of the head, eyes, ears, 
nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
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gastrointestinal, genitourinary, and neurological systems.  Any abnormality identified at 
baseline should be recorded on the General Medical History and Baseline Conditions 
eCRF. 
At protocol designated visits (or as clinically indicated), limited, symptom-directed 
physical examinations should be performed which 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, if appropriate, on the AE 
eCRF. 
4.6.6 
Vital Signs  
Vital signs will include measurements of resting SpO2 (see Section 4.6.7 for 
measurement), respiratory rate, pulse rate, temperature, and systolic and diastolic blood 
pressures after the patient has been in a seated or supine position for at least 
10 minutes.  Patients in intensive care may have vital signs assessed following local 
procedures, but those procedures should be captured in the eCRF in accordance with 
the eCRF instructions.  
4.6.7 
Oxygen Saturation Measurements 
To ensure that the respiratory status is well recorded, the following daily measurements 
will be performed.  Unless clinically contraindicated, all patients will have their SpO2 
recorded daily in the morning between 4 am − 10 am local time.  Patients on low-flow O2 
will have a daily trial of their SpO2 while on and off the supplementation, as outlined in 
Appendix 2, and both values will be recorded.   
4.6.8 
Laboratory, Biomarker, and Other Biological Samples  
Samples for the laboratory tests listed in Table 3 and Table 4 will be sent to the study 
site's local laboratory for analysis at screening and during the study, respectively. 
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Table 3 
Laboratory Tests at Screening 
Hematology: 
Serum Chemistry: 
Hemoglobin 
Sodium 
Hematocrit 
Potassium 
Erythrocyte count (RBC) 
Bicarbonate 
Leukocytes (WBC) 
Chloride 
Neutrophils, segmented 
Calcium 
Lymphocytes 
Phosphorus 
Monocytes 
Magnesium 
Eosinophils 
Glucose (fasting) 
Basophils 
Urea nitrogen (BUN) 
Platelets 
Creatinine 
 
Total cholesterol 
Coagulation: 
Total protein 
Activated partial thromboplastin time (APTT)
Albumin 
Prothrombin time (PT) 
Total bilirubin 
International Normalized Ratio (INR) 
Alkaline phosphatase 
 
Aspartate aminotransferase (AST) 
Urine Chemistry: 
Alanine aminotransferase (ALT) 
pH 
Amylase 
Specific gravity 
 
Glucose 
Serology: 
Creatinine 
HIV Serology 
Total protein to creatinine ratio 
 
Albumin 
Misc: 
Ketones 
Thyroid stimulating hormone (optional) 
Occult blood 
Pregnancy Test (urine or serum; women of 
child-bearing potential) 
Bilirubin 
Urobilinogen 
 
Nitrite 
 
Leukocyte esterase 
 
Microscopic examination (if clinically indicated) 
Note:  Investigators must document their review of each laboratory report by signing (or 
nitialing) and dating each report. 
i  
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Table 4 
Laboratory Tests During the Study 
Hematology: 
Clinical Chemistry (Blood):  
Hemoglobin 
Sodium 
Hematocrit 
Potassium 
Erythrocyte count (RBC) 
Bicarbonate 
Leukocytes (WBC) 
Chloride 
Neutrophils, segmented 
Calcium 
Lymphocytes 
Phosphorus 
Monocytes 
Magnesium 
Eosinophils 
Glucose (random) 
Basophils 
Urea nitrogen (BUN) 
Platelets 
Creatinine 
Erythrocyte Sedimentation Rate (ESR) 
Total cholesterol 
 
Total protein 
Coagulation:  
Albumin 
Activated partial thromboplastin time (APTT) 
Total bilirubin 
Prothrombin time (PT) 
Alkaline phosphatase 
International Normalized Ratio (INR) 
Aspartate aminotransferase (AST) 
 
Alanine aminotransferase (ALT) 
Urine Chemistry: 
Amylase 
pH 
Gamma-glutamyl transpeptidase (GGT) 
 (if clinically indicated) 
Specific gravity 
 
Glucose 
Misc:  
Creatinine 
C-reactive protein (CRP) 
Total protein to creatinine ratio 
Pregnancy Test (if clinically indicated) 
Albumin 
 
Ketones 
 
Occult blood 
 
Bilirubin 
 
Urobilinogen 
 
Nitrite 
 
Leukocyte esterase 
 
Microscopic examination (if clinically indicated) 
Note:  Investigators must document their review of each laboratory report by signing (or initialing) 
g each report. 
and datin
  
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The following samples will be sent to the Sponsor or a designee for PK or ATA analysis: 
• 
 
 
 
  
 
  
 
 
   
 
 
 
 
   
 
 
 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.   
4.6.9 
Electrocardiograms 
Single ECG recordings will be obtained at specified timepoints, as outlined in the 
schedule of assessments (see Appendix 1a and Appendix 1b), 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 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 QTcF 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. 
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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 QT interval corrected using 
Fridericia’s formula (QTcF) has stabilized on two successive ECGs.  The Medical 
Monitor should be notified.  SOC 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 4.8.2.  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). 
4.6.10 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
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4.7 
APACHE AND SOFA SCORES 
Acute Physiology and Chronic Health Evaluation (APACHE) and Sequential Organ 
Failure Assessment (SOFA) scores are for patients that are admitted into the ICU.  
These assessments are not required for study conduct or entry but should be collected if 
available.  The initial scores for APACHE and SOFA should be taken within 24 hours of 
entry into the ICU and at specified time points as seen in Appendix 1a. 
For the calculation of the initial APACHE and SOFA scores, the worst values in the first 
24 hours of ICU admission should be used.  SOFA scores are only for patients admitted 
into the ICU that have available data for calculation (i.e., particle pressure of 
oxygen/fraction of inspired oxygen [PaO2/FiO2] in mmHg).  See Appendix 7 for SOFA 
score calculation. 
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4.8 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
4.8.1 
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 or 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 from the study will not be replaced. 
4.8.2 
Study Treatment Discontinuation 
Patients must discontinue MHAA4549A infusion and therefore treatment if they 
experience any of the following: 
• 
Infusion related reactions 
Patients must discontinue oseltamivir treatment if they experience any of the following: 
• 
Pregnancy 
• 
Serious skin/hypersensitivity reactions 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.   
4.8.3 
Study Completion/Early Discontinuation Visit 
Patients who complete all study visits through Day 30 are considered to have completed 
study.  All patients who choose to discontinue from study early will be asked to complete 
the early discontinuation visit.  Please see Schedule of Assessments provided in 
Appendix 1a for assessments performed at the Study Completion/Early Discontinuation 
visit. 
4.8.4 
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.   
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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 (GCP) 
• 
No further study activity (i.e., all patients have completed and all obligations have 
been fulfilled) 
 
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 (interim) studies and is 
designed to ensure patient safety.  It will include specific eligibility criteria and monitoring 
assessments as detailed below and above in Section 4.1. 
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. 
During the study, the incidence and nature of adverse events, serious adverse events, 
and laboratory abnormalities will be assessed.  An ongoing review of safety will be 
performed by an internal Genentech Safety Review Committee, composed of the 
Medical Monitor, a drug safety scientist, and a biostatistician.  External experts may be 
consulted as appropriate.  An unblinded review of safety will be performed by an iDMC 
as described in Section 4.2 and the iDMC charter.   
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and non-serious adverse events of special interest; 
measurement of protocol-specified safety laboratory assessments; measurement of 
protocol-specified vital signs; and 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 GCP, an adverse event is any untoward medical 
occurrence in a clinical investigation patient 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 5.3.5.9. 
• 
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 30 
or Early Discontinuation).  If clinically significant signs or laboratory values are observed 
in a study participant, the investigator should repeat an assessment at the earliest 
opportunity.  Only those events or laboratory values that exceed the level of clinical 
significance upon the repeat assessment will be considered an adverse event. 
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: 
• 
Fatal (i.e., the adverse event actually causes or leads to death) 
• 
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 5.3.5.10) 
• 
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) 
• 
Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
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• 
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 
listed above) 
 
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 Division of 
AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS); see 
Section 5.3.3, Appendix 8, and Appendix 9); 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 
Non-Serious Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) 
Non-serious adverse events of special interest (AESI) 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 5.3.5.6) 
• 
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 AEs associated with IRR, 
see Section 5.3.5.1 below): 
− 
Fever and/or shaking chills 
− 
Flushing and/or itching 
− 
Alterations in heart rate and blood pressure 
− 
Dyspnea or chest discomfort 
− 
Back or abdominal pain 
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− 
Nausea, vomiting, and/or diarrhea 
− 
Various types of skin rashes 
− 
Anaphylaxis 
• 
Anaphylaxis due to IV drugs most often presents with the following signs and 
symptoms:   
− 
Cutaneous symptoms: flushing, itching, urticaria, 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: such as 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 Section 5.4 − 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, regardless of relationship to study 
drug, will be reported until the Day 30 visit or Early Discontinuation visit.  After this period, 
the investigator is not required to actively monitor patients for adverse events; however, 
the Sponsor should be notified if the investigator becomes aware of any death or other 
serious adverse event that occurs after discharge, regardless of causality.  The Sponsor 
should also be notified if the investigator becomes aware of a congenital anomaly/birth 
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defect in a subsequently conceived offspring of a female patient exposed to study drug 
(see Section 5.6). 
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 AEs, and SAEs, 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 
AE severity (see Table 5). 
Table 5 
Adverse Event Grading (Severity) Scale 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
ESTIMATING SEVERITY GRADE 
Clinical AE 
NOT identified 
elsewhere in 
this DAIDS AE 
Grading Table  
Symptoms 
causing no or 
minimal 
interference with 
usual social and 
functional 
activities 
Symptoms 
causing greater 
than minimal 
interference with 
usual social & 
functional 
activities 
Symptoms 
causing inability 
to perform usual 
social & 
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 
 
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 or 
not 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 6): 
• 
Temporal relationship of event onset to the initiation of study drug 
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• 
Course of the event, considering especially 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 6 
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., chronic obstructive pulmonary 
disease [COPD] diagnosed 2 days after first dose of study drug). 
 
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
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 
Diagnosis versus Signs and Symptoms 
Infusion-Related Reactions  
Adverse events that occur during or within 24 hours after study drug infusion should be 
captured as individual signs and symptoms rather than a diagnosis of allergic reaction or 
infusion reaction. 
Other Adverse Events 
For adverse events other than infusion-related reactions, 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 
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transaminases).  However, if a constellation of signs 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. 
5.3.5.2 
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. 
5.3.5.3 
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.  If a persistent adverse event 
becomes more severe, it should be recorded 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 event became more severe.  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; see Section 5.4.2 for reporting 
instructions).  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 event became 
serious. 
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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. 
5.3.5.4 
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 meets any of the following criteria: 
• 
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 
• 
Clinically significant in the investigator’s judgment (laboratory abnormalities should 
be repeated at the first opportunity and only considered clinically significant if they 
persist on repeat assessment) 
 
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. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 × upper limit of normal [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 not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 
5.3.5.5 
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 meets any of the following criteria: 
• 
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 
• 
Clinically significant in the investigator’s judgment.  Abnormal vital sign values 
should be repeated at the first opportunity and only considered clinically significant if 
they persist on repeat assessment) 
 
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 not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 
5.3.5.6 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × baseline value) 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.  
Therefore, investigators must report as an adverse event the occurrence of either of the 
following: 
• 
Treatment-emergent ALT or AST > 3 × baseline value in combination with total 
bilirubin > 2 × ULN (of which 35% is direct bilirubin) 
• 
Treatment-emergent ALT or AST > 3 × baseline value 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 a non-serious adverse event of special 
interest (see Section 5.4.2). 
5.3.5.7 
Deaths 
For this protocol, mortality is an efficacy endpoint.  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 severe influenza or any related co-morbidities 
should be recorded on the Study Completion/Early Discontinuation eCRF.  All other 
on-study deaths, regardless of relationship to study drug, must be recorded on the 
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Adverse Event eCRF, and immediately reported to the Sponsor as an SAE (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 
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. 
5.3.5.8 
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.  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"). 
5.3.5.9 
Lack of Efficacy or Worsening of Influenza A Infection 
Medical occurrences or symptoms of deterioration that are anticipated as part of 
influenza A should only 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 "). 
5.3.5.10 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization following initial discharge (i.e., in-patient 
admission to a hospital) or prolonged hospitalization (after the current study 
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 
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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 that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
5.3.5.11 
Adverse Events Associated with an Overdose 
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 serious 
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 clinical 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. 
5.4 
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 
• 
Non-serious adverse events of special interest 
• 
Pregnancies 
 
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 
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• 
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 IRB/IEC. 
5.4.1 
Emergency Medical Contacts 
Medical Monitor Contact Information  
 Medical Monitor contact information: 
Primary Medical Monitor: 
 
Telephone Nos.: 
US Office: 
 
 
US Mobile: 
 
 
Secondary Medical Monitor: 
  
Telephone Nos.: 
US Office: 
 
 
US Mobile: 
 
 
Genentech Medical Monitor contact information for all sites if above medical monitor 
cannot be reached: 
Medical Monitor: 
 
Telephone Nos.: 
US Mobile
 
 
US Office 
 
 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Non-Serious 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.  
A paper Serious Adverse Event Reporting Form and fax cover sheet should be 
completed and faxed to the Sponsor's Safety Risk Management department or its 
designee immediately (i.e., no more than 24 hours after learning of the event), using the 
fax numbers provided below per region: 
Asia Pacific: 
 
Europe: 
Latin America: 
North America:  
 
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5.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events and non-serious adverse events of 
special interest will be reported until the patient is at Day 30 or Early Discontinuation.  
Although the investigator is not required to actively monitor patients for adverse events 
after the patient has been discharged from the study, the Sponsor should be notified if 
the investigator becomes aware of any death or other serious adverse event that occurs 
after discharge, regardless of causality.  The Sponsor should also be notified if the 
investigator becomes aware of a congenital anomaly/birth defect in a subsequently 
conceived offspring of a female patient exposed to study drug (see Section 5.4.3).   
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, a paper Serious Adverse Event 
Reporting Form and fax cover sheet should be completed and faxed to Safety Risk 
Management or its designee immediately (i.e., no more than 24 hours after learning of 
the event), using the fax numbers provided to investigators (see fax numbers 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 after the last 
dose of study drug.  A Pregnancy Report eCRF should be completed by the investigator 
immediately (i.e., no more than 24 hours after learning of the pregnancy) and submitted 
via the EDC system.  A pregnancy report will automatically be generated and sent to 
Safety Risk Management.  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 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 the event that the EDC system is unavailable, a paper Clinical Trial Pregnancy 
Reporting Form and fax cover sheet should be completed and faxed to Safety Risk 
Management or its designee immediately (i.e., no more than 24 hours after learning of 
the pregnancy), using the fax numbers provided to investigators (see fax numbers 
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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. 
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 within 30 days after the dose of 
study drug.  A Pregnancy Report eCRF should be completed by the investigator 
immediately (i.e., no more than 24 hours after learning of the pregnancy) and submitted 
via the EDC system.  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.  Once the 
authorization has been signed, the investigator will update the Pregnancy Report eCRF 
with additional information on the course and outcome of the pregnancy.  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. 
In the event that the EDC system is unavailable, follow reporting instructions provided in 
Section 5.4.3.1. 
5.4.3.3 
Congenital Anomalies/Birth Defects and Abortions 
Any congenital anomaly/birth defect in a child born to a female patient or 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).  
5.4.4 
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. 
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.  If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF and the 
Investigator document a discharge plan.  
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All pregnancies reported during the study should be followed until pregnancy outcome.  
If the EDC system is not available at the time of pregnancy outcome, follow reporting 
instructions provided in Section 5.4.3.1. 
5.4.5 
Sponsor Follow-Up 
For serious adverse events, non-serious 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. 
5.5 
POSTSTUDY ADVERSE EVENTS 
At the time of study completion or study discontinuation, the investigator should instruct 
each patient to report to the investigator any subsequent adverse events that the patient 
or their personal physician believes could be related to prior study drug treatment or 
study procedures.   
The investigator is not required to actively monitor patients for adverse events after the 
end of the adverse event reporting period (defined as 30 days after the dose of study 
drug).  However, the Sponsor should be notified if the investigator becomes aware of 
any death, other serious adverse event, or non-serious adverse event of special interest 
occurring after the end of the adverse event reporting period, regardless of causality.  
The Sponsor should also be notified if the investigator becomes aware of the 
development of cancer or a congenital anomaly/birth defect in a subsequently conceived 
offspring of a female patient or a female partner of a male patient exposed to study drug. 
The investigator should report these events by completing and faxing a paper Serious 
Adverse Event Reporting Form and fax cover sheet to Safety Risk Management using 
the fax numbers provided to investigators (see Section 5.4.2.1). 
5.6 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events including suspected 
unexpected serious adverse reactions (SUSARs) and non-serious adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, IECs, 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 documents: 
• 
MHAA4549A Investigator's Brochure 
• 
Local prescribing information for oseltamivir 
 
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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. 
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: 
• 
Elevations of ALT, AST, and or amylase that have been shown to be increased 
during influenza A infection (Polakos 2006) 
• 
Influenza associated disease and or complications of influenza 
 
An iDMC 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 
All 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: 
• 
Randomized patients who have confirmed influenza A infection as confirmed by a 
central PCR test from Day 1 samples 
 
Safety analyses will include all patients who were included in the randomization and who 
received at least one dose of study medication, with patients allocated to the treatment 
arm associated with the regimen actually received.  
No formal hypothesis testing will be done in this study.  As a result, no adjustment for 
a type 1 error will be made to account for the multiplicity of analyses. 
Final efficacy and safety analyses of the total study population will be conducted at the 
end of the study after all patients have completed all study assessments and the 
database has been cleaned and closed.  Further details of the analyses, including 
analysis of the exploratory endpoints, will be contained in the statistical analysis plan 
(SAP) which will be prepared and finalized before the optional interim analysis (see 
Section 6.7) or the final efficacy and safety analysis, if no interim analysis takes place.   
6.1 
DETERMINATION OF SAMPLE SIZE 
The purpose of this study is estimation of the effect size and hypothesis generation 
regarding the effect of MHAA4549A on the time to normalization of respiratory function 
relative to the standard of care rather than hypothesis testing.  Point and interval 
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estimates will be obtained.  A total of 334 patients will be enrolled in this study in order to 
obtain approximately 300 evaluable patients (an estimated dropout rate of 10%).  It is 
assumed that the median time to normalization of respiratory function in the control arm 
is 5 days.  Operating characteristics (power) for true differences of 1 to 2 days are 
provided in Table 7. 
Table 7 
Operating Characteristics for Proposed Study Design for Several 
Possible True Underlying Median Values 
 
True Underlying Median for MHAA4549A 
 
3 days 
3.5 days 
4 days 
Hazard Ratio 
0.60 
0.70 
0.80 
Power of log-rank test a 
99% 
86% 
48% 
95% confidence interval 
for true hazard ratio b 
(0.48, 0.75) 
(0.56, 0.88) 
(0.64, 1.00) 
Note:  Operating characteristics are based on the following assumptions:  300 evaluable 
patients, event times are exponentially distributed, median time to normalization of respiratory 
function in the control arm is 5 days, and patients are followed for 30 days. 
a Two-sided α = 0.05. 
b Confidence intervals are based on the assumption that the point estimate is equal to the true 
underlying value of the hazard ratio in each column. 
  
It should be noted that the study is underpowered for detection of minimally clinically 
meaningful differences such as a true hazard ratio of 0.80 (see third column of Table 7).   
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. 
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6.4 
EFFICACY ANALYSES 
The primary and secondary 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. 
Time to event data will be computed using Kaplan-Meier methodology and stratified Cox 
proportional hazards models 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. 
6.4.1 
Primary Efficacy Endpoint 
• 
Median time to normalization of respiratory function 
 
6.4.2 
Secondary Efficacy Endpoints 
• 
Proportion of patients with clinical failure 24 hours post-infusion of study drug 
• 
Median time to clinical resolution of vital signs 
• 
Hazard ratio for mortality at Day 14 and Day 30 
• 
Mean and median AUC of viral load 
• 
Mean and median peak viral load 
• 
Median duration of viral shedding in upper respiratory samples 
• 
Median duration of hospitalization 
• 
Median duration of ICU stay 
• 
Proportion of patients requiring antibiotics for respiratory indications during study 
• 
Proportion of patients with influenza secondary complications 
• 
Median duration of ventilation 
• 
Proportion of patients who are readmitted by Day 30 
 
6.4.3 
Subgroup Analyses 
Subgroup analyses will be performed to examine the consistency of the treatment 
estimates with use of the primary and selected secondary endpoints.  Subgroups will 
include the stratification factors as well as patients who are identified at baseline as 
influenza A positive by the upper, lower, or both airways and by patients with bacterial 
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co-infections at admission.  Additional subgroups may be added following assessment of 
baseline characteristics as exploratory analyses. 
6.5 
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 (including SpO2 measurements), 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.  SAEs 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. 
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 
6.6 
PHARMACOKINETIC ANALYSES  
Individual and mean serum MHAA4549A concentration versus time data will be 
tabulated and plotted.  The serum pharmacokinetics of MHAA4549A will be summarized 
by estimating total serum drug exposure (i.e., AUC), Cmax, Cmin, 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. 
 
 
  
 
 
 
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6.7 
OPTIONAL INTERIM ANALYSIS  
To adapt to information that may emerge during the course of this study (e.g. additional 
results of competitor studies), the Sponsor may choose to conduct one interim efficacy 
analysis.  Below are the specifications in place to ensure the study continues to meet the 
highest standards of integrity when an optional interim analysis is executed. 
The Sponsor will remain blinded.  The interim analysis will be conducted by an external 
statistical group and reviewed by the iDMC.  Interactions between the iDMC and 
Sponsor will be carried out as specified in the iDMC charter.  
The decision to conduct the optional interim analysis, along with the rationale, timing, 
and statistical details for the analysis, will be documented in the SAP, and the SAP will 
be submitted to relevant health authorities at least 2 months prior to the conduct of the 
interim analysis.  The iDMC charter will document potential recommendations the iDMC 
can make to the Sponsor as a result of the analysis (e.g., stop the study for positive 
efficacy, stop the study for futility), and the iDMC charter will also be made available to 
relevant health authorities. 
If there is a potential for the study to be stopped for positive efficacy as a result of the 
interim analysis, the type I error rate will be controlled to ensure statistical validity is 
maintained.  Specifically, the Lan-DeMets α-spending function that approximates the 
O’Brien-Fleming boundary will be applied to determine the significance (α) level for the 
interim analysis (DeMets and Lan 1994).  A statistically valid conclusion of positive 
efficacy based on an interim analysis of the specified endpoint would require a p-value 
below this α level.  Additional criteria for recommending that the study be stopped for 
positive efficacy may be added to the iDMC charter.  If the study continues beyond the 
interim analysis, the α level at the final analysis would be lowered accordingly to 
maintain the protocol-specified overall type I error rate. 
If there is a potential for the study to be stopped for futility as a result of the interim 
analysis, the threshold for declaring futility will include an assessment of the predictive 
probability that the specified endpoint will achieve statistical significance.  If the 
predictive probability is below 20%, the iDMC should consider recommending that the 
study be stopped for futility.  Additional criteria for recommending that the study be 
stopped for futility may be added to the iDMC charter.  An interim analysis that might 
lead to stopping the study for futility will not occur before at least 50% of the information 
has been accumulated. 
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 I error penalty of 0.0001 will be taken. 
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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. 
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 
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.  
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. 
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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 7.5. 
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/IEC review.  The study site must also allow 
inspection by applicable health authorities. 
7.4 
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. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, 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. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for GCP 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).  
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Studies conducted in the United States or under a U.S. Investigational New Drug (IND) 
application will comply with U.S. Food and Drug Administration (FDA) regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the EU Clinical Trial Directive (2001/20/EC). 
8.2 
INFORMED CONSENT 
The Sponsor’s sample ICFs (and ancillary sample ICFs) 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/IEC submission.  The final 
IRB/IEC−approved Consent Forms must be provided to the Sponsor for health authority 
submission purposes according to local requirements. 
The Consent Forms must be signed and dated by the patient or the patient’s authorized 
representative as applicable and in accordance with local regulations, and IRB/IEC 
policies, 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/IEC-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/IEC policy) during their participation in the study.  For any updated or revised 
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 
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. 
For sites in the United States, 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. 
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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/IEC by the Principal 
Investigator and reviewed and approved by the IRB/IEC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/IEC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/IEC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/IEC.  Investigators are 
also responsible for promptly informing the IRB/IEC of any protocol amendments (see 
Section 9.5). 
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/IEC.  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/IEC, 
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 ICF (or separate authorization for use and 
disclosure of personal health information) signed by the patient, unless permitted or 
required by law. 
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. 
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/IEC 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 
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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/IEC 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/IEC in accordance with established IRB/IEC 
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/IECs to inspect facilities and records relevant to this study. 
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, clinical monitoring and site management, data quality 
support, medical monitoring, and some safety reporting and regulatory activities as 
specified in study management plans.  Genentech will provide CRO oversight, develop 
the database and randomization scheme, and conduct statistical programming and 
analysis.  An iDMC will provide an additional level of safety monitoring for the study.   
EDC will be utilized for this study.  An IxRS will be used to assign patient numbers, 
randomize patients into study, 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.   
9.5 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/IEC and to regulatory authorities in accordance with local 
regulatory requirements. 
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Approval must be obtained from the IRB/IEC 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). 
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10. 
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Blackwood B, Alderdice F, Burns K, et al. Use of weaning protocols for reducing duration 
of mechanical ventilation in critically ill adult patients: Cochrane systematic review and 
meta-analysis. BMJ 2011;342(c7237). 
Centers for Disease Control and Prevention (CDC). Antiviral agents for the treatment 
and chemoprophylaxis of influenza: recommendations of the Advisory Committee on 
Immunization Practices (ACIP). MMRW Morb Mortal Weekly Rep 2001;60(RR01):1−24. 
Centers for Disease Control and Prevention (CDC). 2011-2012 Influenza antiviral 
medications [resource on the Internet]. 2012b [Updated 2014, Mar 21; cited 2014 Apr]. 
Available from: http://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm. 
DeMets D, Lan KKG. Interim analysis: the alpha spending function approach. Stat Med 
1994;13:1341−52. 
Doshi S, Kamimoto L, Finellie L, et al. Description of antiviral treatment among adults 
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Fiore AE, Fry A, Shay D, et al. (2011). Antiviral agents for the treatment and 
chemoprophylaxis of influenza---recommendations of the Advisory Committee on 
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mortality weekly report. Recommendations and reports/Centers for Disease Control. 
2011; 60(1):1−24. 
Harper SA, Bradley JS, Englund JA, et al. Expert Panel of the Infectious Diseases 
Society of America. Seasonal influenza in adults and children--diagnosis, treatment, 
chemoprophylaxis, and institutional outbreak management: clinical practice guidelines of 
the Infectious Diseases Society of America. Clin Infect Dis 2009 Apr 15;48(8):1003−32. 
 
 
Koch GG, Carr GJ, Amara IA, et al. Categorical data analysis. In: Berry DA, editor. 
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1989:291−475. 
Lawton MP, Brody EM. Assessment of older people: self-maintaining and instrumental 
activities of daily living. Gerontologist 1969;9:179−86. 
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influenza. Antiviral Therapy 2012:17(1 Pt B):143−57. 
Louie JK, Yang S, Acosta M, et al. Treatment with neuraminidase inhibitors for critically 
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Marty FM, Man CY, van der Horst C, et al. Safety and pharmacokinetics of intravenous 
zanamivir treatment in hospitalized adults with influenza: an open-label, multicenter, 
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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 
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Polakos NK, Cornejo JC, Murray DA, et al. Kupffer cell-dependent hepatitis occurs 
during influenza infection. Am J Pathol 2006;168(4):1169−78. 
Thompson WW, Shay DK, Weintraub E, et al. Influenza-associated hospitalizations in 
the United States. JAMA 2004;292(11):1333−40. 
Zhou H, Thompson WW, Vioud CG, et al. Hospitalizations associated with influenza and 
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2012;54(10):1427−36. 
  


 
APPENDIX 1a 
 
Schedule of Assessments:  Hospitalization Days  
Notes: Unless otherwise indicated, all assessments should be performed prior to study drug administration; x’s within parentheses, i.e., 
(x), indicate optional assessments.  Please refer to Follow-up Period table for visits to be completed when patient is discharged from 
hospital prior to Day 30.  
Screening 
Hospitalized Days (only to be completed while patients are hospitalized) 
Day (D) 
D -2, -1 
D1 
(Randomization) 
D2
D3
D4
D5
D6
D7
D8 
D9
D10
D14
D20
D25
Hospital 
Discharge a
D30  
Study Completion or 
Early 
Discontinuation 
while Hospitalized 
Confirm study drug administration can occur within 48 hours of hospital admission 
Informed consent b 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rapid influenza A test c 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Local influenza A PCR test d 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm onset of flu 
symptoms (≤ 5 days prior to 
study drug administration on 
Day 1) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm history of baseline 
SpO2 > 92% 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy screening e 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm O2 requirement f 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Resting oximetry reading g 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant medications h 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vital signs i 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
APACHE score j 
 
(xz) 
 
 
 
 
 
 
 
 
 
(x) 
 
 
(x) 
(x) 
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APPENDIX 1a (cont’d)  
Schedule of Assessments:  Hospitalization Days  
d If the Sponsor-supplied rapid influenza test is negative, local influenza PCR testing can be used to confirm influenza A and satisfy entry criteria if 
results are received within screening/hospitalization window (48 hours)  
e A urine pregnancy test should be sent only for women considered by the investigator to be of childbearing potential, see exclusion criteria.  This 
result must be available prior to randomization.  If urine testing is not available at the site, blood already collected from an existing sample may 
be tested for pregnancy. 
f Confirm patient requires supplement O2 or PPV with 24 hours of hospitalization. . 
g All patients will have their on-study SpO2 recorded daily in the morning between 4 am − 10 am local time; screening SpO2 may be taken outside 
this window.  Patients on low flow O2 should have a daily trial of their SpO2 while on and off the supplementation and both values will be 
recorded.  
h Concomitant medications should be recorded for 30 days prior to screening, through the study completion/early discontinuation visit.  See 
exclusion criteria in Section 4.5.2 for prohibited therapies. 
i Vital signs will be collected within 1 hour before MHAA4549A infusion and within 1 hour after completion of MHAA4549A infusion  include 
temperature, 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.  In patients who have multiple 
vital signs taken during any day, the most abnormal value should be recorded from that 24-hour period.  Temperature, blood pressure, 
respiratory rate, and heart rate will be completed after the patient has been supine for > 5 minutes.  
j APACHE scores are optional and only for patients that are in the ICU.  For calculation of the screening APACHE score, the worst values in the 
preceding 24 hours should be used.  APACHE scores are not required for study conduct or entry but should be collected if available.  
k SOFA scores are only for patients in the ICU that have available data such as PaO2/FiO2 (mmHg).  See Appendix 7 for SOFA score calculation. 
l Patient should rest in a supine position for 10 minutes prior. 
m  Patient will be a resident for at least 24 hours following administration of MHAA4549A. 
n Oseltamivir must be given for a minimum of 5 days.  Treatment longer than 5 days is permitted based on the discretion of the investigator 
[indicated by (x)]. 
o 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 adverse events, if appropriate.  
p 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 adverse events, if appropriate. 
q Height will be obtained at screening only.  Weight will be obtained at all indicated visits.  Height and weight will be recorded in centimeters and 
kilograms, respectively.  The eCRF will calculate BMI.  
r Local laboratory measurements should be utilized. 
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APPENDIX 1a (cont’d)  
Schedule of Assessments:  Hospitalization Days  
s Urinalysis includes pH, specific gravity, glucose, creatinine, total protein to creatinine ratio, albumin, ketones, occult blood, bilirubin, urobilinogen, 
nitrite, and leukocyte esterase.  Microscopic examination (e.g., sediment, RBCs, WBCs, casts, crystals, epithelial cells, bacteria) will be 
performed if clinically indicated. 
 
 
  
 
 
 
v Day 1 serum PK samples are to be drawn 30 (± 5) minutes pre-dose of MHAA4549A, 60 (± 15) minutes after the end of infusion.  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.  
 
 
 
x If patient is discharged on or before Day 5, the oseltamivir PK sample should be taken on the discharge day. 
 
 
 
 
z Assessment to be conducted based on entry into ICU; may vary from patient to patient. 
 
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APPENDIX 1b 
 
Schedule of Assessments:  Follow-Up Period  
• 
If a patient is discharged prior to Day 14, he/she will need to complete the following assessments for Day 14 and Day 30 below. 
• 
If a patient is discharged prior to Day 30 and after Day 14, he/she will need to complete the following assessments for Day 30 below. 
• 
If patient is hospitalized for Day 14, and/or Day 30, please refer to Appendix 1a.  
Day (D) 
D14 ± 1 
(If Discharged BEFORE D14) 
D30 ± 4 (Study Completion)  
or Early Discontinuation 
Concomitant medications a 
x 
x 
Vital signsb 
x 
x 
Electrocardiogram (12-lead) c 
x 
x 
Weight & height, BMI d 
x 
x 
Adverse events 
x 
x 
Hematology e
 
x 
x 
Chemistry 20 panel e 
x 
x 
Coagulation panel e 
x 
x 
Urinalysis e 
x 
x 
Flu antibodies (HAI) 
x 
x 
 
 
x 
Serum for MHAA4549A PK measurements f 
x 
x 
 
x 
x 
 
x 
x 
  
 
x 
 
 
x 
 
 
x 
  
 
x 
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APPENDIX 1b (cont’d)  
Schedule of Assessments:  Follow-up Period  
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; ATA = Anti-therapeutic antibodies; BMI = body mass index; D = day; 
Dx = diagnostics; eCFR = electronic Case Report Form; ECG = electrocardiogram; HAI = hemagglutinin inhibition; 
  
 
 PD = pharmacodynamics; PK = pharmacokinetic. 
a Concomitant medications should be recorded for 30 days prior to screening, through the study completion/early discontinuation visit.  See 
exclusion criteria in Section 4.5.2 for prohibited therapies. 
b Vital signs include temperature, 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 study drug administration of any antipyretic drugs.  
In patients who have multiple vital signs taken during any day, the most abnormal value should be recorded from that 24-hour period.  
Temperature, blood pressure, respiratory rate, and heart rate will be completed after the patient has been supine for > 5 minutes.  
c ECG should be recorded after the patient has rested in a supine position for 10 minutes. 
d Height will be obtained at screening only.  Weight will be obtained at all indicated visits.  Height and weight will be recorded in meters and kg, 
respectively.  The eCRF will calculate BMI.  
e Local laboratory measurements should be used. 
f PK samples should be drawn from the contralateral arm from the one used for drug infusion and must be labeled with the exact time of draw.  
 
 
 
 
 


 
APPENDIX 2  
Time to Normalization of Respiratory Function 
For the purposes of this study, the time to normalization of respiratory function will be 
defined as the time to removal of the patient from O2 supplementation in order to 
maintain an SpO2 > 95%.  
Patients who are on low flow O2 (2-6L/min) should receive a daily trial off O2 in the 
morning between 4 am − 10 am as described below.  
1. Patient should be resting or sitting. 
2. Patient should be fitted with pulse oximeter, and their SpO2 should be checked 
once while on O2 and then again a minute after turning off O2 supplementation.  
3. If the SpO2 > 95%, then the time and reading should be recorded.  Notify the 
study doctor so that he/she can make a clinical judgment to determine whether 
the O2 can be removed. 
4. If the patient is off O2 for 24 hours and his/her reading the subsequent day is 
>95%, then the endpoint is considered satisfied.  The recorded time for the 
endpoint corresponds with the initial discontinuation of O2 and reading. 
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APPENDIX 4  
  
 
 
 
 
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APPENDIX 5  
  
 
 
  
 
   
 
 
 
  
 
 
  
 
   
 
 
  
 
 
 
 
 
 
 
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APPENDIX 6  
 
  
 
  
 
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APPENDIX 7  
SOFA Score Calculation  
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 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 1:1000 solution for intravenous (IV) or endotracheal injection 
• 
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: 
1. 
Stop the study drug infusion. 
2. 
Maintain an adequate airway. 
3. 
Administer antihistamines, epinephrine, or other medications as required by patient 
status and directed by the physician in charge. 
4. 
Continue to observe the patient and document observations. 
 
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APPENDIX 8  
DAID 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. 
 
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APPENDIX 8 (cont’d)  
DAID Toxicity Grading Tables for Clinical Abnormalities 
 
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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 
 
 
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 
 


 
APPENDIX 9  
DAID Toxicity Grading Tables for Laboratory Abnormalities 
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 
Abbreviations used in the table: 
 
; CPK = creatine phosphokinase; Dec = Decreased; 
IV = Intravenous; LLN = Lower limit of normal; Mod = Moderate; Req = Required; 
Rx = Therapy; SGOT = serum glutamic oxaloacetic transaminase; SGPT = serum 
glutamic pyruvic transaminase; ULN = Upper limit of normal. 
 
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 gm/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 x 
ULN 
1.26 – 1.50 x 
ULN 
1.51 – 3.0 x 
ULN 
>3 x ULN 
Activated Partial 
Thromboplastin 
Time (APTT) 
1.01 – 1.66 x 
ULN 
1.67 – 2.33 x 
ULN 
2.34 – 3 x ULN 
>3 x ULN 
Methemoglobin 
5.0 – 9.9% 
10.0 – 14.9% 
15.0 – 19.9% 
>20.0% 
From the FDA Guidance document ‘Toxicity Grading Scale from Healthy Adult and Adolescent 
olunteers Enrolled in Preventative Vaccine Clinical Trials’ 
V 
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APPENDIX 9 (cont’d)  
DAID Toxicity Grading Tables for Laboratory Abnormalities 
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CHEMISTRIES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hyponatremia 
130 – 135 
mEq/L 
123 – 129 
mEq/L 
116 – 122  
mEq/L 
<116 mEq/L or 
abnormal sodium with 
mental status changes 
or seizures 
Hypernatremia 
146 – 150 
mEq/L 
151 – 157 
mEq/L 
158 – 165  
mEq/L 
>165 mEq/L or 
abnormal sodium with 
mental status changes 
or seizures 
Hypokalemia 
3.0 – 3.4 
mEq/L 
2.5 – 2.9 
mEq/L 
2.0 – 2.4 mEq/L  
or intensive 
replacement 
therapy or 
hospitalization 
required 
<2.0 mEq/L or abnormal 
potassium with paresis 
ileus or life-threatening 
arrhythmia 
Hyperkalemia 
5.6 – 6.0 
mEq/L 
6.1 – 6.5 
mEq/L 
6.6 – 7.0  
mEq/L 
>7.0 mEq/L or abnormal 
potassium with life-
threatening arrhythmia 
Hypoglycemia 
55 – 64  
mg/dL 
40 – 54  
mg/dL 
30 – 39  
mg/dL 
<30 mg/dL or abnormal 
glucose with mental 
status changes or coma 
Hyperglycemia 
(nonfasting and no prior 
diabetes) 
116 – 160 
mg/dL 
161 – 250 
mg/dL 
251 – 500  
mg/dL 
>500 mg/dL or abnormal 
glucose with 
ketoacidosis or seizures 
Hypocalcemia (corrected 
for albumin) 
8.4 – 7.8 
mg/dL 
7.7 – 7.0 
mg/dL 
6.9 – 6.1  
mg/dL 
<6.1 mg/dL or abnormal 
calcium with life 
threatening arrhythmia 
or tetany 
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  
Hyperbilirubinemia 
(when accompanied by 
any increase in other 
liver function test) 
1.1 – <1.25 x 
ULN 
1.25 – <1.5 x 
ULN 
1.5 – 1.75 x  
ULN 
>1.75 x ULN 
Hyperbilirubinemia 
(when other liver 
function are in the 
normal range) 
1.1 – <1.5 x 
ULN 
1.5 – <2.0 x 
ULN 
2.0 – 3.0 x  
ULN 
>3.0 x ULN 
From the FDA Guidance document ‘Toxicity Grading Scale from Healthy Adult and Adolescent 
olunteers Enrolled in Preventative Vaccine Clinical Trials’ 
V 


APPENDIX 9 (cont’d)  
DAID Toxicity Grading Tables for Laboratory Abnormalities 
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ENZYMES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
AST (SGOT) 
1.1 - <2.0 x ULN 
2.0 - <3.0 x ULN 
3.0 – 8.0 x ULN 
>8.0 x ULN 
ALT (SGPT) 
1.1 - <2.0 x ULN 
2.0 - <3.0 x ULN 
3.0 – 8.0 x ULN 
>8.0 x ULN 
GGT 
1.1 - <2.0 x ULN 
2.0 - <3.0 x ULN 
3.0 – 8.0 x ULN 
>8.0 x ULN 
Alkaline 
Phosphatase 
1.1 - <2.0 x ULN 
2.0 - <3.0 x ULN 
3.0 – 8.0 x ULN 
>8.0 x ULN 
Amylase 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.1 – 5.0 x ULN 
>5.1 x ULN 
Lipase 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.1 – 5.0 x ULN 
>5.1 x ULN 
*CPK – mg/dL 
1.25 – 1.5 x ULN 
1.6 – 3.0 x ULN 
3.1 – 10.0 x ULN 
>10 x ULN 
*From the FDA Guidance document ‘Toxicity Grading Scale from Healthy Adult and Adolescent 
olunteers Enrolled in Preventative Vaccine Clinical Trials’ 
V  
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 
From the FDA Guidance document ‘Toxicity Grading Scale from Healthy Adult and Adolescent 
olunteers Enrolled in Preventative Vaccine Clinical Trials’ 
V 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Title
14-Aug-2014 21:44:24
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 GV29216, Version 2 
PROTOCOL 
TITLE: 
A PHASE 2 RANDOMIZED, DOUBLE-BLIND 
PLACEBO-CONTROLLED TRIAL OF MHAA4549A, 
A MONOCLONAL ANTIBODY, IN COMBINATION 
WITH OSELTAMIVIR VERSUS OSELTAMIVIR FOR 
TREATMENT OF SEVERE INFLUENZA A 
INFECTION 
PROTOCOL NUMBER: GV29216 
VERSION NUMBER: 
2 
EUDRACT NUMBER: 
2014-000461-43 
IND NUMBER: 
117,318 
TEST PRODUCT: 
MHAA4549A 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
Genentech, Inc. 
DATE FINAL: 
30 May 2014 
DATE AMENDED: 
See electronic date stamp below 
 


PROTOCOL AMENDMENT RATIONALE: 
VERSION 2 AMENDMENT 
RATIONALE 
Protocol GV29216 was amended in Version 2 to reflect the following changes: 
•
More frequent review of safety data will be facilitated by employing an Internal
Monitoring Committee (IMC) in combination with a Scientific Oversight Committee
(SOC) rather than a single Independent Data Monitoring Committee (iDMC)
•
Allowing the inclusion of patients diagnosed with influenza A as determined by a
Sponsor-supplied rapid influenza test and/or local molecular test (PCR) allows
enrollment flexibility.
•
Allowing the Sponsor to choose to conduct up to two interim analyses to assess
safety and efficacy was for administrative purposes only.
•
Adding a Day 60 timepoint allows for a longer follow up period.
•
Patients who are discharged from the hospital with oseltamivir will be required to
complete a medication diary and return the medication diary as well as empty (used)
oseltamivir packets and unused oseltamivir capsules to the study site at the next
follow up visit.  Patients will record the date and time when each oseltamivir capsule
is administered.  This allows the capture of oseltamivir administration after hospital
discharge.
•
Patients who are on low-flow oxygen should receive a daily trial off oxygen in the
morning between 6 am and 12 pm.  Patients should be fitted with pulse oximeter,
and their SpO2 should be checked once while on oxygen and then again
3-5 minutes after turning off oxygen supplementation.  The time change will give a
more accurate oximeter reading.
•
Updated background clinical safety and efficacy data from the Phase 2a challenge
study (GV28985) were added to provide investigators with the most current
information concerning MHAA4549A.
•
Updated Genentech Medical Monitor and contact information was added since the
Medical Monitor has changed for this project.
•
Updated randomization of patients will be managed by a central Interactive Voice
and Web Response System through the use of a dynamic hierarchical algorithm.
The Sponsor considers that changes in this amendment will increase the safety 
monitoring in this Phase 2b study without any significant impact on the scientific value of 
the trial, nor will they have any significant impact on the safety or mental or physical 
integrity of study patients. 
MHAA4549A—Genentech, Inc. 
Protocol GV29216, Version 2 
2 


SUMMARY OF CHANGES: 
VERSION 2 AMENDMENT 
COVER PAGE 
, M.D., Ph.D. 
Genentech, Inc./Roche Registration Ltd.. 
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol. 
GENERAL REVISIONS 
The following changes were made consistently throughout the protocol: 
•
The meaning of the abbreviation “SOC” was changed from “standard of care” to
“Scientific Oversight Committee.”  “Standard of care” was spelled out throughout the
protocol.
•
A Day 60 visit was added to the study.  Text was revised or added, as appropriate,
throughout the protocol to account for this addition.
•
“DAID” was changed to “DAIDS” throughout the protocol.
SECTION 1.2:  BACKGROUND ON MHAA4549A 
This section was updated to include recently available data from Studies GV28916 and 
GV28985.  Three subsection headers were added to organize the section.  Data was 
also revised or added to Table 1. 
SECTION 1.3.1:  Study Rationale 
Preliminary Data from the Phase 2a study also provides evidence that the 3600 mg dose 
of MHAA4549A is effective in reducing viral titers in healthy volunteers inoculated with 
influenza A virus.   
SECTION 1.3.2.1:  Treatment in Combination with Oseltamivir 
All patients in the study will receive oseltamivir as the current SOCstandard of care 
treatment of oseltamivir , either with or without MHAA4549A.  Therefore, at a minimum, 
all patients at minimum will be treated with SOCstandard of care for influenza.  Given 
that MHAA4549A is an antibody, the potential for a drug-drug interaction with 
oseltamivir is very low.  In the ongoing Phase 2a challenge study (GV28985), several 
study subjects received MHAA4549A followed by oseltamivir with no AEs attributable to 
the combination therapy noted to date.  In addition, in this study the PK profile of 
oseltamivir in concomitantly treated subjects will be assessed. 
MHAA4549A—Genentech, Inc. 
Protocol GV29216, Version 2 
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Protocol GV29216, Version 2 
4 
SECTION 1.3.2.3:  Rational for Selection of Phase 2b Population 

Clinical safety data for MHAA4549A demonstrate a well-tolerated safety profile.
There were mild, related
o
AEs observed in the Phase 1 study (GV28916) were mild and MHAA4549A was
well tolerated.  did not show a dose relationship; there were no ATAs were
detected.  Safety data from in patients treated with MHAA4549A.
o
In the ongoing Phase 2a challenge study (GV28985) was), MHAA4549A was 
generally well tolerated.  A few subjects in all treatment groups were observed 
to have mild and moderate transient elevations in alanine transaminase (ALT), 
aspartate transaminase (AST), and amylase levels that may be related to either 
MHAA4549A or to influenza infection.).  There was no dose-dependent 
relationship of the ALT/AST/amylase elevations with MHAA4549A and the 
overall event rate was in line with that of previous challenge studies (published 
rates associated with the influenza challenge model regardless of treatment arm: 
27/100 [27%] in the studyGV28985 vs. approximately 26%) (% in previous 
challenge studies (Polakos 2006).  There were no SAEs that were related to study 
drug were observed.  Testing for ATAs in Study GV28985 has not yet been 
concluded.  There were a total of 3 SAEs unrelated to MHAA4549A in two 
subjects.  One subject reported depressive psychosis associated with influenza. 
There were a total of 3 SAEs unrelated to MHAA4549A in two subjects.  One 
subject reported depressive psychosis associated with influenza. The second 
subject reported a broken knee with a subsequent infection following a surgical 
procedure.

Interim efficacy data in the Phase 2a challenge study (GV28985) interim efficacy
data demonstrated a significant decrease in viral shedding in the upper respiratory
tract at the 3600 mg dose.  There was a 97.5% (p  0.00920051) decrease in the
area under viral loadtime curve (AUEC) and a 77% (p  0.00540024) decrease in
peak viral load by qPCR measurement in comparison to the placebo group, thus
confirming proof of antiviral activity at the 3600 mg dose level.  Symptom data in the
Phase 2a study showed a decrease in the AUC of symptoms scores for the 3600-mg
dose that is consistent with the virological results as illustrated in Table 1.
SECTION 1.3.2.4:  Patient Monitoring and Supervision 
An independent Data Monitoring Committee (iDMC) will evaluate the safety of 
MHAA4549A at a timepoint to be specified in the iDMC charter.An internal monitoring 
committee (IMC) in combination with a scientific oversight committee (SOC) will 
provide safety monitoring for the study in addition to the ongoing review of safety by 
the Medical Monitor and Safety Scientist.  See Section 3.1.2 for more information.  
The 120-day follow-up period in the Phase 1 and 2a studies allowed for monitoring of 
subjects for approximately 5 half-lives of the study drug.MHAA4549A.  No ATAs were 
detected in the Phase 1 study, and the ATA testing forwhile one subject in the Phase 2a 
study is ongoing.tested positive for ATAs at baseline and post-baseline timepoints as 
described in Section 1.2.2.  The Phase 2b study will also include a safety follow-up 


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Protocol GV29216, Version 2 
5 
period of up to 30 60 days and an unlimited collection of all SAEs believed related to 
MHAA4549A.   
SECTION 3.1.1:  Overview of Study Design 
At the time of randomization, patients who are eligible for enrollment, as described 
above, will be randomized to receive MHAA4549A at a dose of 3600 mg or placebo.  
Patients will be stratified by countrysite, PPV versus supplemental O2 on the day of 
admissionat randomization, and suspected or confirmed bacterial pneumonia versus no 
bacterial pneumonia based on the status on the day of admissionat randomization. 
A follow-up study visit should occur on Day 14  1 (if discharged before Day 14) and); 
Day 30  4 days, (if discharged before Day 30.); and Day 60  4 days (if discharged 
before Day 60). 
Safety evaluations will be provided by an IMC and SOC, as defined in the IMC and SOC 
agreement (see Section 3.1.2) 
SECTION 3.1.2:  Independent Data Monitoring Committee Independent 
Monitoring Committee and Scientific Oversight Committee 
Text describing the Independent Data Monitoring Committee and its function was 
replaced with text describing an Independent Monitoring Committee and a Scientific 
Oversight Committee and their respective functions.   
An iDMC, which consists of two independent physicians and one independent 
biostatistician, will review safety data of the trial to ensure the safety of the patients 
enrolled.  This should allow early detection of any potential safety concern and, thus, 
ensure the best possible protection of patients’ safety.  In addition, it includes a 
non voting biostatistician from an independent data coordinating center (IDCC) who 
prepares the safety reports, including information on patient accrual and SAEs from the 
study.  The iDMC reviews the safety reports, addresses any safety concerns, and 
informs the Sponsor whether or not to continue the study.   
SECTION 3.2.2:  Rationale for Patient Population and Primary Endpoint 
Severe influenza, for the purpose of this study, is defined as requiring one of the 
following treatments: PPV or any supplemental O2 to maintain an SpO2  92%.% or PPV.  
PPV is defined as any mechanical positive pressure device to maintain oxygenation; this 
can include mask ventilation positive pressure mask and intubation.   
SECTION 3.2.4:  Rationale for MHAA4549A Dosage 
The dose is adequately supported by safety data from the completed Phase 1 study and 
ongoing Phase 2a study in healthy volunteers, which has completed dosing..  
MHAA4549A was shown to be safe and well-tolerated at all dose levels (ranging from 


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1.5 mg/kg to 45 mg/kg for Phase 1 and 400-3600 mg for Phase 2a) through a follow-up 
period of 120 days post-dose in the Phase 1 and Phase 2a study.  The dose level used in 
this study was determined following an interim analysis of the 1200 mg and 3600 mg 
doses indata from the Phase 2a study, GV28985, which demonstrated the following: 
 
The 3600-mg dose demonstrated a significant decrease in viral shedding in upper 
respiratory samples.  Based on current interim analysis data, there was a 97.5% 
(p  0.00920051) decrease in AUEC and a 77.3% decrease in peak viral load by 
qPCR measurement compared to the placebo group.   
 
Symptom data in the Phase 2a study showed a decrease in the AUC of symptoms 
scores for the 3600-mg dose, as illustrated in Table 1, which is consistent with the 
virological results. 
 
Hospitalized patients generally have a longer duration of viral shedding and 
significantly more viral burden in the lower lung compartments; therefore, high 
concentrations of mAb are likely needed to achieve sufficient occupancy of the virus 
binding sites in the upper and lower respiratory compartments.  Furthermore, higher 
concentrations of mAb are necessary to mitigate the risk of resistance for 
MHAA4549A and neuraminidase inhibitors such as oseltamivir. 
 
SECTION 3.3.3:  Secondary Efficacy Outcome Measures 
The secondary efficacy outcome measures for this study are as follows: 
 
Clinical failure after 24 hours post-infusion of study drug; defined as: 
 
SECTION 3.3.5:  Secondary Efficacy Outcome Measures 
The exploratory outcome measures for this study are as follows: 
 
 
 
SECTION 4.1.1:  Inclusion Criteria 
 
Diagnosis of influenza A where one or both of the following are used as aid(s) in 
diagnosis:as determined by the Sponsored supplied rapid influenza test 
 If negativeA Sponsor-supplied rapid influenza A test, a positive 
 
A local molecular test (PCR) is required test 
 
SECTION 4.2:  METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
The randomization of patients will be managed by a central Interactive Voice and Web 
Response System (IxRS) through use of a dynamic hierarchical algorithm.  The 
treatment assignments will be unblinded to selected Sponsor personnel to facilitate 
ongoing monitoring of safety and tolerability, including members of the IMC and SOC.  
All patients will be randomly assigned to receive either MHAA4549A 3600 mg or placebo 
at a 1:1 ratio stratified by countrysite, whether patient is on PPV vs supplemental O2 on 
the day of admissionat randomization, and whether the patient has suspected or 


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confirmed bacterial pneumonia vs no bacterial pneumonia on the day of admission.at 
randomization.  All patients will receive oseltamivir (75 mg or 150 mg BID) for a 
minimum of 5 days.  Treatment for longer than 5 days is permitted based on local 
investigator discretion. 
The treatment assignments will be unblinded to an external IDCC to facilitate the iDMC 
assessment of safety.  
SECTION 4.3.2.2:  Oseltamivir-Neuraminidase Inhibitor (NAI) 
Patients who are discharged from the hospital with oseltamivir will be required to 
complete a medication diary and return the medication diary, empty (used) oseltamivir 
packets and unused oseltamivir capsules to the study site at the next follow up visit.  
Patients will record the date and time when each oseltamivir capsule is administered. 
SECTION 4.6.2:  Diagnostic Testing for Enrollment 
Patients may be enrolled based on a positive local molecular test (PCR) result within 
the 48-hour screening window, but the rapid influenza test must still be conducted 
prior to randomization.   
SECTION 4.6.7:  Oxygen Saturation Measurements 
Unless clinically contraindicated, all patients will have their SpO2 and corresponding 
respiratory assessments recorded daily in the morning between 4 6 am  10 am12 pm 
local time.   
If the patient is on oxygen supplementation, SpO2 measured by pulse oximetry and the 
corresponding respiratory assessments (e.g. FiO2, flow rate) will be recorded. If the 
patient is on PPV, partial pressure of O2 (PaO2) and the corresponding respiratory 
assessments (e.g. FiO2, ventilator mode, ventilator respiratory rate, positive end-
expiratory pressure) will be recorded. 
SECTION 4.6.8:  Laboratory, Biomarker, and Other Biological Samples 
Table 3 (Laboratory Tests at Screening) was revised to remove the chemistry panel, 
coagulation tests, and the urinalysis at screening.  “Bands” were added to the 
hematology tests.  The table was reorganized because of the deletions.   
Table 4 (Laboratory Tests During the Study) was revised to remove creatinine, total 
protein-to-creatinine ratio, albumin, and urobilinogen from the urinalysis.  “Bands” were 
added to the hematology tests; “random” was removed from glucose; and “or urea” was 
added after urea nitrogen (BUN).  The table was reorganized because of the deletions. 


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SECTION 4.6.9:  Electrocardiograms 
If QTcF is not available, QTcB may be recorded.  SOCStandard of care treatment may 
be instituted per the discretion of the investigator.   
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 4.6.10:  
 
 
 
 
  
 
 
   
SECTION 4.6.10.1:  
 
 
 
 
 
    
SECTION 4.6.10.2:  
 
 
 
 
   
SECTION 4.6.10.3:  
 
  
 
  
SECTION 4.8:  OSELTAMIVIR MEDICATION DIARY 
Patients who are discharged from the hospital with oseltamivir will be required to 
complete a medication diary and return the medication diary, empty (used) oseltamivir 
packets, and unused oseltamivir capsules to the study site at the next follow up visit.  


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Patients will record the date and time when each oseltamivir capsule is administered. 
SECTION 4.9.2:  Study Treatment Discontinuation 
The IMC and SOC may recommend permanently discontinuing dosing for all patients 
within one or both study arms in the event of a general safety concern. 
SECTION 4.9.3:  Study Completion/Early Discontinuation Visit 
Patients who complete all study visits through Day 3060 are considered to have 
completed study.  All patients who choose to discontinue from the study early will be 
asked to complete all assessments for the current visit day and for the early 
discontinuation visit. without duplication.   
SECTION 5.1:  STUDY PLAN 
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 performedcarried out by an internal Genentech Safety Review Committee, composed 
of the Medical Monitor, a  and a drug safety scientist, and a biostatistician.  External 
experts may be consulted as appropriate..  An unblinded review of safety will be 
performed by an iDMC on an ongoing regular basis by the IMC and SOC as described 
in Section the IMC and the iDMC charter. SOC agreement.  
SECTION 5.3.5.6:  Abnormal Liver Function Tests 
 
Treatment-emergent ALT or AST  3  baseline value in combination with total 
bilirubin  2  ULN (of which  35% is direct bilirubin) 
SECTION 5.4.2.2:  Events That Occur after Study Drug Initiation 
Although the investigator is not required to actively monitor patients for adverse events 
after the patient has been discharged from the study, the Sponsor should be notified if 
the investigator becomes aware of any death or other serious adverse event that occurs 
after discharge from the study, regardless of causality if determined to be related to 
study drug by the investigator.   
SECTION 5.6:  EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND ETHICS 
COMMITTEES 
 
Asymptomatic eElevations of ALT, AST, and or amylase without corresponding 
elevations of bilirubin that have been shown to be increased during influenza A 
infection (Polakos 2006) 
 
An iDMCIMC 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. 


SECTION 6.1:  DETERMINATION OF SAMPLE SIZE 
This sample size provides 78% power to detect a treatment difference of 1 day for the primary 
endpoint assuming a 2-sided alpha of 0.2.  
Operating characteristics (power) under other possible assumptions for 2-sided alpha of 0.05 
andfor true differences of 1 to 2 days are provided in Table 7. 
It should be noted that the study is underpowered for detection of minimally clinically 
meaningful differences at a 2-sided alpha of 0.05 such as a true hazard ratio of 0.80 (see 
third column of Table 7.     
SECTION 6.7:  OPTIONAL INTERIM ANALYSIS 
To adapt to information that may emerge duringGiven the coursehypothesis-generating 
nature of this study (e.g. additional results of competitor studies),, the Sponsor may 
choose to conduct oneup to two interim efficacy analysis.  Below are the specifications 
in place to ensure the study continues to meet the highest standards of integrity when 
analyses.  The decision to conduct an optional interim analysis is executed.Sponsor will 
remain blinded.  The interim analysis will be conducted by an external statistical group 
and reviewed by the iDMC.  Interactions between the iDMC and Sponsor will be carried 
out as specified in the iDMC charter.  
The decision to conduct the optional interim analysis, along with the rationale, the timing, 
and statistical details for of the analysis, will be documented in the SAP, and the SAP 
will be submitted to relevant health authorities at least 2 monthsSponsor’s trial master 
file prior to the conduct of the interim analysis.  The iDMC charter will document 
potential recommendations the iDMC can make to the Sponsor as a result of the 
analysis (e.g., stop the study for positive efficacy, stop the study for futility), and the 
iDMC charter will also be made available to relevant health authorities. 
If there is a potential for the study to be stopped for positive efficacy as a result of the 
interim analysis, the type I error rate will be controlled to ensure statistical validity is 
maintained.  Specifically, the Lan DeMets α spending function that approximates the 
O’Brien Fleming boundary will be applied to determine the significance (α) 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 for the interim analysis ().  A statistically valid conclusion of positive efficacy based 
on an interim analysis of the specified endpoint would require a p value below this 
α level.  Additional criteria for recommending that the study be stopped for positive 
efficacy may be added to the iDMC charter.  If the study continues beyond the interim 
analysis, the α level at the final analysis would be lowered accordingly to maintain the 
protocol specified overall type I error rate. 
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TABLE OF CONTENTS 
PROTOCOL ACCEPTANCE FORM .................................................................. 19 
PROTOCOL SYNOPSIS .................................................................................... 20 
1. 
BACKGROUND .......................................................................................... 29 
1.1 
Background on Influenza ....................................................... 29 
1.2 
Background on MHAA4549A ................................................. 29 
1.2.1 
Nonclinical Background ......................................................... 29 
1.2.2 
Clinical Safety Background .................................................... 30 
1.2.3 
Clinical Efficacy Background ................................................. 31 
1.3 
Study Rationale and Benefit-Risk Assessment ...................... 33 
1.3.1 
Study Rationale ..................................................................... 33 
1.3.2 
Benefit-Risk Assessment ....................................................... 33 
1.3.2.1 
Treatment in Combination with Oseltamivir ........................... 33 
1.3.2.2 
Drug Mechanism and Preclinical Studies .............................. 34 
1.3.2.3 
Rationale for Selection of Phase 2b Study 
Population .............................................................................. 34 
1.3.2.4 
Patient Monitoring and Supervision ....................................... 35 
2. 
OBJECTIVES .............................................................................................. 35 
2.1 
Safety Objectives ................................................................... 35 
2.2 
Primary Efficacy Objectives ................................................... 35 
2.3 
Secondary Efficacy Objectives .............................................. 36 
2.4 
Pharmacokinetic Objectives .................................................. 36 
2.5 
Exploratory Objectives ........................................................... 36 
3. 
STUDY DESIGN ......................................................................................... 37 
3.1 
Description of the Study......................................................... 37 
3.1.1 
Overview of Study Design ..................................................... 37 
3.1.2 
Independent Monitoring Committee and Scientific 
Oversight Committee ............................................................. 39 
3.1.3 
End of Study .......................................................................... 40 
3.2 
Rationale for Study Design .................................................... 40 
3.2.1 
Rationale for Study Design .................................................... 40 
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3.2.2 
Rationale for Patient Population and Primary 
Endpoint ................................................................................ 40 
3.2.3 
Rationale for Control Group and Treatment 
Window .................................................................................. 41 
3.2.4 
Rationale for MHAA4549A Dosage ....................................... 42 
3.2.5 
Rationale for Biomarker Assessments ................................... 43 
3.3 
Outcome Measures ............................................................... 43 
3.3.1 
Safety Outcome Measures .................................................... 43 
3.3.2 
Primary Efficacy Outcome Measure ...................................... 43 
3.3.3 
Secondary Efficacy Outcome Measures ................................ 43 
3.3.4 
Pharmacokinetic Outcome Measures .................................... 44 
3.3.5 
Exploratory Outcome Measures ............................................ 45 
4. 
MATERIALS AND METHODS .................................................................... 45 
4.1 
Patients .................................................................................. 45 
4.1.1 
Inclusion Criteria .................................................................... 46 
4.1.2 
Exclusion Criteria ................................................................... 46 
4.2 
Method of Treatment Assignment and Blinding ..................... 47 
4.3 
Study Treatment .................................................................... 48 
4.3.1 
Formulation, Packaging, and Handling .................................. 48 
4.3.1.1 
MHAA4549A and Placebo ..................................................... 48 
4.3.1.2 
Oseltamivir (Tamiflu).............................................................. 49 
4.3.2 
Dosage, Administration, and Compliance .............................. 49 
4.3.2.1 
MHAA4549A and Placebo ..................................................... 49 
4.3.2.2 
Oseltamivir-Neuraminidase Inhibitor (NAI) ............................ 50 
4.3.3 
Investigational Medicinal Product Accountability ................... 50 
4.4 
Post-Trial Access to MHAA4549A ......................................... 51 
4.5 
Concomitant Therapy and Food ............................................ 51 
4.5.1 
Permitted Therapy ................................................................. 51 
4.5.2 
Prohibited Therapy ................................................................ 52 
4.5.3 
Prohibited Food ..................................................................... 52 
4.6 
Study Assessments ............................................................... 52 
4.6.1 
Informed Consent Forms and Screening Log ........................ 52 
4.6.2 
Diagnostic Testing for Enrollment .......................................... 52 
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5.3.3 
Assessment of Severity of Adverse Events ........................... 64 
5.3.4 
Assessment of Causality of Adverse Events ......................... 65 
5.3.5 
Procedures for Recording Adverse Events ............................ 65 
5.3.5.1 
Diagnosis versus Signs and Symptoms................................. 66 
5.3.5.2 
Adverse Events That Are Secondary to Other 
Events.................................................................................... 66 
5.3.5.3 
Persistent or Recurrent Adverse Events ................................ 66 
5.3.5.4 
Abnormal Laboratory Values ................................................. 67 
5.3.5.5 
Abnormal Vital Sign Values ................................................... 68 
5.3.5.6 
Abnormal Liver Function Tests .............................................. 68 
5.3.5.7 
Deaths ................................................................................... 69 
5.3.5.8 
Pre-existing Medical Conditions ............................................ 69 
5.3.5.9 
Lack of Efficacy or Worsening of Influenza A 
Infection ................................................................................. 69 
5.3.5.10 
Hospitalization or Prolonged Hospitalization .......................... 70 
5.3.5.11 
Adverse Events Associated with an Overdose ...................... 70 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor .......................................................... 70 
5.4.1 
Emergency Medical Contacts ................................................ 71 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest ...................................................................... 71 
5.4.2.1 
Events That Occur prior to Study Drug Initiation .................... 71 
5.4.2.2 
Events That Occur after Study Drug Initiation ........................ 72 
5.4.3 
Reporting Requirements for Pregnancies .............................. 72 
5.4.3.1 
Pregnancies in Female Patients ............................................ 72 
5.4.3.2 
Pregnancies in Female Partners of Male Patients ................. 73 
5.4.3.3 
Congenital Anomalies/Birth Defects and 
Abortions ............................................................................... 73 
5.4.4 
Investigator Follow-Up ........................................................... 73 
5.4.5 
Sponsor Follow-Up ................................................................ 74 
5.5 
Poststudy Adverse Events ..................................................... 74 
5.6 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees ................................................................. 74 
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6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ....................... 75 
6.1 
Determination of Sample Size ............................................... 76 
6.2 
Summaries of Conduct of Study ............................................ 76 
6.3 
Summaries of Treatment Group Comparability ..................... 77 
6.4 
Efficacy Analyses .................................................................. 77 
6.4.1 
Primary Efficacy Endpoint ...................................................... 77 
6.4.2 
Secondary Efficacy Endpoints ............................................... 77 
6.4.3 
Subgroup Analyses ............................................................... 78 
6.5 
Safety Analyses ..................................................................... 78 
6.6 
Pharmacokinetic Analyses ..................................................... 78 
6.7 
Optional Interim Analysis ....................................................... 79 
7. 
DATA COLLECTION AND MANAGEMENT ............................................... 79 
7.1 
Data Quality Assurance ......................................................... 79 
7.2 
Electronic Case Report Forms ............................................... 80 
7.3 
Source Data Documentation .................................................. 80 
7.4 
Use of Computerized Systems .............................................. 80 
7.5 
Retention of Records ............................................................. 81 
8. 
ETHICAL CONSIDERATIONS .................................................................... 81 
8.1 
Compliance with Laws and Regulations ................................ 81 
8.2 
Informed Consent .................................................................. 81 
8.3 
Institutional Review Board or Ethics Committee .................... 82 
8.4 
Confidentiality ........................................................................ 83 
8.5 
Financial Disclosure .............................................................. 83 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 83 
9.1 
Study Documentation ............................................................ 83 
9.2 
Protocol Deviations ................................................................ 83 
9.3 
Site Inspections ..................................................................... 84 
9.4 
Administrative Structure......................................................... 84 
9.5 
Protocol Amendments ........................................................... 84 
10. REFERENCES ........................................................................................... 85 
 
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PROTOCOL SYNOPSIS 
TITLE: 
A PHASE 2 RANDOMIZED, DOUBLE-BLIND 
PLACEBO-CONTROLLED TRIAL OF MHAA4549A, A 
MONOCLONAL ANTIBODY IN COMBINATION WITH 
OSELTAMIVIR VERSUS OSELTAMIVIR FOR 
TREATMENT OF SEVERE INFLUENZA A INFECTION 
PROTOCOL NUMBER: 
GV29216 
VERSION NUMBER: 
2 
EUDRACT NUMBER: 
2014-000461-43 
IND NUMBER: 
117,318 
TEST PRODUCT: 
MHAA4549A 
INDICATION: 
INFLUENZA A 
SPONSOR: 
Genentech, Inc. 
Objectives 
Safety Objectives 
The safety objectives for this study are as follows: 
•
To evaluate the safety of MHAA4549A in combination with oseltamivir compared with
placebo and oseltamivir in patients with severe influenza A, focusing on the nature, 
frequency, and severity of serious and non-serious adverse events, as well as effects on 
laboratory values, vital signs, electrocardiogram (ECG) parameters, anti-therapeutic 
antibodies (ATA), or other safety biomarkers 
Efficacy Objectives 
The primary efficacy objective for this study is as follows: 
•
To determine the time to normalization of respiratory function of patients dosed with
MHAA4549A in combination with oseltamivir compared to patients dosed with placebo and 
oseltamivir 
The secondary efficacy objectives for this study are as follows: 
•
To measure clinical failure after 24 hours post-infusion of study drug
•
To determine the time to clinical resolution of vital signs
•
To measure mortality in patients
•
To determine changes in the extent and duration of viral shedding in upper respiratory
samples
•
To measure the duration of hospital and/or intensive care unit (ICU) stay
•
To measure antibiotic usage for respiratory indications
•
To measure the frequency and severity of the following secondary complications of
influenza:
− 
Pneumonia (hospital acquired pneumonia [HAP]/ ventilator acquired pneumonia [VAP]) 
− 
Exacerbations of chronic lung disease 
− 
Myocarditis 
− 
Acute respiratory distress syndrome (ARDS) 
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window.  All patients will receive oseltamivir for a minimum of 5 days (10 doses), starting on 
Day 1 beginning no later than 8 hours after study drug administration.  All patients will be 
followed for 60 days from the time of study drug administration. 
Number of Patients 
The study has a planned enrollment of approximately 334 patients (adult men and women) 
globally.  Patients will receive MHAA4549A or placebo in 1:1 ratio.  The number of patients on 
PPV should not exceed 45% of the total enrolled patients. 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• Men or women ≥ 18 years of age on day of signing informed consent or obtaining surrogate 
consent from an authorized representative 
• Diagnosis of influenza A as determined by one or both of the following: 
− 
A Sponsor-supplied rapid influenza test 
− 
A local molecular test (PCR)  
• One of the following markers of severity within 24 hours of hospital admission: 
− 
Requirement for PPV, OR 
− 
Requirement for O2 supplementation to maintain SpO2 > 92% 
• 
A negative urine or serum pregnancy test for women of childbearing potential 
• 
Patients of reproductive potential must agree to use reliable means of contraception as 
described below as a minimum (adherence to more stringent local requirements may be 
required): 
− 
For female patients:  Use of two acceptable methods of contraception throughout the 
trial, including the active treatment phase AND for 24 weeks after the last dose of 
MHAA4549A.  Acceptable methods of contraception include:  intrauterine device, 
systemic hormonal contraception (oral or depot), vaginal ring, tubal ligation of the female 
partner, vasectomy of the male partner, use of latex condoms plus spermicide by the 
male partner, or cervical cap plus spermicide (where the spermicide could be foam, 
vaginal suppository, gel, cream, etc.). 
− 
For male patients:  Use of condoms for 30 days after dosing when circulating drug levels 
remain high. 
− 
Non-reproductive potential is defined below (but could be superseded by local definitions, 
if they are more stringent): 
Women who are postmenopausal (i.e., spontaneous amenorrhea for the past year 
confirmed by an follicle stimulating hormone [FSH] level greater than 40 mIU/mL 
unless the patient is receiving a hormonal therapy for their menopause)  
Women who are surgically sterile (i.e., hysterectomy, complete bilateral 
oophorectomy) 
Men who are surgically sterile (castration) 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Pregnant or lactating, or intending to become pregnant during the study 
− 
Women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) 
or who are not surgically sterile must have a negative urine or serum pregnancy test 
result within 2 days prior to study treatment 
• 
Hypersensitivity to monoclonal antibodies or any constituents of study drug 
• 
Investigational therapy within the 30 days prior to study treatment  
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• 
Received prior therapy with any anti-influenza monoclonal antibody therapy including 
MHAA4549A 8 months prior to study treatment 
• 
Current treatment (within 7 days of dosing) with amantadine or rimantidine 
• 
Patients who have taken more than a total of 3 days (6 doses) of approved anti-influenza 
therapy (i.e., oral oseltamivir, inhaled zanamivir, or oral ribavirin) in the period from onset of 
symptoms and prior to enrollment 
• 
Admission > 48 hours prior to study treatment 
• 
Onset of influenza symptoms > 5 days prior to study treatment 
• 
Positive influenza B or influenza A + B infection within 2 weeks prior to study treatment 
• 
High probability of mortality in the next 48 hours as determined by the investigator  
• 
Patient requiring home or baseline oxygenation therapy 
• 
Patient with history of chronic lung disease resulting in baseline SpO2 < 95%  
• 
Patient on chronic dose of corticosteroids exceeding 10 mg/day of prednisone or equivalent 
steroid dose for a duration of greater than 14 days within 30 days of entry into study 
• 
Patients with the following significant immune suppression: 
− 
Bone marrow or solid organ transplant in the previous 12 months 
− 
Cancer chemotherapy in the previous 12 month 
− 
HIV infection with most recent CD4 < 200 cells/mL 
− 
Other significant immune suppression as determined by the investigator in discussion 
with the Sponsor Medical Monitor or representative 
• 
Patient on extracorporeal membrane oxygenation (ECMO) at time of randomization 
• 
Any disease or condition that would, in the opinion of the site investigator or Sponsor, place 
the subject at an unacceptable risk of injury or render the subject unable to meet the 
requirements of the protocol 
Length of Study 
This study will consist of the following study periods: 
• A screening period of 48 hours, beginning at time of hospital submission 
• A treatment period of 1 day, during which patients will receive a single dose of MHAA4549A 
or placebo and a minimum of 5 days of oseltamivir. 
• A follow-up period beginning at hospital discharge through 60 days post study drug 
(MHAA4594A/placebo) administration 
End of Study 
The end of the study is defined as the first day when all patients have had a study completion 
visit or early termination visit or have otherwise been discontinued from the study. 
Outcome Measures 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
Adverse events and clinical laboratory abnormalities 
• 
Vital signs, physical findings, ATAs, and clinical laboratory results during and following 
administration of MHAA4549A 
Efficacy Outcome Measures 
The primary outcome measure for this study is as follows: 
• Time to normalization of respiratory function defined as: 
− 
The time to cessation of O2 support resulting in a stable SpO2 >95% for at least 24 hours 
The secondary efficacy outcome measures for this study are as follows: 
• Clinical failure after 24 hours post-infusion of study drug defined as: 
MHAA4549A—Genentech, Inc. 
Protocol GV29216, Version 2 
23 






Estimation of the treatment difference of proportions and its 95% confidence interval will be 
calculated using stratum-adjusted Mantel-Haenszel methodology.  For continuous endpoints, 
Analysis of Covariance methods (after appropriate transformation of data) will be used to 
estimate treatment differences at 95% confidence intervals.  
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 I error penalty of 0.0001 will be taken.  In addition, as discussed below, the 
Sponsor will conduct interim safety analyses separate from and in conjunction with the above. 
Determination of Sample Size   
A total of 334 patients will be enrolled in this study in order to obtain approximately 
300 evaluable patients (an estimated dropout rate of 10%).  It is assumed that the median time 
to normalization of respiratory function in the control arm is 5 days 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation Definition 
 
 
AE 
Adverse event 
AESI 
Adverse events of special interest 
ALT 
Alanine aminotransferase 
ARDS 
Acute respiratory distress syndrome 
AST 
Aspartate aminotransferase 
ATA 
Anti-therapeutic antibody 
AUC 
Area under serum concentration−time curve  
AUEC 
Area under viral load−time curve  
BID 
Twice a day 
°C 
Celsius 
Cmax 
Maximum observed concentration 
Cmin 
Minimum observed concentration 
CPK 
Creatine phosphokinase 
CRO 
Contract (or Clinical) Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAIDS 
Division of Acquired Immunodeficiency Syndrome 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ECMO 
Extracorporeal membrane oxygenation 
EDC 
Electronic data capture 
FDA 
Food and Drug Administration 
FiO2 
Fraction of inspired oxygen 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
HA 
Hemagglutinin  
HAI 
Hemagglutinin inhibition 
HAP 
Hospital Acquired Pneumonia 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HR 
Heart rate 
 
 
ICH 
International Conference on Harmonisation 
ICU 
Intensive Care Unit 
IEC 
Independent Ethics Committee 
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Abbreviation Definition 
IMC 
Internal Monitoring Committee 
IMP 
Investigational medicinal product 
IND 
Investigational New Drug (application) 
IRB 
Institutional Review Board 
IRR 
Infusion-related reactions 
IV 
Intravenous 
LFTs 
Liver function tests 
mAB 
Monoclonal antibody 
NAI 
Neuraminidase inhibitor 
NP 
Nasopharyngeal 
PaO2 
Partial pressure of arterial oxygen 
PCR 
Polymerase Chain Reaction 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PPV 
Positive pressure ventilation 
qPCR 
Quantitative Polymerase Chain Reaction 
QTcB 
QT interval corrected using Bazett’s formula 
QTcF 
QT interval corrected using Fridericia’s formula 
RBC 
Red blood cell 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SOC 
Scientific Oversight Committee 
SpO2 
Oxygen saturation by pulse oximetry 
SUSAR 
Suspected unexpected serious adverse reactions 
ULN 
Upper limit of normal 
VAP 
Ventilation Acquired Pneumonia 
 


 
1. 
BACKGROUND 
1.1 
BACKGROUND ON INFLUENZA 
Influenza A is a membrane-enveloped RNA virus that causes significant morbidity and 
mortality.  Currently, there is a great need in hospitalized influenza patients for a 
parenteral therapeutic option that is well tolerated, can rapidly resolve influenza-related 
signs and symptoms, decrease mortality, reduce hospital and intensive care unit (ICU) 
stays, as well as have a prolonged window for initiation of treatment beyond the current 
standard of care (i.e., within 48 hours of the onset of flu symptoms). 
Approximately 200,000 to 278,000 patients are hospitalized with severe influenza 
infections annually in the United States (U.S.) (Thompson et al. 2004; Zhou et al. 2012), 
and assuming the same rate reported in the U.S., an estimated 319,000 to 
445,000 patients are hospitalized in the European Union (E.U.).  Hospitalization due to 
severe influenza is associated with high mortality (4%−8%), ICU admission (5%−17%; 
Lee and Ison 2012), mechanical ventilation support in an ICU setting (7%−11%; 
Doshi et al. 2011), and prolonged hospital stays (5−9 days; Lee and Ison 2012).  During 
a pandemic season, the outcomes may be more serious, with up to 34% of patients 
requiring ICU care and a mortality rate as high as 15% (Lee and Ison 2012). 
Influenza infection is an upper and lower respiratory disease with a broad spectrum of 
presentations that can result in fever, shortness-of-breath, pneumonia, respiratory failure, 
secondary respiratory infections, and even death.  The standard of care therapy for 
patients hospitalized with influenza consists of supportive measures and administration 
of available antiviral agents, primarily neuraminidase inhibitors (NAI) that include but are 
not limited to oseltamivir, zanamivir, and peramivir.  However, a significant unmet 
medical need still exists in the severely ill patient population, as evidenced by the 
considerable degree of morbidity and mortality in this setting.  To address this need, 
Genentech Inc. /F.Hoffmann-La Roche Ltd. (Genentech) is developing a highly-specific 
anti-influenza A (MHAA4549A) antibody therapy for treatment of hospitalized patients 
with severe influenza. 
1.2 
BACKGROUND ON MHAA4549A 
1.2.1 
Nonclinical Background 
MHAA4549A is a human monoclonal IgG1 antibody (mAb) that binds to the influenza A 
virus and is 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 stalk region, which allows broad neutralization 
of the influenza A virus by blocking the hemagglutinin-mediated, membrane-fusion event 
in the late endosome. 
In vitro, MHAA4549A is capable of neutralizing all current clinically relevant influenza A 
strains.  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.  
MHAA4549A—Genentech, Inc. 
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MHAA4549A—Genentech, Inc. 
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MHAA4549A specifically targets an epitope on the human influenza A hemagglutinin 
glycoprotein, which does not appear to be endogenously expressed on human or rat 
tissues and, therefore, is unlikely to be present in the absence of viral infection.  Weekly 
administration of MHAA4549A (total of 5 doses) in Sprague-Dawley rats was well 
tolerated up to the maximum feasible dose of 150 mg/kg.  Ex vivo tissue cross-reactivity 
study data showed no specific binding of MHAA4549A to any of the human or rat tissues 
examined. 
1.2.2 
Clinical Safety Background 
To date, MHAA4549A has been shown to be safe and well tolerated in two clinical 
studies, which altogether enrolled 122 healthy volunteers.  The first study was a 
Phase 1 study (GV28916) in 21 healthy volunteers where single doses of 1.5 mg/kg, 
5 mg/kg, 15 mg/kg, and 45 mg/kg were tested with an extended follow-up period of 
120 days.  MHAA4549A was safe and well tolerated with no serious adverse events 
(SAEs).  All adverse events (AEs) were mild or mild-to-moderate and resolved fully 
before the end of the study’s follow-up period.  No anti-therapeutic antibodies (ATAs) 
were detected in this study.  In addition, the MHAA4549A pharmacokinetics were 
generally dose proportional, and appeared to have a pharmacokinetic (PK) profile 
consistent with that of a human IgG1 antibody that lacks known endogenous host targets.  
The second study was a Phase 2a challenge study (GV28985) in 101 healthy volunteers 
infected with a H3N2 (A/Wisconsin/67/2005) strain of influenza virus.  Fixed dosing was 
selected for this study and is further described in Section 1.3.2.3.  Sixty subjects 
received doses of 400 mg, 1200 mg, or 3600 mg MHAA4549A and 41 subjects received 
placebo following nasal inoculation of influenza A virus one day earlier.  The interim 
efficacy analysis in Table 1 includes the Intent-to-Treat (ITT) infected population who 
received placebo (N  21), 400 mg MHAA4549A (N  11), 1200 mg MHAA4549A 
(N  13), 3600 mg MHAA4549A (N=14), and oseltamivir (N  2).  All subjects have 
completed dosing, and interim PK and efficacy data are available in the Investigator’s 
Brochure and upon request.  During this study, elevated ALT, AST, and amylase levels 
were observed within the first 2 weeks after inoculation with A/Wisconsin/67/2005 and 
dosing with MHAA4549A.  Previous experience with this challenge model has shown 
ALT/AST/amylase elevations to be associated with the influenza infection itself 
(Polakos 2006).  Consistent with previous trials, in GV28985, there was no relationship 
of elevations in AST, ALT, or amylase with either dose or exposure (e.g., placebo: 
22.0%, 400 mg: 35.0%,1200 mg: 25.0%, 3600 mg: 20.0%).   
In GV28985, most AEs were Grade 1 or Grade 2 (mild or moderate) and appeared to 
reflect the symptoms of the influenza infection.  In the 400 mg group, 15 (75.0%), 1 
(5.0%), and 2 (10.0%) subjects reported Grade 1, 2, and 3 AEs respectively.  In the 
1200-mg group, 9 (45.0%), 6 (30.0%), and 1 (5.0%) subjects reported Grade 1, 2, and 3 
AEs, respectively.  In the 3600-mg group, 10 (50.0%), 5 (25.0%), 1 (5.0%) subjects 
reported Grade 1, 2, and 3 AEs, respectively.  One (5.0%) subject reported a Grade 4 


 
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Protocol GV29216, Version 2 
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AE in the 3600-mg group, which was a lower limb fracture, not related to 
MHAA4549A.  Subjects in the placebo group reported 18 (56.3%) Grade 1 AEs, 8 
(25.0%) Grade 2 AEs, and 2 (6.3%) Grade 3 AEs.  In addition, there were no drug 
related SAEs, deaths, or discontinuations due to AEs.  There were a total of 3 SAEs 
unrelated to MHAA4549A in two subjects.  One subject reported depressive psychosis 
associated with influenza.  There were a total of 3 SAEs unrelated to MHAA4549A in 
two subjects.  One subject reported depressive psychosis associated with influenza.  The 
second subject reported a broken knee with a subsequent infection following a surgical 
procedure. 
In GV28985, 1 patient tested positive for anti-therapeutic antibodies (ATAs).  This 
patient tested positive for ATA at baseline and post baseline.  This patient was in the 
placebo group, which included 32 other subjects, resulting in an immunogenicity 
prevalence rate (ATA-positive rate at baseline) of 3.1% and an immunogenicity 
incidence rate (ATA titers post-baseline) of 3.1%, as well, within the placebo group.  
Overall, study GV28985 had an immunogenicity prevalence rate of 1%.  The 
immunogenicity incidence rate amongst the 60 subjects who received MHAA4549A 
was 0%.  
Based on this data, MHAA4549A is considered generally safe and well tolerated to date 
at all doses tested, including the 3600 mg dose.   
1.2.3 
Clinical Efficacy Background 
Analysis of efficacy from the 3600-mg dose level demonstrated a statistically significant 
decrease in viral shedding from upper respiratory tract as measured by the area under 
the curve (97% reduction by quantitative polymerase chain reaction [qPCR]) and peak 
viral load (77% reduction by qPCR) as shown in Table 1. 
In this study, oseltamivir was started on Day 7 for a 5-day course, and there were no 
observed AEs or imbalances in safety events that were considered attributable to 
interactions between oseltamivir and MHAA4549A.  The PK profile of MHAA4549A and 
oseltamivir in GV28985 are being analyzed to exclude potential drug-drug interactions 
and will be available before the start of this study GV29216.   


 
Table 1 
Interim Efficacy Results from Phase 2a Challenge Study 
(GV28985) 
Endpoint 
Placebo 
(N=21) 
MHAA4549A 
Oseltamivir 
400 mg 
(N=11) 
% reduction 
(p-value)a 
1200 mg 
(N=13) 
% reduction 
(p-value)a 
3600 mg 
(N=14) 
% reduction 
(p-value)a 
75 mg BID 
(N=2) 
% reduction  
(p-value)a 
Median qPCR 
Viral AUEC 
(log10 vc/mL x 
hour) 
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 qPCR 
Peak Viral Load 
(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 Total 
Clinical Symptom 
AUEC 
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) 
AUEC = area under viral load−time curve; qPCR = quantitative polymerase chain reaction. 
a Comparison of active and placebo using nonparametric Wilcoxon rank-sum test.  All p-values 
are unadjusted for multiple testing. 
  
The A/Wisconsin/67/2005 virus induced mild symptoms that were predominantly 
captured in the upper respiratory tract symptoms that included runny nose, stuffy nose 
and sneezing. 
The Symptom Diary Cards used 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 from Study GV28985 for the Intent-to-Treat (ITT) infected population who 
received placebo (N = 21), 400 mg MHAA4549A (N = 11), 1200 mg MHAA4549A 
(N = 13), 3600 mg MHAA4549A (N = 14), and oseltamivir (N = 2) are shown in Table 1. 
Given the variability of the symptom scores the results were not statistically 
significant.  However, there was a decrease in the AUEC of symptoms scores for the 
3600 mg dose, which is consistent with the virological results described in the Table 1 
above.  Data from the oseltamivir treated group is also shown but it should be noted 
that only 2 subjects were in the ITT infected population. 
See the MHAA4549A Investigator’s Brochure for additional details on nonclinical and 
clinical studies. 
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1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
1.3.1 
Study Rationale 
The Phase 1 and Phase 2a studies have demonstrated that MHAA4549A is safe and 
well tolerated to date in healthy volunteers including those who were inoculated with 
influenza A virus.  Data from the Phase 2a study also provides evidence that the 
3600 mg dose of MHAA4549A is effective in reducing viral titers in healthy volunteers 
inoculated with influenza A virus.  These findings, when combined with previous 
nonclinical studies showing MHAA4549A to have in vitro and in vivo efficacy, a 
well-tolerated safety profile, and anti-viral activity, support further clinical development of 
MHAA4549A. 
In this Phase 2b study (GV29216), MHAA4549A is being evaluated in combination with 
the current standard of care (oseltamivir), to decrease the severity and duration of viral 
infection with influenza A virus with the ultimate goal of reducing the clinical symptoms of 
infection as compared to oseltamivir with placebo.  There are three primary goals for this 
Phase 2b study:  
• 
Demonstrate the safety and efficacy of MHAA4549A in combination with oseltamivir 
in hospitalized influenza A patients  
• 
 
 
  
• 
Demonstrate and evaluate the optimal endpoints for study in hospitalized patients 
with influenza A, given the lack of precedence for approval in patients hospitalized 
with influenza infection, an area of high unmet medical need 
 
This Phase 2b study has been designed to estimate the improvement in outcome of a 
combination therapy of MHAA4549A 3600 mg with oseltamivir versus placebo with 
oseltamivir.  All patients will be on oseltamivir, which is part of the recommended 
standard of care.  In addition, and as discussed above, MHAA4549A is a human 
monoclonal antibody that has, to date, shown an acceptable safety profile, a PK profile 
consistent with that of a IgG1 human antibody that lacks known endogenous host targets, 
and a demonstrated antiviral activity at the planned dose level of 3600 mg. 
1.3.2 
Benefit-Risk Assessment 
1.3.2.1 
Treatment in Combination with Oseltamivir 
All patients in the study will receive oseltamivir as the current standard of care treatment, 
either with or without MHAA4549A.  Therefore, at a minimum, all patients will be treated 
with standard of care for influenza.  Given that MHAA4549A is an antibody, the potential 
for a drug-drug interaction with oseltamivir is very low.  In the ongoing Phase 2a 
challenge study (GV28985), study subjects received MHAA4549A followed by 
oseltamivir with no AEs attributable to the combination therapy noted to date.  In addition, 
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Protocol GV29216, Version 2 
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in this study the PK profile of oseltamivir in concomitantly treated subjects will be 
assessed. 
1.3.2.2 
Drug Mechanism and Preclinical Studies 
The available pre-clinical data suggest that there is low risk for drug target-related safety 
events in healthy humans since MHAA4549A specifically targets an epitope on a viral 
protein (i.e., the human influenza A virus hemagglutinin glycoprotein), which is not 
endogenously expressed in human tissues.  Furthermore, there were no adverse 
MHAA4549A-related findings demonstrated in nonclinical studies at doses up to 
150 mg/kg administered weekly for 5 weeks and no evidence of target present in host 
tissues.   
1.3.2.3 
Rationale for Selection of Phase 2b Study Population 
The target patient population of hospitalized patients with severe influenza A requiring 
oxygen (O2) or positive pressure ventilation (PPV) is considered an appropriate 
population to test MHAA4549A for the following reasons: 
 
Nonclinical safety data does not show any expected or unexpected toxicity. 
 
Clinical safety data for MHAA4549A demonstrate a well-tolerated safety profile:   
o AEs in the Phase 1 study (GV28916) were mild and did not show a dose 
relationship; there were no ATAs detected in patients treated with 
MHAA4549A.   
o In the ongoing Phase 2a study (GV28985), MHAA4549A was generally well 
tolerated.  A few subjects in all treatment groups were observed to have 
transient elevations in alanine transaminase (ALT), aspartate transaminase 
(AST), and amylase levels.  There was no dose-dependent relationship of the 
ALT/AST/amylase elevations with MHAA4549A and the overall event rate was 
in line with published rates associated with the influenza challenge model 
regardless of treatment arm:  27/100 [27%] in GV28985 vs. approximately 26% 
in previous challenge studies (Polakos 2006).  There were no SAEs related to 
study drug.  There were a total of 3 SAEs unrelated to MHAA4549A in two 
subjects.  One subject reported depressive psychosis associated with influenza. 
The second subject reported a broken knee with a subsequent infection 
following a surgical procedure.   
 
Interim efficacy data in the Phase 2a challenge study (GV28985) demonstrated a 
significant decrease in viral shedding in the upper respiratory tract at the 3600 mg 
dose.  There was a 97.5% (p  0.0051) decrease in the area under viral loadtime 
curve (AUEC) and a 77% (p  0.0024) decrease in peak viral load by qPCR 
measurement in comparison to the placebo group, thus confirming proof of antiviral 
activity at the 3600 mg dose level.  Symptom data in the Phase 2a study showed a 
decrease in the AUC of symptoms scores for the 3600-mg dose that is consistent 
with the virological results as illustrated in Table 1. 
 


 
1.3.2.4 
Patient Monitoring and Supervision 
MHAA4549A will be administered to enrolled patients in a hospital environment under 
close medical supervision by physician investigators.  Medical staff will be available for 
prompt evaluation and treatment of any adverse events.  Emergency resuscitation 
equipment and emergency facilities will be readily available.  Patients will undergo 
screening assessments to confirm eligibility, will be closely monitored during the 
administration of MHAA4549A, and will be resident for at least 24 hours following the 
administration of MHAA4549A.  Furthermore, safety laboratory tests relating to the blood 
chemistries, including liver function tests, will be conducted. 
.An internal monitoring committee (IMC) in combination with a scientific oversight 
committee (SOC) will provide safety monitoring for the study in addition to the 
ongoing review of safety by the Medical Monitor and Safety Scientist.  See 
Section 3.1.2 for more information.  
The 120-day follow-up period in the Phase 1 and 2a studies allowed for monitoring of 
subjects for approximately 5 half-lives of MHAA4549A.  No ATAs were detected in the 
Phase 1 study, while one subject in the Phase 2a study tested positive for ATAs at 
baseline and post-baseline timepoints as described in Section 1.2.2.  The Phase 2b 
study will also include a safety follow-up period of 60 days and an unlimited collection of 
all SAEs believed related to MHAA4549A.   
Based on the above data and design of this study, the Sponsor concludes that the 
benefit−risk profile of MHAA4549A in the population with severe influenza is favorable.  
2. 
OBJECTIVES 
2.1 
SAFETY OBJECTIVES 
The safety objectives for this study are as follows: 
• 
To evaluate the safety of MHAA4549A in combination with oseltamivir compared 
with placebo and oseltamivir in patients with severe influenza A, focusing on the 
nature, frequency, and severity of serious and non-serious adverse events as well 
as effects on laboratory values, vital signs, electrocardiogram (ECG) parameters, 
ATAs, or other safety biomarkers 
 
2.2 
PRIMARY EFFICACY OBJECTIVES 
The primary efficacy objective for this study is as follows: 
• 
To determine the time to normalization of respiratory function of patients dosed with 
MHAA4549A in combination with oseltamivir compared to patients dosed with 
placebo and oseltamivir. 
 
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2.3 
SECONDARY EFFICACY OBJECTIVES 
The secondary efficacy objectives for this study are as follows: 
• 
To measure clinical failure, as defined in Section 3.3.3, after 24 hours post-infusion 
of study drug  
• 
To determine the time to clinical resolution of vital signs  
• 
To measure mortality in patients  
• 
To determine changes in the extent and duration of viral shedding in upper 
respiratory samples  
• 
To measure the duration of hospital and/or ICU stay 
• 
To measure antibiotic usage for respiratory indications  
• 
To measure the frequency and severity of the following secondary complications of 
influenza:  
o Pneumonia (hospital acquired pneumonia [HAP]/ ventilator acquired pneumonia 
[VAP]) 
o Exacerbations of chronic lung disease 
o Myocarditis 
o Acute respiratory distress syndrome (ARDS) 
o Otitis media 
o Other related complications 
o Readmission rates at 30 and 60 days after study treatment 
• 
To measure duration of PPV 
• 
To measure readmission rates 
 
2.4 
PHARMACOKINETIC OBJECTIVES  
The major PK objective for this study is as follows: 
• 
To characterize the PK profile of MHAA4549A in serum 
 
The exploratory PK objectives for this study are as follows: 
 
 
 
 
 
 
2.5 
EXPLORATORY OBJECTIVES 
The exploratory objectives of this study are as follows: 
• 
 
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3. 
STUDY DESIGN  
3.1 
DESCRIPTION OF THE STUDY 
3.1.1 
Overview of Study Design 
This is a Phase 2b, randomized, double-blind, placebo-controlled study designed to 
assess the safety and clinical activity of a single intravenous (IV) dose of MHAA4549A in 
hospitalized patients with severe influenza A in combination with oseltamivir versus a 
comparator arm of placebo with oseltamivir.  This study is planned to take place in 
approximately 170 study centers globally. 
Patients will be randomized 1:1 into two treatment groups:  a single IV dose of 3600 mg 
of MHAA4549A with oseltamivir or a single IV dose of placebo with oseltamivir.  All 
patients will receive oseltamivir, a NAI, as standard therapy for a minimum of 5 days 
after study drug administration.  Oseltamivir at doses of 75 mg BID or 150 mg BID is 
permitted in order to be consistent with local standard of care practice.  Treatment for 
longer than 5 days is permitted based on local investigator discretion.  The patient must 
start Sponsor-supplied oseltamivir within 8 hours of study drug administration.  The 
study has a planned enrollment of approximately 334 patients globally. 
Hospitalized patients with an O2 or PPV requirement will be evaluated for influenza A 
infection.  Enrollment in this study requires ongoing treatment within 24 hours of hospital 
admission with one of the following:  
• 
any PPV or  
• 
any supplemental O2 to maintain oxygen saturation (SpO2) >92% (see Section 3.3.2)   
 
Patients on PPV should not exceed 45% of the total patients enrolled. 
A Sponsor-supplied rapid influenza test and/or a local polymerase chain reaction (PCR) 
test must be used as an aid in the diagnosis of influenza A infection.   
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At the time of randomization, patients who are eligible for enrollment, as described 
above, will be randomized to receive MHAA4549A at a dose of 3600 mg or placebo.  
Patients will be stratified by site, PPV versus supplemental O2 at randomization, and 
suspected or confirmed bacterial pneumonia versus no bacterial pneumonia based on 
the status at randomization. 
Eligible patients who are enrolled into the study will receive either a single IV infusion of 
MHAA4549A or a single IV infusion of placebo on Day 1.  All patients must have the 
study drug infused within 48 hours of hospital admission or sooner if possible.  All 
patients will receive oseltamivir for a minimum of 5 days (10 doses), starting on Day 1, 
beginning no later than 8 hours after study drug administration.   
All patients will be followed and evaluated at minimum on a daily basis for the duration of 
their hospital stay consistent with the planned schedule of assessments.  Any suspicion 
of bacterial superinfection should be thoroughly evaluated including microbiological 
confirmation, if possible.  A follow-up study visit should occur on Day 14 ± 1 (if 
discharged before Day 14); Day 30 ± 4 days (if discharged before Day 30); and 
Day 60 ± 4 days (if discharged before Day 60). 
Safety evaluations will be provided by an IMC and SOC, as defined in the IMC and 
SOC agreement (see Section 3.1.2) 
A schedule of assessments is provided in Appendix 1a and Appendix 1b.  A diagram of 
the study design is presented in Figure 1.  
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Figure 1 Phase 2b Study Design (GV29216) 
 
  
3.1.2 
Independent Monitoring Committee and Scientific Oversight 
Committee 
A combined approach with both an IMC and a SOC is proposed to enhance patient 
safety.  The IMC consists of Sponsor representatives from the following functions: 
Clinical Science, Drug Safety, Biostatistics, and Statistical Programming and Analysis.  
The IMC members will be unblinded to patient treatment and assignment.  The Clinical 
Science representative on the IMC (IMC Chair) will be a person other than the Study 
Medical Monitor and will not be involved in the conduct of the study or have any 
contact with study investigators or site staff.  The Study Medical Monitor will remain 
blinded to individual treatment assignments, unless, in exceptional cases, specific 
circumstances require Study Medical Monitor unblinding after IMC Chair approval.  
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.  The Biostatistician and 
Statistical Programmer are the only IMC members involved in the conduct of the study; 
however, they do not have any contact with study investigators, and all discussion 
within the IMC are 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 two SOC members are external experts in the field and will be unblinded to 
treatment allocation.  The SOC may be further expanded by the IMC during the course 
of the study to include additional external experts if the need arises.  
A detailed description of the procedures, data flow, and meeting schedule of the IMC 
and SOC will be provided in a separate IMC and SOC agreement. 
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3.1.3 
End of Study 
The end of study is defined as the first day when all patients have had a study 
completion visit or early termination visit or have otherwise been discontinued from the 
study. 
3.2 
RATIONALE FOR STUDY DESIGN 
3.2.1 
Rationale for Study Design 
Hospitalized influenza A infection represents a high unmet need, which, when left 
untreated, may progress to a more serious disease that may result in significant 
morbidity and mortality in otherwise healthy adults as well as in vulnerable populations.   
This study is designed to estimate the improvement in outcome of a combination 
regimen of MHAA4549A with oseltamivir compared to a standard of care arm of placebo 
with oseltamivir.  The study population will include hospitalized patients with influenza A 
requiring O2 support and/or PPV support within 24 hours of hospital admission.  
Study GV29216 will be a Phase 2b study involving approximately 334 patients.  The 
sample size was determined based on an expected clinically meaningful difference of 
1 − 2 days improvement in time to normalization of respiratory function between the 
control and treatment arms, assuming a 5-day median time to the time to normalization 
of respiratory function in the standard of care arm (Blackwood 2011; PREMIER 
database).   
This design ensures that all patients in the trial will receive the current NAI treatment, 
oseltamivir, as standard of care at a minimum, and will evaluate the clinical benefit of 
combining MHAA4549A with this standard of care regimen.  Therefore, this study aims to 
identify a regimen that could deliver maximum benefit in this high unmet need disease, 
while still treating all enrolled patients with the currently accepted standard of care. 
3.2.2 
Rationale for Patient Population and Primary Endpoint 
Severe influenza, for the purpose of this study, is defined as requiring one of the 
following treatments: any supplemental O2 to maintain an SpO2 > 92% or PPV.  PPV is 
defined as any mechanical positive pressure device to maintain oxygenation; this can 
include positive pressure mask and intubation.  A Sponsor-supplied rapid influenza test 
and/or a local PCR must be used as an aid in the diagnosis of influenza A infection. 
This patient population was chosen based on the rationale that respiratory failure is a 
hallmark of influenza and a major driver of morbidity and mortality, as well as 
hospitalization.  The recovery from ventilator support has been shown to be directly 
proportional to time spent in the ICU (Blackwood 2011; PREMIER database).  Based 
upon an analysis of morbidity and mortality, the patient population that requires 
supplemental O2 or ventilation on their first day of admission was determined to have a 
high unmet medical need as they have an estimated mortality of 9%−32%, and 27% 
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require admission to the ICU, according to analysis of a database of over 70,000 
hospitalized patients in the US from 2005−2012 (PREMIER database).   
Support for use of the respiratory endpoint in this population comes from recently 
published data demonstrating that a composite endpoint that captured respiratory rate, 
fever, heart rate, and blood pressure resolution was primarily driven by the respiratory 
component of the endpoint (Marty et al. 2014).   
3.2.3 
Rationale for Control Group and Treatment Window 
In this study, the standard of care regimen for the control or comparator group is 
oseltamivir, an NAI.  In the treatment groups, MHAA4549A will be dosed in addition to 
an oseltamivir standard of care regimen.  The oseltamivir dose will be consistent with the 
local investigator practice at each site where the study will be conducted.  Either 75 mg 
or 150 mg orally BID oseltamivir for a minimum of 5 days is permitted following treatment 
with MHAA4549A.  Treatment for longer than 5 days is permitted based on local 
investigator discretion.  The oseltamivir dosing regimen, including the renal dosing 
adjustment, is listed in Table 2.  This control treatment was based on consideration of 
safety, ethics, and efficacy for treatment of severe influenza and is consistent with 
guidelines for antiviral treatment of hospitalized patients with influenza                   
(Harper et al. 2009, Fiore 2011).  
Table 2 
Oseltamivir Dosing Regimen 
Neuraminidase Inhibitor 
Dosing Regimen 
Duration of 
Therapy 
Oseltamivir 
75 mg or 150 mg orally BID a 
75 mg oral once daily for adult patients with 
creatinine clearance (CrCL) between  
10 and 30 mL/minb 
5 days c 
a 75 mg or 150 mg dose at the discretion of the investigator, and dose must be documented.  
Capsules can be opened and the granules administered via nasogastric tube, if required. 
b No recommended dosing regimens are available for patients with end-stage renal disease 
undergoing routine hemodialysis or continuous peritoneal dialysis treatment. 
c Longer treatment times are at the discretion of the investigator. 
From a safety standpoint there are no expected drug interactions between MHAA4549A, 
a monoclonal antibody, and any NAI, which are small molecule drugs that bind to a 
different viral protein than MHAA4549A.  In the Phase 2a challenge study, all subjects 
that were dosed with MHAA4549A also received a 5-day course of oseltamivir starting 
on Day 7.  There were no safety effects attributable to the combination when the drugs 
were present concurrently.  The pharmacokinetics of oseltamivir and its potential 
interaction with MHAA4549A are being assessed from this Phase 2a. 
For this Phase 2b study, a combination of MHAA4549A and oseltamivir was determined 
to be the most clinically feasible treatment regimen, both from an ethical as well as a 
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practical perspective.  The treatment of all patients with oseltamivir ensures that all 
patients will receive standard of care given the high morbidity and mortality of 
hospitalized patients with influenza A along with guidelines from Centers for Disease 
Control and Prevention (CDC) and Infectious Diseases Society of America (IDSA) 
stating NAIs are the standard of care for hospitalized patients with influenza A     
(Harper et al. 2009 and CDC Website).  Further, pre-clinical efficacy data from a study 
using MHAA4549A and oseltamivir in combination, showed a potential synergistic effect 
of both compounds which may be due to the different and potentially complementary 
mechanisms of action, i.e. targeting viral hemagglutinin and neuraminidase. 
Dosing of MHAA4549A is confined to a treatment window designed for best expected 
treatment success and to ensure that any observed effects can be attributed to the study 
drug with high confidence.  MHAA4549A shall only be dosed within 5 days of symptom 
onset, within 3 days of initial treatment with a NAI, and no later than 48 hours after 
admission to the hospital.  This proposed window is supported by data demonstrating 
that hospitalized influenza patients benefit from NAI treatment even at 5 days from 
symptom onset (Louie et al. 2012).  
3.2.4 
Rationale for MHAA4549A Dosage 
A single IV dose of 3600 mg of MHAA4549A was selected to assess the efficacy of 
MHAA4549A and to provide data for further clinical development.  The selection of dose 
in this study for severely ill patients was based on the observed human 
pharmacokinetics in Phase 1 and the relationship between the pharmacokinetics, 
pharmacodynamics, and efficacy observed in a Phase 2a human challenge model of 
influenza.  MHAA4549A was shown to be safe and well-tolerated at all dose levels 
(ranging from 1.5 mg/kg to 45 mg/kg for Phase 1 and 400-3600 mg for Phase 2a) 
through a follow-up period of 120 days post-dose in the Phase 1 and Phase 2a study.  
The dose level used in this study was determined following analysis of data from the 
Phase 2a study, GV28985, which demonstrated the following: 
•
The 3600-mg dose demonstrated a significant decrease in viral shedding in upper
respiratory samples.  Based on current interim analysis data, there was a 97.5%
(p = 0.0051) decrease in AUEC and a 77.3% decrease in peak viral load by qPCR
measurement compared to the placebo group.
•
Symptom data in the Phase 2a study showed a decrease in the AUC of symptoms
scores for the 3600-mg dose, as illustrated in Table 1, which is consistent with the
virological results.
•
The 1200-mg dose level was not efficacious
•
There are no safety concerns at the 3600-mg dose level to date.
•
Hospitalized patients generally have a longer duration of viral shedding and
significantly more viral burden in the lower lung compartments; therefore, high
concentrations of mAb are likely needed to achieve sufficient occupancy of the virus
binding sites in the upper and lower respiratory compartments.  Furthermore, higher
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concentrations of mAb are necessary to mitigate the risk of resistance for 
MHAA4549A . 
 
The Phase 1 study was conducted using body-weight based dosing followed by a fixed 
dosing strategy that was used in the Phase 2a study.  Thus, the fixed dosing regimen 
that was used in the Phase 2a study will be used for this study, given the practical 
advantages and positive safety profile of MHAA4549A to date.  Further, fixed dosing is 
generally recommended with monoclonal antibodies, due to their minimal PK variability 
(Bai et al. 2012).  The PK variability introduced by different dosing regimens (i.e., 
body-weight based dosing versus fixed dosing) is moderate relative to the variability 
generally observed in pharmacodynamics, efficacy, and safety and would not be 
expected to be clinically meaningful.   
3.2.5 
Rationale for Biomarker Assessments  
 
 
 
 
 
 
 
 
  
3.3 
OUTCOME MEASURES  
3.3.1 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
Adverse events and clinical laboratory abnormalities  
• 
Vital signs, physical findings, ATAs, and clinical laboratory results during 
and following administration of MHAA4549A 
 
3.3.2 
Primary Efficacy Outcome Measure 
The primary outcome measure for this study is as follows: 
• 
Time to normalization of respiratory function defined as: 
− 
The time to cessation of O2 support resulting in a stable SpO2 >95% for at least 
24 hours (see Appendix 2 for details) 
 
3.3.3 
Secondary Efficacy Outcome Measures 
The secondary efficacy outcome measures for this study are as follows: 
• 
Clinical failure after 24 hours post-infusion of study drug; defined as: 
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− 
Progression to increased O2 requirement defined by an increase in oxygen 
supplementation from low flow oxygen (2 − 6 L/min) to high flow oxygen 
( > 6 L/min) or from oxygen supplementation alone to any PPV 
− 
Progression to ICU 
− 
Prolonged ventilation or O2 support defined by  > 2 weeks, or 
− 
Death 
• 
Time to clinical normalization of vital signs (3/5 criteria must be met): 
− 
SpO2 > 95% without supplemental O2 for at least 24 hours 
− 
Core temperature < 37.2°C immediately prior to receipt of any antipyretic drug, 
and at least 6-8 hours from the last dose of antipyretic or core temperature 
> 36°C in patients who are initially hypothermic 
− 
Heart rate (HR) < 100/minute 
− 
Systolic blood pressure (SBP) > 90 mmHg 
• 
All-cause mortality at Day 14, Day 30, and Day 60 
• 
Influenza A viral load in nasopharyngeal samples   
− 
AUEC 
− 
Peak viral load 
− 
Time to resolution of infection  
• 
Duration of hospitalization 
• 
Duration of ICU stay 
• 
Antibiotic usage for respiratory infections 
• 
Complications of influenza: 
− 
Pneumonia (HAP/VAP) 
− 
Exacerbations of chronic lung disease 
− 
Myocarditis 
− 
ARDS 
− 
Otitis media 
− 
Other related complications 
• 
All-cause readmission at Day 30 and Day 60 
• 
Duration of ventilation 
 
3.3.4 
Pharmacokinetic Outcome Measures  
The primary PK outcome measures for this study are as follows: 
• 
PK parameters for MHAA4549A in serum including total exposure (i.e., AUC), 
maximum observed concentration (Cmax), clearance, half-life, and volume of 
distribution, when appropriate, as data allow   
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4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Hospitalized men or women ≥ 18 years of age on the day of signing the informed 
consent or obtaining surrogate consent from an authorized representative 
• 
Diagnosis of influenza A where one or both of the following are used as aid(s) in 
diagnosis: 
− A Sponsor-supplied rapid influenza test 
− 
A local molecular (PCR) test 
• 
One of the following markers of severity within 24 hours of hospital admission: 
− 
Requirement for PPV  − or −  
− 
Requirement for O2 supplementation to maintain SpO2 > 92% 
• 
A negative urine or serum pregnancy test for women of child-bearing potential 
• 
Patients of reproductive potential must agree to use reliable means of contraception 
as described below as a minimum (adherence to more stringent local requirements 
may be required): 
− 
For female patients:  Use of two acceptable methods of contraception 
throughout the trial, including the active treatment phase AND for 24 weeks after 
the last dose of MHAA4549A.  Acceptable methods of contraception 
include:  intrauterine device, systemic hormonal contraception (oral or depot), 
vaginal ring, tubal ligation of the female partner, vasectomy of the male partner, 
use of latex condoms plus spermicide by the male partner, or cervical cap plus 
spermicide (where the spermicide could be foam, vaginal suppository, gel, 
cream, etc.). 
− 
For male patients:  Use of condoms for 30 days after dosing when circulating 
drug levels remain high. 
− 
Non-reproductive potential is defined below (but could be superseded by local 
definitions, if they are more stringent): 
Women who are postmenopausal (i.e., spontaneous amenorrhea for the past 
year confirmed by an FSH level greater than 40 mIU/mL unless the patient is 
receiving a hormonal therapy for their menopause)  
Women who are surgically sterile (i.e., hysterectomy, complete bilateral 
oophorectomy) 
Men who are surgically sterile (castration) 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Pregnant or lactating or intending to become pregnant during the study 
− 
Women who are not postmenopausal (≥ 12 months of non-therapy-induced 
amenorrhea) or who are not surgically sterile must have a negative urine or 
serum pregnancy test result within 2 days prior to study treatment. 
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• 
Hypersensitivity to mABs or any constituents of study drug 
• 
Investigational therapy within the 30 days prior to study treatment  
• 
Received prior therapy with any anti-influenza monoclonal antibody therapy 
including MHAA4549A 8 months prior to study treatment 
• 
Current treatment (within 7 days of dosing) with amantadine or rimantidine 
• 
Patients who have taken more than a total of 3 days (6 doses) of approved 
anti-influenza therapy (e.g., oral oseltamivir, inhaled zanamivir, or oral ribavirin) in 
the period from onset of symptoms and prior to enrollment 
• 
Admission > 48 hours prior to study treatment 
• 
Onset of influenza symptoms > 5 days prior to study treatment 
• 
Positive influenza B or influenza A + B infection within 2 weeks prior to study 
treatment 
• 
High probability of mortality in the next 48 hours as determined by the investigator  
• 
Patient requiring home or baseline oxygenation therapy 
• 
Patient with history of chronic lung disease resulting in baseline SpO2 < 95%  
• 
Patient on a chronic dose of corticosteroids exceeding 10 mg/day of prednisone or 
equivalent steroid dose for a duration of greater than 14 days within 30 days of entry 
into study 
• 
Patients with the following significant immune suppression:  
− 
Bone marrow or solid organ transplant in the previous 12 months 
− 
Cancer chemotherapy in the previous 12 month 
− 
HIV infection with most recent CD4 < 200 cells/mL 
− 
Other significant immune suppression as determined by the investigator in 
discussion with the Sponsor Medical Monitor or representative 
• 
Patient on extracorporeal membrane oxygenation (ECMO) at time of randomization 
• 
Any disease or condition that would, in the opinion of the site investigator or 
Sponsor, place the subject at an unacceptable risk of injury or render the subject 
unable to meet the requirements of the protocol 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
The randomization of patients will be managed by a central Interactive Voice and Web 
Response System (IxRS) through use of a dynamic hierarchical algorithm.  The 
treatment assignments will be unblinded to selected Sponsor personnel to facilitate 
ongoing monitoring of safety and tolerability, including members of the IMC and SOC.  
All patients will be randomly assigned to receive either MHAA4549A 3600 mg or placebo 
at a 1:1 ratio stratified by site, whether patient is on PPV vs supplemental O2 at 
randomization, and whether the patient has suspected or confirmed bacterial 
pneumonia vs no bacterial pneumonia at randomization.  All patients will receive 
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oseltamivir (75 mg or 150 mg BID) for a minimum of 5 days.  Treatment for longer than 5 
days is permitted based on local investigator discretion. 
Blinded personnel at each study site will make appropriate preparations and perform the 
IV infusions of study drug, as described in Section 4.3.3.  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.  
Bioanalytical laboratory 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 (e.g., to evaluate a possible error in study drug administration). 
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 in IxRS.  
Treatment codes should not be broken except in emergency situations.  If the 
investigator wishes to know the identity of the study drug for any other reason, they 
should 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 suspected unexpected serious adverse 
reactions (SUSAR)(see Section 5.6) that are considered by the investigator or Sponsor 
to be related to study drug. 
4.3 
STUDY TREATMENT  
4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
MHAA4549A and Placebo 
MHAA4549A, matching placebo, and up to 10-day supply of oseltamivir (Tamiflu®) will 
be supplied by the Sponsor.  For information on the formulation, packaging, and 
handling of MHAA4549A and placebo; see the Pharmacy Manual and the 
MHAA4549A Investigator's Brochure. 
The MHAA4549A vial delivers 10 mL (500 mg) of drug product solution, but may contain 
more (approximately 10.3 mL) than the stated volume to enable delivery of the entire 
10 mL volume.  MHAA4549A is formulated as 50 mg/mL in 10 mM sodium succinate, 
240 mM sucrose, and 0.02% (w/v) polysorbate 20 at pH 5.5 and is contained in a 15 mL 
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forma vitrum (USP/PH. Eur. Type 1) glass vial.  The drug product is suitable for single 
use only and contains no preservatives. 
Placebo for MHAA4549A has the same composition as the drug product (without 
MHAA4549A) and is supplied in an identical vial configuration.  The placebo contains no 
preservatives and is suitable for single-use only.  Placebo is formulated as 10 mM 
sodium succinate, 240 mM sucrose, and 0.02% polysorbate 20 at pH 5.5 in a total 
volume of 10 mL in a 15 mL forma vitrum (USP/PH. Eur. Type 1) glass vial. 
MHAA4549A and placebo are supplied in identical blinded vials labeled with unique kit 
numbers.  IxRS will assign kit numbers for each treatment arm; all treatment arms will be 
assigned the same total number of vials for each treatment, and the same preparation 
instructions.  Placebo is identical to active MHAA4549A in formulation and appearance 
but does not contain active drug substance. 
4.3.1.2 
Oseltamivir (Tamiflu) 
Oseltamivir (Tamiflu) is an influenza NAI indicated for treatment of acute, uncomplicated 
influenza.  For information on the formulation, packaging, and handling of oseltamivir; 
see the local prescribing information for oseltamivir. 
Storage: Capsules should be stored at 25°C (77.7°F); excursions permitted to 15° to 
30°C (59° to 86°F). 
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 3600 mg IV 
or placebo IV at a 1:1 ratio.  Oseltamivir will be dispensed via IxRS.  Oseltamivir dosing 
is described in Table 2.  
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 will be on site during study drug administration for all 
patients. 
A single dose of MHAA4549A or placebo will be delivered by IV infusion following 
dilution in 0.9% normal saline over approximately 60 minutes.  Study drug should be 
delivered using a 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 for 
preparation of study drug can be found in the Pharmacy Manual.   
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There are no recommended dosage modifications for MHAA4549A since it is a single 
infusion.  Any overdose or incorrect administration of study drug should be noted on the 
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 AEs associated with overdose.  Patients experiencing such AEs 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.  
4.3.2.2 
Oseltamivir-Neuraminidase Inhibitor (NAI)  
The Sponsor will be providing oseltamivir (Tamiflu®) for this study for up to a 10-day 
course.  Dosage and administration should follow local prescribing information for 
oseltamivir.  Either 75 mg or 150 mg of oseltamivir will be administered twice daily as 
described in Table 2.  Capsules can be opened and the granules administered via 
nasogastric tube, if required.  
Guidelines for dosage modification for renal dosing are presented in Table 2.   
Any overdose or incorrect administration of oseltamivir should be noted on the 
oseltamivir Administration eCRF.  Adverse events associated with an overdose or 
incorrect administration of oseltamivir should be recorded on the Adverse Event eCRF. 
Patients who are discharged from the hospital with oseltamivir will be required to 
complete a medication diary and return the medication diary, empty (used) oseltamivir 
packets and unused oseltamivir capsules to the study site at the next follow up visit.  
Patients will record the date and time when each oseltamivir capsule is administered. 
4.3.3 
Investigational Medicinal Product Accountability 
Investigational medicinal products (IMPs) required for completion of this study (i.e., 
MHAA4549A and oseltamivir) 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 to 8°C until use.  MHAA4549A does not contain antimicrobial 
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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 to 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. 
The total duration from the preparation of dose solutions to the end of infusion should 
not exceed 24 hours.  Vials are intended for single use only; therefore, any remaining 
solution should be discarded (see the Pharmacy Manual).  
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 or their delegate 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. 
4.4 
POST-TRIAL ACCESS TO MHAA4549A 
As this is single dose administration, Genentech 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. 
4.5 
CONCOMITANT THERAPY AND FOOD 
4.5.1 
Permitted Therapy  
Concomitant medication 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 concomitant medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF.  For any NAIs (e.g., oseltamivir, peramivir, zanamivir, 
laninimavir) that have been taken prior to study drug therapy, the number of doses and 
duration of therapy must be recorded. 
Patients who use oral contraceptives, hormone-replacement therapy, or other 
maintenance therapy should continue their use. 
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All therapies required for management of the patient’s acute illness are permitted except 
for those listed below in Section 4.5.2. 
4.5.2 
Prohibited Therapy 
Use of the following therapies is prohibited during the study and for at least 7 days prior 
to study treatment, unless otherwise specified below:  probenecid, amantadine, or 
rimantidine 
Use of other NAIs, including but not limited to oral oseltamivir, inhaled zanamivir, oral 
ribavirin, laninimivir, and peramivir, are prohibited during the study, but allowed up to 
3 days (6 doses) prior to study treatment as outlined in the exclusion criteria.  If 
oseltamivir resistance is highly suspected or identified during treatment then, following 
discussion with the sponsor medical representative, an alternative NAI to oseltamivir 
may be used. 
4.5.3 
Prohibited Food  
There are no prohibited foods for this study.  
4.6 
STUDY ASSESSMENTS  
Please see Appendix 1a and Appendix 1b for the schedule of assessments performed 
during the study. 
4.6.1 
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.  Informed consent by 
authorized representatives may be obtained only if allowed by and in accordance with 
local regulations and Independent Review Board (IRB)/Independent Ethics Committee 
(IEC) policies and procedures.  Informed Consent Forms (ICF) 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. 
4.6.2 
Diagnostic Testing for Enrollment 
All hospitalized patients with severe influenza A will be assessed for disease 
confirmation and enrollment into the study.  A Sponsor-supplied rapid influenza test is 
required for the diagnosis of influenza A infection and uses a nasopharyngeal swab.  
When the Sponsor-supplied rapid influenza test is negative, the study inclusion criteria 
can be satisfied with a positive local molecular test (PCR) if the result is within the 
48-hour screening window.  Patients may be enrolled based on a positive local molecular 
test (PCR) result within the 48-hour screening window, but the rapid influenza test 
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must still be conducted prior to randomization.  Other tests may not be used for 
enrollment in the study unless the Sponsor has reviewed and approved the use of the 
diagnostic. 
4.6.3 
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.  A careful assessment of the patient’s baseline SpO2 should be 
made especially if the patient has a history of severe chronic lung disease. 
Demographic data will include age, sex, and self-reported race/ethnicity. 
4.6.4 
Priority of Assessments 
When events warrant, or in the opinion of the investigator, safety issues become 
paramount, safety assessments will always have priority over all other measurements 
and procedures.  Under routine circumstances, however, PK, nasal virological, and 
biomarker serum/plasma samples have priority over other measurements.  The timing 
and number of safety measurements may be modified based on clinical evaluations. 
4.6.5 
Physical Examinations 
A complete physical examination 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 protocol designated visits (or as clinically indicated), limited, symptom-directed 
physical examinations should be performed which 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, if appropriate, on the AE 
eCRF. 
4.6.6 
Vital Signs  
Vital signs will include measurements of resting SpO2 (see Section 4.6.7 for 
measurement), respiratory rate, pulse rate, temperature, and systolic and diastolic blood 
pressures after the patient has been in a seated or supine position for at least 
10 minutes.  Patients in intensive care may have vital signs assessed following local 
procedures, but those procedures should be captured in the eCRF in accordance with 
the eCRF instructions.  
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4.6.7 
Oxygen Saturation Measurements 
To ensure that the respiratory status is well recorded, the following daily measurements 
will be performed.  Unless clinically contraindicated, all patients will have their SpO2 and 
corresponding respiratory assessments recorded daily in the morning between 6 am  12 
pm local time.  Patients on low-flow O2 will have a daily trial of their SpO2 while on and 
off the supplementation, as outlined in Appendix 2, and both values will be recorded.  
If the patient is on oxygen supplementation, SpO2 measured by pulse oximetry and the 
corresponding respiratory assessments (e.g. FiO2, flow rate) will be recorded. If the 
patient is on PPV, partial pressure of O2 (PaO2) and the corresponding respiratory 
assessments (e.g. FiO2, ventilator mode, ventilator respiratory rate, positive end-
expiratory pressure) will be recorded. 
4.6.8 
Laboratory, Biomarker, and Other Biological Samples  
Samples for the laboratory tests listed in Table 3 and Table 4 will be sent to the study 
site's local laboratory for analysis at screening and during the study, respectively. 
Table 3 
Laboratory Tests at Screening 
Hematology: 
Clinical Chemistry: 
Hemoglobin 
Thyroid stimulating hormone (optional) 
Hematocrit 
 
Erythrocyte count (RBC) 
Serology: 
Leukocytes (WBC) 
HIV Serology 
Neutrophils, segmented & bands 
 
Lymphocytes 
Misc: 
Monocytes 
Pregnancy Test (urine or serum; women of 
child-bearing potential) 
Eosinophils 
Basophils 
 
Platelets 
 
Note:  Investigators must document their review of each laboratory report by signing (or 
initialing) and dating each report. 
 
  


 
Table 4 
Laboratory Tests During the Study 
Hematology: 
Clinical Chemistry (Blood):  
Hemoglobin 
Sodium 
Hematocrit 
Potassium 
Erythrocyte count (RBC) 
Bicarbonate 
Leukocytes (WBC) 
Chloride 
Neutrophils, segmented & bands 
Calcium 
Lymphocytes 
Phosphorus 
Monocytes 
Magnesium 
Eosinophils 
Glucose  
Basophils 
Urea nitrogen (BUN) or urea 
Platelets 
Creatinine 
Erythrocyte Sedimentation Rate (ESR) (optional) Total cholesterol 
 
Total protein 
Coagulation:  
Albumin 
Activated partial thromboplastin time (APTT) 
Total bilirubin 
Prothrombin time (PT) 
Alkaline phosphatase 
International Normalized Ratio (INR) 
Aspartate aminotransferase (AST) 
 
Alanine aminotransferase (ALT) 
Urinalysis: 
Amylase 
pH 
Gamma-glutamyl transpeptidase (GGT) 
 (if clinically indicated) 
Specific gravity 
Glucose 
C-reactive protein (CRP) (optional) 
Protein 
 
Ketones 
Misc:  
Blood 
Pregnancy Test (if clinically indicated) 
Bilirubin 
 
Nitrite 
 
Leukocyte esterase 
 
Microscopic examination (if clinically indicated) 
Note:  Investigators must document their review of each laboratory report by signing (or initialing) 
and dating each report. 
  
The following samples will be sent to the Sponsor or a designee for PK or ATA analysis: 
• 
 
• 
  
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• 
  
 
 
   
 
 
 
 
   
 
 
 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.   
4.6.9 
Electrocardiograms 
Single ECG recordings will be obtained at specified timepoints, as outlined in the 
schedule of assessments (see Appendix 1a and Appendix 1b), 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 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 QTcF 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 QT interval corrected using 
Fridericia’s formula (QTcF) has stabilized on two successive ECGs.  The Medical 
Monitor should be notified.  If QTcF is not available, QTcB may be recorded.  Standard 
of care treatment may be instituted per the discretion of the investigator.  If a PK sample 
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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 4.9.2.  
The investigator should also evaluate the patient for potential concurrent risk factors 
(e.g., electrolyte abnormalities, medications known to prolong the QT interval, severe 
bradycardia). 
4.6.10 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
   
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4.7 
APACHE AND SOFA SCORES 
Acute Physiology and Chronic Health Evaluation (APACHE) and Sequential Organ 
Failure Assessment (SOFA) scores are for patients that are admitted into the ICU.  
These assessments are not required for study conduct or entry but should be collected if 
available.  The initial scores for APACHE and SOFA should be taken within 24 hours of 
entry into the ICU and at specified time points as seen in Appendix 1a. 
For the calculation of the initial APACHE and SOFA scores, the worst values in the first 
24 hours of ICU admission should be used.  SOFA scores are only for patients admitted 
into the ICU that have available data for calculation (i.e.,  partial pressure of arterial 
oxygen/fraction of inspired oxygen [PaO2/FiO2] in mmHg).  See Appendix 7 for SOFA 
score calculation. 
4.8 
OSELTAMIVIR MEDICATION DIARY 
Patients who are discharged from the hospital with oseltamivir will be required to 
complete a medication diary and return the medication diary, empty (used) oseltamivir 
packets, and unused oseltamivir capsules to the study site at the next follow up visit.  
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Patients will record the date and time when each oseltamivir capsule is administered.  
4.9 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
4.9.1 
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 or 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 from the study will not be replaced. 
4.9.2 
Study Treatment Discontinuation 
Patients must discontinue MHAA4549A infusion and therefore treatment if they 
experience any of the following: 
• 
Infusion related reactions 
Patients must discontinue oseltamivir treatment if they experience any of the following: 
• 
Pregnancy 
• 
Serious skin/hypersensitivity reactions 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.   
The IMC and SOC may recommend to permanently discontinue dosing for all patients 
within one or both study arms in the event of a general safety concern. 
4.9.3 
Study Completion/Early Discontinuation Visit 
Patients who complete all study visits through Day 60 are considered to have completed 
study.  All patients who discontinue from the study early will be asked to complete all 
assessments for the current visit day and for the early discontinuation visit without 
duplication.  Please see Schedule of Assessments provided in Appendix 1a for 
assessments performed at the Study Completion/Early Discontinuation visit. 
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4.9.4 
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 (GCP) 
• 
No further study activity (i.e., all patients have completed and all obligations have 
been fulfilled) 
 
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 (interim) studies and is 
designed to ensure patient safety.  It will include specific eligibility criteria and monitoring 
assessments as detailed below and above in Section 4.1. 
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. 
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 and SOC agreement.  
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5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and non-serious adverse events of special interest; 
measurement of protocol-specified safety laboratory assessments; measurement of 
protocol-specified vital signs; and 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. 
5.2.1 
Adverse Events 
According to the ICH guideline for GCP, an adverse event is any untoward medical 
occurrence in a clinical investigation patient 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 5.3.5.9. 
• 
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 60 
or Early Discontinuation).  If clinically significant signs or laboratory values are observed 
in a study participant, the investigator should repeat an assessment at the earliest 
opportunity.  Only those events or laboratory values that exceed the level of clinical 
significance upon the repeat assessment will be considered an adverse event. 
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: 
• 
Fatal (i.e., the adverse event actually causes or leads to death) 
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• 
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 5.3.5.10) 
• 
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) 
• 
Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
• 
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 
listed above) 
 
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 Division of 
AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS); see 
Section 5.3.3, Appendix 8, and Appendix 9); 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 
Non-Serious Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) 
Non-serious adverse events of special interest (AESI) 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 5.3.5.6) 
• 
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. 
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•
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 AEs associated with IRR,
see Section 5.3.5.1 below):
− 
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
•
Anaphylaxis due to IV drugs most often presents with the following signs and
symptoms:
− 
Cutaneous symptoms: flushing, itching, urticaria, 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: such as 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 Section 5.4 − 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. 
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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, regardless of relationship to study 
drug, will be reported until the Day 60 visit or Early Discontinuation visit.  After this period, 
the investigator is not required to actively monitor patients for adverse events; however, 
the Sponsor should be notified if the investigator becomes aware of any death or other 
serious adverse event that occurs after discharge, regardless of causality.  The Sponsor 
should also be notified if the investigator becomes aware of a congenital anomaly/birth 
defect in a subsequently conceived offspring of a female patient exposed to study drug 
(see Section 5.6). 
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 AEs, and SAEs, 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 
AE severity (see Table 5). 
Table 5 
Adverse Event Grading (Severity) Scale 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE-
THREATENING 
ESTIMATING SEVERITY GRADE 
Clinical AE 
NOT identified 
elsewhere in 
this DAIDS AE 
Grading Table  
Symptoms 
causing no or 
minimal 
interference with 
usual social and 
functional 
activities 
Symptoms 
causing greater 
than minimal 
interference with 
usual social & 
functional 
activities 
Symptoms 
causing 
inability to 
perform usual 
social & 
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 
 
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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 or 
not 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 6): 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, considering especially 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 6 
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., chronic obstructive pulmonary 
disease [COPD] diagnosed 2 days after first dose of study drug). 
 
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
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. 
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5.3.5.1 
Diagnosis versus Signs and Symptoms 
Infusion-Related Reactions  
Adverse events that occur during or within 24 hours after study drug infusion should be 
captured as individual signs and symptoms rather than a diagnosis of allergic reaction or 
infusion reaction. 
Other Adverse Events 
For adverse events other than infusion-related reactions, 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 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. 
5.3.5.2 
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. 
5.3.5.3 
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.  If a persistent adverse event 
becomes more severe, it should be recorded as a separate event on the Adverse Event 
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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 event became more severe.  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; see Section 5.4.2 for reporting 
instructions).  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 event became 
serious. 
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. 
5.3.5.4 
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 meets any of the following criteria: 
• 
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 
• 
Clinically significant in the investigator’s judgment (laboratory abnormalities should 
be repeated at the first opportunity and only considered clinically significant if they 
persist on repeat assessment) 
 
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. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 × upper limit of normal [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." 
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Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 
5.3.5.5 
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 meets any of the following criteria: 
• 
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 or a change in concomitant therapy 
• 
Clinically significant in the investigator’s judgment.  Abnormal vital sign values 
should be repeated at the first opportunity and only considered clinically significant if 
they persist on repeat assessment) 
 
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 not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 
5.3.5.6 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × baseline value) 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.  
Therefore, investigators must report as an adverse event the occurrence of either of the 
following: 
• 
Treatment-emergent ALT or AST > 3 × baseline value in combination with total 
bilirubin > 2 × ULN (of which ≥ 35% is direct bilirubin) 
• 
Treatment-emergent ALT or AST > 3 × baseline value 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 
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the event) either as a serious adverse event or a non-serious adverse event of special 
interest (see Section 5.4.2). 
5.3.5.7 
Deaths 
For this protocol, mortality is an efficacy endpoint.  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 severe influenza or any related co-morbidities 
should be recorded 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 as an SAE (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 
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. 
5.3.5.8 
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.  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"). 
5.3.5.9 
Lack of Efficacy or Worsening of Influenza A Infection 
Medical occurrences or symptoms of deterioration that are anticipated as part of 
influenza A should only 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 "). 
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5.3.5.10 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization following initial discharge (i.e., in-patient 
admission to a hospital) or prolonged hospitalization (after the current study 
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 
• 
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 that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
5.3.5.11 
Adverse Events Associated with an Overdose 
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 serious 
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 clinical 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. 
5.4 
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: 
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• 
Serious adverse events 
• 
Non-serious adverse events of special interest 
• 
Pregnancies 
 
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 IRB/IEC. 
5.4.1 
Emergency Medical Contacts 
Medical Monitor Contact Information  
 Medical Monitor contact information: 
Primary Medical Monitor: 
 
Telephone Nos.: 
US Office: 
 
 
US Mobile: 
 
 
Secondary Medical Monitor: 
  
Telephone Nos.: 
US Office: 
 
 
US Mobile: 
 
 
Genentech Medical Monitor contact information for all sites if above medical monitor 
cannot be reached: 
Medical Monitor: 
 
Telephone Nos.: 
US Mobile 
 
 
US Office 
 
 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Non-Serious 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.  
A paper Serious Adverse Event Reporting Form and fax cover sheet should be 
completed and faxed to the Sponsor's Safety Risk Management department or its 
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designee immediately (i.e., no more than 24 hours after learning of the event), using the 
fax numbers provided below per region: 
Asia Pacific: 
 
Europe: 
 
Latin America: 
 
North America:  
 
 
5.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events and non-serious adverse events of 
special interest will be reported until the patient is at Day 60 or Early Discontinuation.  
Although the investigator is not required to actively monitor patients for adverse events 
after the patient has been discharged from the study, the Sponsor should be notified if 
the investigator becomes aware of any death or other serious adverse event that occurs 
after discharge from the study, if determined to be related to study drug by the 
investigator.  The Sponsor should also be notified if the investigator becomes aware of 
a congenital anomaly/birth defect in a subsequently conceived offspring of a female 
patient exposed to study drug (see Section 5.4.3).   
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, a paper Serious Adverse Event 
Reporting Form and fax cover sheet should be completed and faxed to Safety Risk 
Management or its designee immediately (i.e., no more than 24 hours after learning of 
the event), using the fax numbers provided to investigators (see fax numbers 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 after the last 
dose of study drug.  A Pregnancy Report eCRF should be completed by the investigator 
immediately (i.e., no more than 24 hours after learning of the pregnancy) and submitted 
via the EDC system.  A pregnancy report will automatically be generated and sent to 
Safety Risk Management.  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 
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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 the event that the EDC system is unavailable, a paper Clinical Trial Pregnancy 
Reporting Form and fax cover sheet should be completed and faxed to Safety Risk 
Management or its designee immediately (i.e., no more than 24 hours after learning of 
the pregnancy), using the fax numbers provided to investigators (see fax numbers 
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. 
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 within 30 days after the dose of 
study drug.  A Pregnancy Report eCRF should be completed by the investigator 
immediately (i.e., no more than 24 hours after learning of the pregnancy) and submitted 
via the EDC system.  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.  Once the 
authorization has been signed, the investigator will update the Pregnancy Report eCRF 
with additional information on the course and outcome of the pregnancy.  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. 
In the event that the EDC system is unavailable, follow reporting instructions provided in 
Section 5.4.3.1. 
5.4.3.3 
Congenital Anomalies/Birth Defects and Abortions 
Any congenital anomaly/birth defect in a child born to a female patient or 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).  
5.4.4 
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.  If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF and the 
Investigator document a discharge plan.  
All pregnancies reported during the study should be followed until pregnancy outcome.  
If the EDC system is not available at the time of pregnancy outcome, follow reporting 
instructions provided in Section 5.4.3.1. 
5.4.5 
Sponsor Follow-Up 
For serious adverse events, non-serious 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. 
5.5 
POSTSTUDY ADVERSE EVENTS 
At the time of study completion or study discontinuation, the investigator should instruct 
each patient to report to the investigator any subsequent adverse events that the patient 
or their personal physician believes could be related to prior study drug treatment or 
study procedures.   
The investigator is not required to actively monitor patients for adverse events after the 
end of the adverse event reporting period (defined as 60 days after the dose of study 
drug).  However, the Sponsor should be notified if the investigator becomes aware of 
any death, other serious adverse event, or non-serious adverse event of special interest 
occurring after the end of the adverse event reporting period, regardless of causality.  
The Sponsor should also be notified if the investigator becomes aware of the 
development of cancer or a congenital anomaly/birth defect in a subsequently conceived 
offspring of a female patient or a female partner of a male patient exposed to study drug. 
The investigator should report these events by completing and faxing a paper Serious 
Adverse Event Reporting Form and fax cover sheet to Safety Risk Management using 
the fax numbers provided to investigators (see Section 5.4.2.1). 
5.6 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events including suspected 
unexpected serious adverse reactions (SUSARs) and non-serious adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, IECs, and applicable 
health authorities based on applicable legislation. 
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To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents: 
• 
MHAA4549A Investigator's Brochure 
• 
Local prescribing information for oseltamivir 
 
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. 
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 2006) 
• 
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 
All 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: 
• 
Randomized patients who have confirmed influenza A infection as confirmed by a 
central PCR test from Day 1 samples 
 
Safety analyses will include all patients who were included in the randomization and who 
received at least one dose of study medication, with patients allocated to the treatment 
arm associated with the regimen actually received.  
No formal hypothesis testing will be done in this study.  As a result, no adjustment for 
a type 1 error will be made to account for the multiplicity of analyses. 
Final efficacy and safety analyses of the total study population will be conducted at the 
end of the study after all patients have completed all study assessments and the 
database has been cleaned and closed.  Further details of the analyses, including 
analysis of the exploratory endpoints, will be contained in the statistical analysis plan 
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(SAP) which will be prepared and finalized before the first optional interim analysis (see 
Section 6.7) or the final efficacy and safety analysis, if no interim analysis takes place.   
6.1 
DETERMINATION OF SAMPLE SIZE 
The purpose of this study is estimation of the effect size and hypothesis generation 
regarding the effect of MHAA4549A on the time to normalization of respiratory function 
relative to the standard of care rather than hypothesis testing.  Point and interval 
estimates will be obtained.  A total of 334 patients will be enrolled in this study in order to 
obtain approximately 300 evaluable patients (an estimated dropout rate of 10%).  It is 
assumed that the median time to normalization of respiratory function in the control arm 
is 5 days.  This sample size (approximately 150 patients per arm) provides 75% power to detect 
a treatment difference of 1 day for the primary endpoint assuming a 2-sided alpha of 0.2.  
Operating characteristics (power) under other possible assumptions for 2-sided alpha of 0.05 
and true differences of 1 to 2 days are provided in Table 7.   
Table 7 
Operating Characteristics for Proposed Study Design for Several 
Possible True Underlying Median Values 
True Underlying Median for MHAA4549A 
3 days 
3.5 days 
4 days 
Hazard Ratio 
0.60 
0.70 
0.80 
Power of log-rank test a 
99% 
86% 
48% 
95% confidence interval 
for true hazard ratio b 
(0.48, 0.75) 
(0.56, 0.88) 
(0.64, 1.00) 
Note:  Operating characteristics are based on the following assumptions:  300 evaluable 
patients, event times are exponentially distributed, median time to normalization of respiratory 
function in the control arm is 5 days, and patients are followed for 60 days. 
a Two-sided α = 0.05. 
b Confidence intervals are based on the assumption that the point estimate is equal to the true 
underlying value of the hazard ratio in each column.
It should be noted that the study is underpowered for detection of minimally clinically 
meaningful differences at a 2-sided alpha of 0.05 such as a true hazard ratio of 0.80 (see 
third column of Table 7.   
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. 
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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 
EFFICACY ANALYSES 
The primary and secondary 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. 
Time to event data will be computed using Kaplan-Meier methodology and stratified Cox 
proportional hazards models 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. 
6.4.1 
Primary Efficacy Endpoint 
• 
Median time to normalization of respiratory function 
 
6.4.2 
Secondary Efficacy Endpoints 
• 
Proportion of patients with clinical failure after 24 hours post-infusion of study drug 
• 
Median time to clinical resolution of vital signs 
• 
Hazard ratio for mortality at Day 14, Day 30, and Day 60 
• 
Mean and median AUC of viral load 
• 
Mean and median peak viral load 
• 
Median duration of viral shedding in upper respiratory samples 
• 
Median duration of hospitalization 
• 
Median duration of ICU stay 
• 
Proportion of patients requiring antibiotics for respiratory indications during study 
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• 
Proportion of patients with influenza secondary complications 
• 
Median duration of ventilation 
• 
Proportion of patients who are readmitted by Day 30 and Day 60 
 
6.4.3 
Subgroup Analyses 
Subgroup analyses will be performed to examine the consistency of the treatment 
estimates with use of the primary and selected secondary endpoints.  Subgroups will 
include the stratification factors as well as patients who are identified at baseline as 
influenza A positive by the upper, lower, or both airways and by patients with bacterial 
co-infections at admission.  Additional subgroups may be added following assessment of 
baseline characteristics as exploratory analyses. 
6.5 
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 (including SpO2 measurements), 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.  SAEs 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. 
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 
6.6 
PHARMACOKINETIC ANALYSES  
Individual and mean serum MHAA4549A concentration versus time data will be 
tabulated and plotted.  The serum pharmacokinetics of MHAA4549A will be summarized 
by estimating total serum drug exposure (i.e., AUC), Cmax, Cmin, 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).  
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Inter-patient variability will be evaluated.  MHAA4549A serum concentration–time data 
may be compared with available data from other MHAA4549A clinical studies. 
 
 
  
 
 
 
 
 
6.7 
OPTIONAL INTERIM ANALYSIS  
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 I 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. 
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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 
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.  
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 7.5. 
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/IEC review.  The study site must also allow 
inspection by applicable health authorities. 
7.4 
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 
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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. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, 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. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for GCP 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. Food and Drug Administration (FDA) regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the EU Clinical Trial Directive (2001/20/EC). 
8.2 
INFORMED CONSENT 
The Sponsor’s sample ICFs (and ancillary sample ICFs) 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/IEC submission.  The final 
IRB/IEC−approved Consent Forms must be provided to the Sponsor for health authority 
submission purposes according to local requirements. 
The Consent Forms must be signed and dated by the patient or the patient’s authorized 
representative as applicable and in accordance with local regulations, and IRB/IEC 
policies, before his or her participation in the study.  The case history or clinical records 
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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/IEC-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/IEC policy) during their participation in the study.  For any updated or revised 
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 
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. 
For sites in the United States, 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/IEC by the Principal 
Investigator and reviewed and approved by the IRB/IEC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/IEC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/IEC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/IEC.  Investigators are 
also responsible for promptly informing the IRB/IEC of any protocol amendments (see 
Section 9.1).  
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/IEC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
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for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/IEC, 
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 ICF (or separate authorization for use and 
disclosure of personal health information) signed by the patient, unless permitted or 
required by law. 
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. 
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/IEC 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/IEC 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 
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data integrity to the Sponsor and to the IRB/IEC in accordance with established IRB/IEC 
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/IECs to inspect facilities and records relevant to this study. 
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, clinical monitoring and site management, data quality 
support, medical monitoring, and some safety reporting and regulatory activities as 
specified in 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 dynamic hierarchical 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.   
9.5 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/IEC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/IEC 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). 
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10. 
REFERENCES 
Bai S, Jorga K, Xin Y, et al. A guide to rational dosing of monoclonal antibodies. Clin 
Pharmacokinet 2012;51(2):119-35. 
Blackwood B, Alderdice F, Burns K, et al. Use of weaning protocols for reducing duration 
of mechanical ventilation in critically ill adult patients: Cochrane systematic review and 
meta-analysis. BMJ 2011;342(c7237). 
Centers for Disease Control and Prevention (CDC). Antiviral agents for the treatment 
and chemoprophylaxis of influenza: recommendations of the Advisory Committee on 
Immunization Practices (ACIP). MMRW Morb Mortal Weekly Rep 2001;60(RR01):1−24. 
Centers for Disease Control and Prevention (CDC). 2011-2012 Influenza antiviral 
medications [resource on the Internet]. 2012b [Updated 2014, Mar 21; cited 2014 Apr]. 
Available from: http://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm. 
DeMets D, Lan KKG. Interim analysis: the alpha spending function approach. Stat Med 
1994;13:1341−52. 
Doshi S, Kamimoto L, Finellie L, et al. Description of antiviral treatment among adults 
hospitalized with influenza before and during the 2009 pandemic: United States, 
2005−2009. J Inf Dis 2011;204:1848−56. 
Fiore AE, Fry A, Shay D, et al. (2011). Antiviral agents for the treatment and 
chemoprophylaxis of influenza---recommendations of the Advisory Committee on 
Immunization Practices (ACIP). MMWR. Recommendations and reports: Morbidity and 
mortality weekly report. Recommendations and reports/Centers for Disease Control. 
2011; 60(1):1−24. 
Harper SA, Bradley JS, Englund JA, et al. Expert Panel of the Infectious Diseases 
Society of America. Seasonal influenza in adults and children--diagnosis, treatment, 
chemoprophylaxis, and institutional outbreak management: clinical practice guidelines of 
the Infectious Diseases Society of America. Clin Infect Dis 2009 Apr 15;48(8):1003−32. 
 
 
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. 
Lawton MP, Brody EM. Assessment of older people: self-maintaining and instrumental 
activities of daily living. Gerontologist 1969;9:179−86. 
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Lee N, Ison MG. Diagnosis, management and outcomes of adults hospitalized with 
influenza. Antiviral Therapy 2012:17(1 Pt B):143−57. 
Louie JK, Yang S, Acosta M, et al. Treatment with neuraminidase inhibitors for critically 
ill patients with influenza A (H1N1). CID 2012;55:1198−204. 
Marty FM, Man CY, van der Horst C, et al. Safety and pharmacokinetics of intravenous 
zanamivir treatment in hospitalized adults with influenza: an open-label, multicenter, 
single-arm, Phase II study. J Infect Dis 2014;209(4):542−50. 
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. 
Polakos NK, Cornejo JC, Murray DA, et al. Kupffer cell-dependent hepatitis occurs 
during influenza infection. Am J Pathol 2006;168(4):1169−78. 
Thompson WW, Shay DK, Weintraub E, et al. Influenza-associated hospitalizations in 
the United States. JAMA 2004;292(11):1333−40. 
Zhou H, Thompson WW, Vioud CG, et al. Hospitalizations associated with influenza and 
respiratory syncytial virus in the United States 1993−2008. Clin Inf Dis 
2012;54(10):1427−36. 
 
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APPENDIX 1a 
 
Schedule of Assessments:  Hospitalization Days  
Notes: Unless otherwise indicated, all assessments on Day 1 should be performed prior to study drug administration; x’s within 
parentheses, i.e., (x), indicate optional assessments.  Please refer to Follow-up Period table for visits to be completed after patient is 
discharged from hospital prior to Day 60.  
Day (D) 
Screening Hospitalized Days (only to be completed while patients are hospitalized) 
Hospital 
Discharge a D30  
D60  
Study Completion or 
Early Discontinuation 
while Hospitalized 
D -2,-1 
D1 
(Randomization) D2 D3 D4 D5 D6 
D7 
D8 
D9 D10 D14 D20 D25 
Confirm study drug administration can occur within 48 hours of hospital admission 
 
Informed consent b 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rapid influenza A test c 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Local influenza A PCR test d 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and 
demographic data 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm onset of flu symptoms 
(≤ 5 days prior to study drug 
administration on Day 1) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm history of baseline 
SpO2 > 92% 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy screening e 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm O2 requirement f 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Respiratory Assessment g 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant medications h 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vital signs i 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
APACHE score j 
 
(xz) 
 
 
 
 
 
 
 
 
 
(x) 
 
 
(x) 
(x) 
(x) 
SOFA score k 
 
(xz) 
 
 
 
 
 
(x) 
 
 
 
(x) 
 
 
(x) 
(x) 
(x) 
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APPENDIX 1a (cont’d)  
Schedule of Assessments:  Hospitalization Days  
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Day (D) 
Screening 
Hospitalized Days (only to be completed while patients are hospitalized) 
Hospital 
Discharge a
D30 
D60  
Study Completion or 
Early Discontinuation 
while Hospitalized 
D -2,-1 
D1 
(Randomization)
D2 D3 D4 D5
D6
D7
D8
D9 D10 D14 D20 D25
Electrocardiogram (12-lead) l 
 
x 
 
 
 
x 
 
 
 
 
 
x 
 
 
x 
x 
x 
Randomization 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MHAA4549A administration 
 
xm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Oseltamivir administration n 
 
x 
x 
x 
x 
x 
(x) 
(x) 
(x) 
(x) 
(x) 
 
 
 
 
 
 
Complete physical 
examination o 
x 
(x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Limited, symptom-directed 
physical examination p 
 
 
x 
x 
x 
x 
 
 
 
 
 
x 
 
 
x 
x 
x 
Weight & height, BMI q
 
xq 
x 
 
 
 
x 
 
 
 
 
 
x 
 
 
x 
x 
x 
Adverse events 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Hematology r 
x 
 
x 
 
 
x 
 
 
 
 
 
x 
 
 
x 
x 
x 
Chemistry panel r 
(x)aa 
x 
x 
 
 
x 
 
 
 
 
 
x 
 
 
x 
x 
x 
Coagulation panel r 
 
x 
 
 
 
x 
 
 
 
 
 
x 
 
 
x 
x 
x 
Erythrocyte sedimentation rate 
 
(x) 
(x)
 
 
(x)
 
 
 
 
 
(x)
 
 
(x) 
(x) 
(x) 
C-reactive protein 
 
(x) 
(x)
 
 
(x)
 
 
 
 
 
(x)
 
 
(x) 
(x) 
(x) 
Urinalysis r, s 
 
x 
x 
 
 
x 
 
 
 
 
 
x 
 
 
x 
x 
x 
Serology (HIV) bb, r  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Upper respiratory tract sample 
(NP sample) t 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Flu antibodies (HAI) 
 
x 
 
 
 
 
 
 
 
 
 
x 
 
 
x 
x 
x 




APPENDIX 1a (cont’d)  
Schedule of Assessments:  Hospitalization Days  
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a Assessments to be performed irrespective of day of discharge.  Assessments on discharge day will supersede assessments for matching day 
except for the study completion/early discontinuation visit (e.g., If a patient is discharged from the hospital on Day X, use assessments under 
“hospital discharge” column instead of the Day X column and record under the hospital discharge folder in the eCRF.  If a patient 
discontinues from the study early on Day X, complete all assessments under the Day X column and “early discontinuation” column without 
duplication, and record under the early discontinuation folder in the eCRF).  
b Informed consent must be obtained from all patients.  For patients who are unable to consent, an authorized representative may be used if 
allowed by local regulations and IRB/IEC policy.   
c Sponsor-supplied rapid influenza test using nasopharyngeal swabs.  
d If the Sponsor-supplied rapid influenza test is negative, local influenza PCR testing can be used to confirm influenza A and satisfy entry criteria if 
results are received within screening/hospitalization window (48 hours).  Patients can be enrolled based on a positive local influenza PCR test 
result within the 48 hour screening window, but the rapid influenza test must still be conducted prior to randomization.  
e A urine pregnancy test should be sent only for women considered by the investigator to be of childbearing potential, see exclusion criteria.  This 
result must be available prior to randomization.  If urine testing is not available at the site, blood already collected from an existing sample may 
be tested for pregnancy. 
f Confirm patient requires supplemental O2 or PPV within 24 hours of hospital admission. 
g All patients will have their on-study SpO2 and corresponding respiratory assessments recorded daily in the morning between 6 am  12 pm local 
time; screening SpO2 may be taken outside this window.  Patients on low flow O2 should have a daily trial of their SpO2 while on and off the 
supplementation and both values will be recorded. If the patient is on oxygen supplementation, SpO2 measured by pulse oximetry and the 
corresponding respiratory assessments (e.g. FiO2, flow rate) will be recorded.  If the patient is on PPV, PaO2 and the corresponding 
respiratory assessments (e.g. FiO2, ventilator mode, ventilator respiratory rate, positive end-expiratory pressure) will be recorded.  
h Concomitant medications should be recorded for 30 days prior to screening, through the study completion/early discontinuation visit.  See 
exclusion criteria in Section 4.5.2 for prohibited therapies. 
i Vital signs will be collected within 1 hour before MHAA4549A infusion and within 1 hour after completion of MHAA4549A infusion  include 
temperature, 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.  In patients who have multiple 
vital signs taken during any day, the most abnormal value should be recorded from that 24-hour period.  Temperature, blood pressure, 
respiratory rate, and heart rate will be completed after the patient has been supine for  5 minutes.  The worst/most abnormal value from the 
last 24-hour period should be recorded for patients who are in the ICU.  
j APACHE scores are optional and only for patients that are in the ICU.  For calculation of the screening APACHE score, the worst values in the 
preceding 24 hours should be used.  APACHE scores are not required for study conduct or entry but should be collected if available.  
k SOFA scores are only for patients in the ICU that have available data such as PaO2/FiO2 (mmHg).  See Appendix 7 for SOFA score calculation. 
l Patient should rest in a supine position for 10 minutes prior. 
m  Patient will be a resident for at least 24 hours following administration of MHAA4549A. 




APPENDIX 1a (cont’d)  
Schedule of Assessments:  Hospitalization Days  
cc Patients who are discharged from the hospital with oseltamivir will be required to complete a medication diary and return the medication 
diary, empty (used) oseltamivir packets and unused oseltamivir capsules to the study site at the next follow up visit.  Patients will record the 
date and time when each oseltamivir capsule is administered.  
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APPENDIX 2  
Time to Normalization of Respiratory Function 
For the purposes of this study, the time to normalization of respiratory function will be 
defined as the time to removal of the patient from O2 supplementation in order to 
maintain an SpO2  95%.  
Patients who are on low flow O2 (2-6L/min) should receive a daily trial off O2 in the 
morning between 6 am  12 pm as described below.  
1. Patient should be resting or sitting. 
2. Patient should be fitted with pulse oximeter, and their SpO2 should be checked 
once while on O2 and then again 3  5 minutes after turning off O2 
supplementation.  
3. If the SpO2  95%, then the time and reading should be recorded.  Notify the 
study doctor so that he/she can make a clinical judgment to determine whether 
the O2 can be removed. 
4. If the patient is off O2 for 24 hours and his/her reading the subsequent day 
is >95%, then the endpoint is considered satisfied.  The recorded time for the 
endpoint corresponds with the initial discontinuation of O2 and reading. 








 
APPENDIX 6  
 
  
 
  
 
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APPENDIX 7  
SOFA Score Calculation  
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 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. 
 
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APPENDIX 8  
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. 
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APPENDIX 8 (cont’d)  
DAIDS Toxicity Grading Tables for Clinical Abnormalities 
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 
 
 
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. 
Protocol GV29216, Version 2 
102 


APPENDIX 9  
DAIDS Toxicity Grading Tables for Laboratory Abnormalities 
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 
Abbreviations used in the table: 
 
 
; CPK = creatine phosphokinase; Dec = Decreased; 
IV = Intravenous; LLN = Lower limit of normal; Mod = Moderate; Req = Required; 
Rx = Therapy; SGOT = serum glutamic oxaloacetic transaminase; SGPT = serum 
glutamic pyruvic transaminase; ULN = Upper limit of normal. 
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 gm/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 x 
ULN 
1.26 – 1.50 x 
ULN 
1.51 – 3.0 x 
ULN 
>3 x ULN 
Activated Partial 
Thromboplastin 
Time (APTT) 
1.01 – 1.66 x 
ULN 
1.67 – 2.33 x 
ULN 
2.34 – 3 x ULN 
>3 x ULN 
Methemoglobin 
5.0 – 9.9% 
10.0 – 14.9% 
15.0 – 19.9% 
>20.0% 
From the FDA Guidance document ‘Toxicity Grading Scale from Healthy Adult and Adolescent 
Volunteers Enrolled in Preventative Vaccine Clinical Trials’ 
MHAA4549A—Genentech, Inc. 
Protocol GV29216, Version 2 
103 


 
APPENDIX 9 (cont’d)  
DAIDS Toxicity Grading Tables for Laboratory Abnormalities 
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  
Hyperbilirubinemia 
(when accompanied by 
any increase in other 
liver function test) 
1.1 – <1.25 x 
ULN 
1.25 – <1.5 x 
ULN 
1.5 – 1.75 x  
ULN 
>1.75 x ULN 
Hyperbilirubinemia 
(when other liver 
function are in the 
normal range) 
1.1 – <1.5 x 
ULN 
1.5 – <2.0 x 
ULN 
2.0 – 3.0 x  
ULN 
>3.0 x ULN 
MHAA4549A—Genentech, Inc. 
Protocol GV29216, Version 2 
104 


 
From the FDA Guidance document ‘Toxicity Grading Scale from Healthy Adult and Adolescent 
Volunteers Enrolled in Preventative Vaccine Clinical Trials’ 
 
ENZYMES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
AST (SGOT) 
1.1 - <2.0 x ULN 
2.0 - <3.0 x ULN 
3.0 – 8.0 x ULN 
>8.0 x ULN 
ALT (SGPT) 
1.1 - <2.0 x ULN 
2.0 - <3.0 x ULN 
3.0 – 8.0 x ULN 
>8.0 x ULN 
GGT 
1.1 - <2.0 x ULN 
2.0 - <3.0 x ULN 
3.0 – 8.0 x ULN 
>8.0 x ULN 
Alkaline 
Phosphatase 
1.1 - <2.0 x ULN 
2.0 - <3.0 x ULN 
3.0 – 8.0 x ULN 
>8.0 x ULN 
Amylase 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.1 – 5.0 x ULN 
>5.1 x ULN 
Lipase 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.1 – 5.0 x ULN 
>5.1 x ULN 
*CPK – mg/dL 
1.25 – 1.5 x ULN 
1.6 – 3.0 x ULN 
3.1 – 10.0 x ULN 
>10 x ULN 
*From the FDA Guidance document ‘Toxicity Grading Scale from Healthy Adult and Adolescent 
Volunteers Enrolled in Preventative Vaccine Clinical Trials’ 
  
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 
From the FDA Guidance document ‘Toxicity Grading Scale from Healthy Adult and Adolescent 
Volunteers Enrolled in Preventative Vaccine Clinical Trials’ 
 
 
MHAA4549A—Genentech, Inc. 
Protocol GV29216, Version 2 
105 


 
Title
25-Sep-2014 21:28:53
Date and Time (UTC)
Company Signatory
Approver's Name
PROTOCOL 
TITLE: 
A PHASE 2 RANDOMIZED, DOUBLE-BLIND 
PLACEBO-CONTROLLED TRIAL OF MHAA4549A, 
A MONOCLONAL ANTIBODY, IN COMBINATION 
WITH OSELTAMIVIR VERSUS OSELTAMIVIR FOR 
TREATMENT OF SEVERE INFLUENZA A 
INFECTION 
PROTOCOL NUMBER: GV29216 
VERSION NUMBER: 
3 (VHP Only) 
EUDRACT NUMBER: 
2014-000461-43 
IND NUMBER: 
117,318 
TEST PRODUCT: 
MHAA4549A 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
Genentech, Inc. 
DATE FINAL: 
30 May 2014 
DATE AMENDED: 
Version 2:  14 August 2014 
Version 3 (VHP Only): See electronic date stamp below 
 
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 GV29216, Version 3 (VHP ONLY) 


PROTOCOL AMENDMENT RATIONALE: 
VERSION 3 (VHP ONLY) AMENDMENT 
RATIONALE 
Protocol GV29216 was amended in Version 3 was revised to incorporate VHP feedback 
and reflects the following changes: 
• 
Male partners of female patients who have had a vasectomy should have 
appropriate post-vasectomy documentation available of the absence of sperm in the 
ejaculate (see Section 4.1.1). 
• 
Female patients should use two acceptable methods of contraception throughout 
the trial, including the active treatment phase AND for 120 days after the last dose 
of MHAA4549A (see Section 4.1.1). 
• 
Male patients should use condoms and refrain from donating sperm until 30 days 
after dosing (see Section 4.1.1). 
• 
Exclusion criteria “hypersensitivity to monoclonal antibodies or to the active 
substance or any excipients of MHAA4549A study drug” and “hypersensitivity to the 
active substance or to any excipients of oseltamivir” (see Section 4.1.2) 
 
MHAA4549A—Genentech, Inc. 
Protocol GV29216, Version 3 (VHP ONLY) 
2 


SUMMARY OF CHANGES:  
VERSION 3 (VHP ONLY) AMENDMENT 
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol. 
SECTION 4.1.1: 
Inclusion Criteria 
• 
Patients of reproductive potential must agree to use reliable means of contraception 
as described below as a minimum (adherence to more stringent local requirements 
may be required): 
− 
For female patients:  Use of two acceptable methods of contraception throughout 
the trial, including the active treatment phase AND for 120 days 24 weeks after 
the last dose of MHAA4549A.  Acceptable methods of contraception 
include:  intrauterine device, systemic hormonal contraception (oral or depot), 
vaginal ring, tubal ligation of the female partner, vasectomy of the male partner, 
use of latex condoms plus spermicide by the male partner, or cervical cap plus 
spermicide (where the spermicide could be foam, vaginal suppository, gel, cream, 
etc.).  Male partners who have had a vasectomy should have the appropriate 
post-vasectomy documentation available of the absence of sperm in the ejaculate.  
The vasectomized male partner should be the sole partner for that patient. 
− 
For male patients:  Use of condoms and refrain from sperm donation until for 
30 days after dosing when circulating drug levels remain high. 
SECTION 4.1.2: 
Exclusion Criteria 
• 
Hypersensitivity to monoclonal antibodies or to the active substance or any 
excipients of MHAA4549A study drug 
• 
Hypersensitivity to the active substance or to any excipients of oseltamivir 
• 
Hypersensitivity to mABs or any constituents of study drug 
SAMPLE INFORMED CONSENT FORM 
The sample Informed Consent Form has been revised to reflect the changes to the 
protocol. 
MHAA4549A—Genentech, Inc. 
Protocol GV29216, Version 3 (VHP ONLY) 
3 


TABLE OF CONTENTS 
PROTOCOL ACCEPTANCE FORM .................................................................. 10 
PROTOCOL SYNOPSIS .................................................................................... 11 
1. 
BACKGROUND .......................................................................................... 20 
1.1 
Background on Influenza ....................................................... 20 
1.2 
Background on MHAA4549A ................................................. 20 
1.2.1 
Nonclinical Background ......................................................... 20 
1.2.2 
Clinical Safety Background .................................................... 21 
1.2.3 
Clinical Efficacy Background ................................................. 22 
1.3 
Study Rationale and Benefit-Risk Assessment ...................... 23 
1.3.1 
Study Rationale ..................................................................... 23 
1.3.2 
Benefit-Risk Assessment ....................................................... 24 
1.3.2.1 
Treatment in Combination with Oseltamivir ........................... 24 
1.3.2.2 
Drug Mechanism and Preclinical Studies .............................. 24 
1.3.2.3 
Rationale for Selection of Phase 2b Study 
Population .............................................................................. 25 
1.3.2.4 
Patient Monitoring and Supervision ....................................... 25 
2. 
OBJECTIVES .............................................................................................. 26 
2.1 
Safety Objectives ................................................................... 26 
2.2 
Primary Efficacy Objectives ................................................... 26 
2.3 
Secondary Efficacy Objectives .............................................. 26 
2.4 
Pharmacokinetic Objectives .................................................. 27 
2.5 
Exploratory Objectives ........................................................... 27 
3. 
STUDY DESIGN ......................................................................................... 28 
3.1 
Description of the Study......................................................... 28 
3.1.1 
Overview of Study Design ..................................................... 28 
3.1.2 
Independent Monitoring Committee and Scientific 
Oversight Committee ............................................................. 29 
3.1.3 
End of Study .......................................................................... 30 
3.2 
Rationale for Study Design .................................................... 30 
3.2.1 
Rationale for Study Design .................................................... 30 
MHAA4549A—Genentech, Inc. 
Protocol GV29216, Version 3 (VHP ONLY) 
4 


3.2.2 
Rationale for Patient Population and Primary 
Endpoint ................................................................................ 31 
3.2.3 
Rationale for Control Group and Treatment 
Window .................................................................................. 31 
3.2.4 
Rationale for MHAA4549A Dosage ....................................... 32 
3.2.5 
Rationale for Biomarker Assessments ................................... 33 
3.3 
Outcome Measures ............................................................... 34 
3.3.1 
Safety Outcome Measures .................................................... 34 
3.3.2 
Primary Efficacy Outcome Measure ...................................... 34 
3.3.3 
Secondary Efficacy Outcome Measures ................................ 34 
3.3.4 
Pharmacokinetic Outcome Measures .................................... 35 
3.3.5 
Exploratory Outcome Measures ............................................ 35 
4. 
MATERIALS AND METHODS .................................................................... 36 
4.1 
Patients .................................................................................. 36 
4.1.1 
Inclusion Criteria .................................................................... 36 
4.1.2 
Exclusion Criteria ................................................................... 37 
4.2 
Method of Treatment Assignment and Blinding ..................... 38 
4.3 
Study Treatment .................................................................... 39 
4.3.1 
Formulation, Packaging, and Handling .................................. 39 
4.3.1.1 
MHAA4549A and Placebo ..................................................... 39 
4.3.1.2 
Oseltamivir (Tamiflu).............................................................. 40 
4.3.2 
Dosage, Administration, and Compliance .............................. 40 
4.3.2.1 
MHAA4549A and Placebo ..................................................... 40 
4.3.2.2 
Oseltamivir-Neuraminidase Inhibitor (NAI) ............................ 41 
4.3.3 
Investigational Medicinal Product Accountability ................... 41 
4.4 
Post-Trial Access to MHAA4549A ......................................... 42 
4.5 
Concomitant Therapy and Food ............................................ 42 
4.5.1 
Permitted Therapy ................................................................. 42 
4.5.2 
Prohibited Therapy ................................................................ 42 
4.5.3 
Prohibited Food ..................................................................... 43 
4.6 
Study Assessments ............................................................... 43 
4.6.1 
Informed Consent Forms and Screening Log ........................ 43 
4.6.2 
Diagnostic Testing for Enrollment .......................................... 43 
MHAA4549A—Genentech, Inc. 
Protocol GV29216, Version 3 (VHP ONLY) 
5 




5.3.3 
Assessment of Severity of Adverse Events ........................... 55 
5.3.4 
Assessment of Causality of Adverse Events ......................... 56 
5.3.5 
Procedures for Recording Adverse Events ............................ 56 
5.3.5.1 
Diagnosis versus Signs and Symptoms................................. 57 
5.3.5.2 
Adverse Events That Are Secondary to Other 
Events.................................................................................... 57 
5.3.5.3 
Persistent or Recurrent Adverse Events ................................ 57 
5.3.5.4 
Abnormal Laboratory Values ................................................. 58 
5.3.5.5 
Abnormal Vital Sign Values ................................................... 59 
5.3.5.6 
Abnormal Liver Function Tests .............................................. 59 
5.3.5.7 
Deaths ................................................................................... 60 
5.3.5.8 
Pre-existing Medical Conditions ............................................ 60 
5.3.5.9 
Lack of Efficacy or Worsening of Influenza A 
Infection ................................................................................. 60 
5.3.5.10 
Hospitalization or Prolonged Hospitalization .......................... 61 
5.3.5.11 
Adverse Events Associated with an Overdose ...................... 61 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor .......................................................... 61 
5.4.1 
Emergency Medical Contacts ................................................ 62 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest ...................................................................... 62 
5.4.2.1 
Events That Occur prior to Study Drug Initiation .................... 62 
5.4.2.2 
Events That Occur after Study Drug Initiation ........................ 63 
5.4.3 
Reporting Requirements for Pregnancies .............................. 63 
5.4.3.1 
Pregnancies in Female Patients ............................................ 63 
5.4.3.2 
Pregnancies in Female Partners of Male Patients ................. 64 
5.4.3.3 
Congenital Anomalies/Birth Defects and 
Abortions ............................................................................... 64 
5.4.4 
Investigator Follow-Up ........................................................... 64 
5.4.5 
Sponsor Follow-Up ................................................................ 65 
5.5 
Poststudy Adverse Events ..................................................... 65 
5.6 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees ................................................................. 65 
MHAA4549A—Genentech, Inc. 
Protocol GV29216, Version 3 (VHP ONLY) 
7 


6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ....................... 66 
6.1 
Determination of Sample Size ............................................... 67 
6.2 
Summaries of Conduct of Study ............................................ 67 
6.3 
Summaries of Treatment Group Comparability ..................... 68 
6.4 
Efficacy Analyses .................................................................. 68 
6.4.1 
Primary Efficacy Endpoint ...................................................... 68 
6.4.2 
Secondary Efficacy Endpoints ............................................... 68 
6.4.3 
Subgroup Analyses ............................................................... 69 
6.5 
Safety Analyses ..................................................................... 69 
6.6 
Pharmacokinetic Analyses ..................................................... 69 
6.7 
Optional Interim Analysis ....................................................... 70 
7. 
DATA COLLECTION AND MANAGEMENT ............................................... 70 
7.1 
Data Quality Assurance ......................................................... 70 
7.2 
Electronic Case Report Forms ............................................... 71 
7.3 
Source Data Documentation .................................................. 71 
7.4 
Use of Computerized Systems .............................................. 71 
7.5 
Retention of Records ............................................................. 72 
8. 
ETHICAL CONSIDERATIONS .................................................................... 72 
8.1 
Compliance with Laws and Regulations ................................ 72 
8.2 
Informed Consent .................................................................. 72 
8.3 
Institutional Review Board or Ethics Committee .................... 73 
8.4 
Confidentiality ........................................................................ 74 
8.5 
Financial Disclosure .............................................................. 74 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 74 
9.1 
Study Documentation ............................................................ 74 
9.2 
Protocol Deviations ................................................................ 74 
9.3 
Site Inspections ..................................................................... 75 
9.4 
Administrative Structure......................................................... 75 
9.5 
Protocol Amendments ........................................................... 75 
10. REFERENCES ........................................................................................... 76 
 
MHAA4549A—Genentech, Inc. 
Protocol GV29216, Version 3 (VHP ONLY) 
8 




PROTOCOL ACCEPTANCE FORM 
TITLE: 
A PHASE 2 RANDOMIZED, DOUBLE-BLIND 
PLACEBO-CONTROLLED TRIAL OF MHAA4549A, 
A MONOCLONAL ANTIBODY, IN COMBINATION 
WITH OSELTAMIVIR VERSUS OSELTAMIVIR FOR 
TREATMENT OF SEVERE INFLUENZA A 
INFECTION 
PROTOCOL NUMBER: GV29216 
VERSION NUMBER: 
3 (VHP Only) 
EUDRACT NUMBER: 
2014-000461-43 
IND NUMBER: 
117,318 
TEST PRODUCT: 
MHAA4549A 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
Genentech, Inc. 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please return a copy of the signed form as instructed by the CRO.  Please retain 
the original for your study files. 
 
MHAA4549A—Genentech, Inc. 
Protocol GV29216, Version 3 (VHP ONLY) 
10 


PROTOCOL SYNOPSIS 
TITLE: 
A PHASE 2 RANDOMIZED, DOUBLE-BLIND 
PLACEBO-CONTROLLED TRIAL OF MHAA4549A, A 
MONOCLONAL ANTIBODY IN COMBINATION WITH 
OSELTAMIVIR VERSUS OSELTAMIVIR FOR 
TREATMENT OF SEVERE INFLUENZA A INFECTION 
PROTOCOL NUMBER: 
GV29216 
VERSION NUMBER: 
3 (VHP Only) 
EUDRACT NUMBER: 
2014-000461-43 
IND NUMBER: 
117,318 
TEST PRODUCT: 
MHAA4549A 
INDICATION: 
Influenza A 
SPONSOR: 
Genentech, Inc. 
 
Objectives 
Safety Objectives 
The safety objectives for this study are as follows: 
• 
To evaluate the safety of MHAA4549A in combination with oseltamivir compared with 
placebo and oseltamivir in patients with severe influenza A, focusing on the nature, 
frequency, and severity of serious and non-serious adverse events, as well as effects on 
laboratory values, vital signs, electrocardiogram (ECG) parameters, anti-therapeutic 
antibodies (ATA), or other safety biomarkers 
Efficacy Objectives 
The primary efficacy objective for this study is as follows: 
• 
To determine the time to normalization of respiratory function of patients dosed with 
MHAA4549A in combination with oseltamivir compared to patients dosed with placebo and 
oseltamivir 
The secondary efficacy objectives for this study are as follows: 
• 
To measure clinical failure after 24 hours post-infusion of study drug  
• 
To determine the time to clinical resolution of vital signs 
• 
To measure mortality in patients 
• 
To determine changes in the extent and duration of viral shedding in upper respiratory 
samples 
• 
To measure the duration of hospital and/or intensive care unit (ICU) stay  
• 
To measure antibiotic usage for respiratory indications  
• 
To measure the frequency and severity of the following secondary complications of 
influenza: 
− 
Pneumonia (hospital acquired pneumonia [HAP]/ ventilator acquired pneumonia [VAP]) 
− 
Exacerbations of chronic lung disease 
− 
Myocarditis 
− 
Acute respiratory distress syndrome (ARDS) 
MHAA4549A—Genentech, Inc. 
Protocol GV29216, Version 3 (VHP ONLY) 
11 




window.  All patients will receive oseltamivir for a minimum of 5 days (10 doses), starting on 
Day 1 beginning no later than 8 hours after study drug administration.  All patients will be 
followed for 60 days from the time of study drug administration. 
Number of Patients 
The study has a planned enrollment of approximately 334 patients (adult men and women) 
globally.  Patients will receive MHAA4549A or placebo in 1:1 ratio.  The number of patients on 
PPV should not exceed 45% of the total enrolled patients. 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• Men or women ≥ 18 years of age on day of signing informed consent or obtaining surrogate 
consent from an authorized representative 
• Diagnosis of influenza A as determined by one or both of the following: 
− 
A Sponsor-supplied rapid influenza test 
− 
A local molecular test (PCR)  
• One of the following markers of severity within 24 hours of hospital admission: 
− 
Requirement for PPV, OR 
− 
Requirement for O2 supplementation to maintain SpO2 > 92% 
• 
A negative urine or serum pregnancy test for women of childbearing potential 
• 
Patients of reproductive potential must agree to use reliable means of contraception as 
described below as a minimum (adherence to more stringent local requirements may be 
required): 
− 
For female patients:  Use of two acceptable methods of contraception throughout the 
trial, including the active treatment phase AND for 120 days after the last dose of 
MHAA4549A.  Acceptable methods of contraception include:  intrauterine device, 
systemic hormonal contraception (oral or depot), vaginal ring, tubal ligation of the female 
partner, vasectomy of the male partner, use of latex condoms plus spermicide by the 
male partner, or cervical cap plus spermicide (where the spermicide could be foam, 
vaginal suppository, gel, cream, etc.).  Male partners who have had a vasectomy should 
have the appropriate post-vasectomy documentation available of the absence of sperm 
in the ejaculate.  The vasectomized male partner should be the sole partner for that 
subject.  
− 
For male patients:  Use of condoms and refrain from sperm donation until 30 days 
after dosing. 
− 
Non-reproductive potential is defined below (but could be superseded by local definitions, 
if they are more stringent): 
Women who are postmenopausal (i.e., spontaneous amenorrhea for the past year 
confirmed by an follicle stimulating hormone [FSH] level greater than 40 mIU/mL 
unless the patient is receiving a hormonal therapy for their menopause)  
Women who are surgically sterile (i.e., hysterectomy, complete bilateral 
oophorectomy) 
Men who are surgically sterile (castration) 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Pregnant or lactating, or intending to become pregnant during the study 
− 
Women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) 
or who are not surgically sterile must have a negative urine or serum pregnancy test 
result within 2 days prior to study treatment 
MHAA4549A—Genentech, Inc. 
Protocol GV29216, Version 3 (VHP ONLY) 
13 


• 
Hypersensitivity to monoclonal antibodies or to the active substance or any excipients of 
MHAA4549Astudy drug 
• 
Hypersensitivity to the active substance or to any excipients of oseltamivir 
• 
Investigational therapy within the 30 days prior to study treatment  
• 
Received prior therapy with any anti-influenza monoclonal antibody therapy including 
MHAA4549A 8 months prior to study treatment 
• 
Current treatment (within 7 days of dosing) with amantadine or rimantidine 
• 
Patients who have taken more than a total of 3 days (6 doses) of approved anti-influenza 
therapy (i.e., oral oseltamivir, inhaled zanamivir, or oral ribavirin) in the period from onset of 
symptoms and prior to enrollment 
• 
Admission > 48 hours prior to study treatment 
• 
Onset of influenza symptoms > 5 days prior to study treatment 
• 
Positive influenza B or influenza A + B infection within 2 weeks prior to study treatment 
• 
High probability of mortality in the next 48 hours as determined by the investigator  
• 
Patient requiring home or baseline oxygenation therapy 
• 
Patient with history of chronic lung disease resulting in baseline SpO2 < 95%  
• 
Patient on chronic dose of corticosteroids exceeding 10 mg/day of prednisone or equivalent 
steroid dose for a duration of greater than 14 days within 30 days of entry into study 
• 
Patients with the following significant immune suppression: 
− 
Bone marrow or solid organ transplant in the previous 12 months 
− 
Cancer chemotherapy in the previous 12 month 
− 
HIV infection with most recent CD4 < 200 cells/mL 
− 
Other significant immune suppression as determined by the investigator in discussion 
with the Sponsor Medical Monitor or representative 
• 
Patient on extracorporeal membrane oxygenation (ECMO) at time of randomization 
• 
Any disease or condition that would, in the opinion of the site investigator or Sponsor, place 
the patient at an unacceptable risk of injury or render the patient unable to meet the 
requirements of the protocol 
Length of Study 
This study will consist of the following study periods: 
• A screening period of 48 hours, beginning at time of hospital submission 
• A treatment period of 1 day, during which patients will receive a single dose of MHAA4549A 
or placebo and a minimum of 5 days of oseltamivir. 
• A follow-up period beginning at hospital discharge through 60 days post study drug 
(MHAA4594A/placebo) administration 
End of Study 
The end of the study is defined as the first day when all patients have had a study completion 
visit or early termination visit or have otherwise been discontinued from the study. 
Outcome Measures 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
Adverse events and clinical laboratory abnormalities 
• 
Vital signs, physical findings, ATAs, and clinical laboratory results during and following 
administration of MHAA4549A 
Efficacy Outcome Measures 
The primary outcome measure for this study is as follows: 
• Time to normalization of respiratory function defined as: 
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Time to event data will be computed using Kaplan-Meier methodology and stratified Cox 
proportional hazards models 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.  For continuous endpoints, 
Analysis of Covariance methods (after appropriate transformation of data) will be used to 
estimate treatment differences at 95% confidence intervals.  
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 I error penalty of 0.0001 will be taken.  In addition, as discussed below, the 
Sponsor will conduct interim safety analyses separate from and in conjunction with the above. 
Determination of Sample Size   
A total of 334 patients will be enrolled in this study in order to obtain approximately 
300 evaluable patients (an estimated dropout rate of 10%).  It is assumed that the median time 
to normalization of respiratory function in the control arm is 5 days 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation Definition 
 
 
AE 
Adverse event 
AESI 
Adverse events of special interest 
ALT 
Alanine aminotransferase 
ARDS 
Acute respiratory distress syndrome 
AST 
Aspartate aminotransferase 
ATA 
Anti-therapeutic antibody 
AUC 
Area under serum concentration−time curve  
AUEC 
Area under viral load−time curve  
BID 
Twice a day 
°C 
Celsius 
Cmax 
Maximum observed concentration 
Cmin 
Minimum observed concentration 
CPK 
Creatine phosphokinase 
CRO 
Contract (or Clinical) Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAIDS 
Division of Acquired Immunodeficiency Syndrome 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ECMO 
Extracorporeal membrane oxygenation 
EDC 
Electronic data capture 
FDA 
Food and Drug Administration 
FiO2 
Fraction of inspired oxygen 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
HA 
Hemagglutinin  
HAI 
Hemagglutinin inhibition 
HAP 
Hospital Acquired Pneumonia 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HR 
Heart rate 
 
 
ICH 
International Conference on Harmonisation 
ICU 
Intensive Care Unit 
IEC 
Independent Ethics Committee 
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Abbreviation Definition 
IMC 
Internal Monitoring Committee 
IMP 
Investigational medicinal product 
IND 
Investigational New Drug (application) 
IRB 
Institutional Review Board 
IRR 
Infusion-related reactions 
IV 
Intravenous 
LFTs 
Liver function tests 
mAB 
Monoclonal antibody 
NAI 
Neuraminidase inhibitor 
NP 
Nasopharyngeal 
PaO2 
Partial pressure of arterial oxygen 
PCR 
Polymerase Chain Reaction 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PPV 
Positive pressure ventilation 
qPCR 
Quantitative Polymerase Chain Reaction 
QTcB 
QT interval corrected using Bazett’s formula 
QTcF 
QT interval corrected using Fridericia’s formula 
RBC 
Red blood cell 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SOC 
Scientific Oversight Committee 
SpO2 
Oxygen saturation by pulse oximetry 
SUSAR 
Suspected unexpected serious adverse reactions 
ULN 
Upper limit of normal 
VAP 
Ventilation Acquired Pneumonia 
 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON INFLUENZA 
Influenza A is a membrane-enveloped RNA virus that causes significant morbidity and 
mortality.  Currently, there is a great need in hospitalized influenza patients for a 
parenteral therapeutic option that is well tolerated, can rapidly resolve influenza-related 
signs and symptoms, decrease mortality, reduce hospital and intensive care unit (ICU) 
stays, as well as have a prolonged window for initiation of treatment beyond the current 
standard of care (i.e., within 48 hours of the onset of flu symptoms). 
Approximately 200,000 to 278,000 patients are hospitalized with severe influenza 
infections annually in the United States (U.S.) (Thompson et al. 2004; Zhou et al. 2012), 
and assuming the same rate reported in the U.S., an estimated 319,000 to 
445,000 patients are hospitalized in the European Union (E.U.).  Hospitalization due to 
severe influenza is associated with high mortality (4%−8%), ICU admission (5%−17%; 
Lee and Ison 2012), mechanical ventilation support in an ICU setting (7%−11%; 
Doshi et al. 2011), and prolonged hospital stays (5−9 days; Lee and Ison 2012).  During 
a pandemic season, the outcomes may be more serious, with up to 34% of patients 
requiring ICU care and a mortality rate as high as 15% (Lee and Ison 2012). 
Influenza infection is an upper and lower respiratory disease with a broad spectrum of 
presentations that can result in fever, shortness-of-breath, pneumonia, respiratory failure, 
secondary respiratory infections, and even death.  The standard of care therapy for 
patients hospitalized with influenza consists of supportive measures and administration 
of available antiviral agents, primarily neuraminidase inhibitors (NAI) that include but are 
not limited to oseltamivir, zanamivir, and peramivir.  However, a significant unmet 
medical need still exists in the severely ill patient population, as evidenced by the 
considerable degree of morbidity and mortality in this setting.  To address this need, 
Genentech Inc. /F.Hoffmann-La Roche Ltd. (Genentech) is developing a highly-specific 
anti-influenza A (MHAA4549A) antibody therapy for treatment of hospitalized patients 
with severe influenza. 
1.2 
BACKGROUND ON MHAA4549A 
1.2.1 
Nonclinical Background 
MHAA4549A is a human monoclonal IgG1 antibody (mAb) that binds to the influenza A 
virus and is 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 stalk region, which allows broad neutralization 
of the influenza A virus by blocking the hemagglutinin-mediated, membrane-fusion event 
in the late endosome. 
In vitro, MHAA4549A is capable of neutralizing all current clinically relevant influenza A 
strains.  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.  
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MHAA4549A specifically targets an epitope on the human influenza A hemagglutinin 
glycoprotein, which does not appear to be endogenously expressed on human or rat 
tissues and, therefore, is unlikely to be present in the absence of viral infection.  Weekly 
administration of MHAA4549A (total of 5 doses) in Sprague-Dawley rats was well 
tolerated up to the maximum feasible dose of 150 mg/kg.  Ex vivo tissue cross-reactivity 
study data showed no specific binding of MHAA4549A to any of the human or rat tissues 
examined. 
1.2.2 
Clinical Safety Background 
To date, MHAA4549A has been shown to be safe and well tolerated in two clinical 
studies, which altogether enrolled 122 healthy volunteers.  The first study was a Phase 1 
study (GV28916) in 21 healthy volunteers where single doses of 1.5 mg/kg, 5 mg/kg, 
15 mg/kg, and 45 mg/kg were tested with an extended follow-up period of 120 days.  
MHAA4549A was safe and well tolerated with no serious adverse events (SAEs).  All 
adverse events (AEs) were mild or mild-to-moderate and resolved fully before the end of 
the study’s follow-up period.  No anti-therapeutic antibodies (ATAs) were detected in this 
study.  In addition, the MHAA4549A pharmacokinetics were generally dose proportional, 
and appeared to have a pharmacokinetic (PK) profile consistent with that of a human 
IgG1 antibody that lacks known endogenous host targets.  
The second study was a Phase 2a challenge study (GV28985) in 101 healthy volunteers 
infected with a H3N2 (A/Wisconsin/67/2005) strain of influenza virus.  Fixed dosing was 
selected for this study and is further described in Section 1.3.2.3.  Sixty subjects 
received doses of 400 mg, 1200 mg, or 3600 mg MHAA4549A and 41 subjects received 
placebo following nasal inoculation of influenza A virus one day earlier.  The interim 
efficacy analysis in Table 1 includes the Intent-to-Treat (ITT) infected population who 
received placebo (N = 21), 400 mg MHAA4549A (N = 11), 1200 mg MHAA4549A 
(N = 13), 3600 mg MHAA4549A (N=14), and oseltamivir (N = 2).  All subjects have 
completed dosing, and interim PK and efficacy data are available in the Investigator’s 
Brochure and upon request.  During this study, elevated ALT, AST, and amylase levels 
were observed within the first 2 weeks after inoculation with A/Wisconsin/67/2005 and 
dosing with MHAA4549A.  Previous experience with this challenge model has shown 
ALT/AST/amylase elevations to be associated with the influenza infection itself (Polakos 
2006).  Consistent with previous trials, in GV28985, there was no relationship of 
elevations in AST, ALT, or amylase with either dose or exposure (e.g., placebo: 22.0%, 
400 mg: 35.0%,1200 mg: 25.0%, 3600 mg: 20.0%).   
In GV28985, most AEs were Grade 1 or Grade 2 (mild or moderate) and appeared to 
reflect the symptoms of the influenza infection.  In the 400 mg group, 15 (75.0%), 1 
(5.0%), and 2 (10.0%) subjects reported Grade 1, 2, and 3 AEs respectively.  In the 
1200-mg group, 9 (45.0%), 6 (30.0%), and 1 (5.0%) subjects reported Grade 1, 2, and 3 
AEs, respectively.  In the 3600-mg group, 10 (50.0%), 5 (25.0%), 1 (5.0%) subjects 
reported Grade 1, 2, and 3 AEs, respectively.  One (5.0%) subject reported a Grade 4 
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AE in the 3600-mg group, which was a lower limb fracture, not related to MHAA4549A.  
Subjects in the placebo group reported 18 (56.3%) Grade 1 AEs, 8 (25.0%) Grade 2 
AEs, and 2 (6.3%) Grade 3 AEs.  In addition, there were no drug related SAEs, deaths, 
or discontinuations due to AEs.  There were a total of 3 SAEs unrelated to MHAA4549A 
in two subjects.  One subject reported depressive psychosis associated with influenza.  
There were a total of 3 SAEs unrelated to MHAA4549A in two subjects.  One subject 
reported depressive psychosis associated with influenza.  The second subject reported a 
broken knee with a subsequent infection following a surgical procedure. 
In GV28985, 1 patient tested positive for anti-therapeutic antibodies (ATAs).  This patient 
tested positive for ATA at baseline and post baseline.  This patient was in the placebo 
group, which included 32 other subjects, resulting in an immunogenicity prevalence rate 
(ATA-positive rate at baseline) of 3.1% and an immunogenicity incidence rate (ATA titers 
post-baseline) of 3.1%, as well, within the placebo group.  Overall, study GV28985 had 
an immunogenicity prevalence rate of 1%.  The immunogenicity incidence rate amongst 
the 60 subjects who received MHAA4549A was 0%.  
Based on this data, MHAA4549A is considered generally safe and well tolerated to date 
at all doses tested, including the 3600 mg dose.   
1.2.3 
Clinical Efficacy Background 
Analysis of efficacy from the 3600-mg dose level demonstrated a statistically significant 
decrease in viral shedding from upper respiratory tract as measured by the area under 
the curve (97% reduction by quantitative polymerase chain reaction [qPCR]) and peak 
viral load (77% reduction by qPCR) as shown in Table 1. 
In this study, oseltamivir was started on Day 7 for a 5-day course, and there were no 
observed AEs or imbalances in safety events that were considered attributable to 
interactions between oseltamivir and MHAA4549A.  The PK profile of MHAA4549A and 
oseltamivir in GV28985 are being analyzed to exclude potential drug-drug interactions 
and will be available before the start of this study GV29216.   
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Table 1 
Interim Efficacy Results from Phase 2a Challenge Study 
(GV28985) 
Endpoint 
Placebo 
(N=21) 
MHAA4549A 
Oseltamivir 
400 mg 
(N=11) 
% reduction 
(p-value)a 
1200 mg 
(N=13) 
% reduction 
(p-value)a 
3600 mg 
(N=14) 
% reduction 
(p-value)a 
75 mg BID 
(N=2) 
% reduction  
(p-value)a 
Median qPCR Viral 
AUEC 
(log10 vc/mL x hour) 
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 qPCR Peak 
Viral Load 
(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 Total Clinical 
Symptom  
AUEC 
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) 
AUEC = area under viral load−time curve; qPCR = quantitative polymerase chain reaction. 
a Comparison of active and placebo using nonparametric Wilcoxon rank-sum test.  All p-values 
are unadjusted for multiple testing. 
  
The A/Wisconsin/67/2005 virus induced mild symptoms that were predominantly 
captured in the upper respiratory tract symptoms that included runny nose, stuffy nose 
and sneezing. 
The Symptom Diary Cards used 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 from Study GV28985 for the Intent-to-Treat (ITT) infected population who 
received placebo (N = 21), 400 mg MHAA4549A (N = 11), 1200 mg MHAA4549A 
(N = 13), 3600 mg MHAA4549A (N = 14), and oseltamivir (N = 2) are shown in Table 1. 
Given the variability of the symptom scores the results were not statistically significant.  
However, there was a decrease in the AUEC of symptoms scores for the 3600 mg dose, 
which is consistent with the virological results described in the Table 1 above.  Data from 
the oseltamivir treated group is also shown but it should be noted that only 2 subjects 
were in the ITT infected population. 
See the MHAA4549A Investigator’s Brochure for additional details on nonclinical and 
clinical studies. 
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
1.3.1 
Study Rationale 
The Phase 1 and Phase 2a studies have demonstrated that MHAA4549A is safe and 
well tolerated to date in healthy volunteers including those who were inoculated with 
influenza A virus.  Data from the Phase 2a study also provides evidence that the 
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3600 mg dose of MHAA4549A is effective in reducing viral titers in healthy volunteers 
inoculated with influenza A virus.  These findings, when combined with previous 
nonclinical studies showing MHAA4549A to have in vitro and in vivo efficacy, a 
well-tolerated safety profile, and anti-viral activity, support further clinical development of 
MHAA4549A. 
In this Phase 2b study (GV29216), MHAA4549A is being evaluated in combination with 
the current standard of care (oseltamivir), to decrease the severity and duration of viral 
infection with influenza A virus with the ultimate goal of reducing the clinical symptoms of 
infection as compared to oseltamivir with placebo.  There are three primary goals for this 
Phase 2b study:  
• 
Demonstrate the safety and efficacy of MHAA4549A in combination with oseltamivir 
in hospitalized influenza A patients  
• 
 
 
  
• 
Demonstrate and evaluate the optimal endpoints for study in hospitalized patients 
with influenza A, given the lack of precedence for approval in patients hospitalized 
with influenza infection, an area of high unmet medical need 
 
This Phase 2b study has been designed to estimate the improvement in outcome of a 
combination therapy of MHAA4549A 3600 mg with oseltamivir versus placebo with 
oseltamivir.  All patients will be on oseltamivir, which is part of the recommended 
standard of care.  In addition, and as discussed above, MHAA4549A is a human 
monoclonal antibody that has, to date, shown an acceptable safety profile, a PK profile 
consistent with that of a IgG1 human antibody that lacks known endogenous host targets, 
and a demonstrated antiviral activity at the planned dose level of 3600 mg. 
1.3.2 
Benefit-Risk Assessment 
1.3.2.1 
Treatment in Combination with Oseltamivir 
All patients in the study will receive oseltamivir as the current standard of care treatment, 
either with or without MHAA4549A.  Therefore, at a minimum, all patients will be treated 
with standard of care for influenza.  Given that MHAA4549A is an antibody, the potential 
for a drug-drug interaction with oseltamivir is very low.  In the ongoing Phase 2a 
challenge study (GV28985), study subjects received MHAA4549A followed by 
oseltamivir with no AEs attributable to the combination therapy noted to date.  In addition, 
in this study the PK profile of oseltamivir in concomitantly treated subjects will be 
assessed. 
1.3.2.2 
Drug Mechanism and Preclinical Studies 
The available pre-clinical data suggest that there is low risk for drug target-related safety 
events in healthy humans since MHAA4549A specifically targets an epitope on a viral 
protein (i.e., the human influenza A virus hemagglutinin glycoprotein), which is not 
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endogenously expressed in human tissues.  Furthermore, there were no adverse 
MHAA4549A-related findings demonstrated in nonclinical studies at doses up to 
150 mg/kg administered weekly for 5 weeks and no evidence of target present in host 
tissues.   
1.3.2.3 
Rationale for Selection of Phase 2b Study Population 
The target patient population of hospitalized patients with severe influenza A requiring 
oxygen (O2) or positive pressure ventilation (PPV) is considered an appropriate 
population to test MHAA4549A for the following reasons: 
• 
Nonclinical safety data does not show any expected or unexpected toxicity. 
• 
Clinical safety data for MHAA4549A demonstrate a well-tolerated safety profile:   
o AEs in the Phase 1 study (GV28916) were mild and did not show a dose 
relationship; there were no ATAs detected in patients treated with MHAA4549A.   
o In the ongoing Phase 2a study (GV28985), MHAA4549A was generally well 
tolerated.  A few subjects in all treatment groups were observed to have 
transient elevations in alanine transaminase (ALT), aspartate transaminase 
(AST), and amylase levels.  There was no dose-dependent relationship of the 
ALT/AST/amylase elevations with MHAA4549A and the overall event rate was 
in line with published rates associated with the influenza challenge model 
regardless of treatment arm:  27/100 [27%] in GV28985 vs. approximately 26% 
in previous challenge studies (Polakos 2006).  There were no SAEs related to 
study drug.  There were a total of 3 SAEs unrelated to MHAA4549A in two 
subjects.  One subject reported depressive psychosis associated with influenza. 
The second subject reported a broken knee with a subsequent infection 
following a surgical procedure.   
• 
Interim efficacy data in the Phase 2a challenge study (GV28985) demonstrated a 
significant decrease in viral shedding in the upper respiratory tract at the 3600 mg 
dose.  There was a 97.5% (p = 0.0051) decrease in the area under viral load−time 
curve (AUEC) and a 77% (p = 0.0024) decrease in peak viral load by qPCR 
measurement in comparison to the placebo group, thus confirming proof of antiviral 
activity at the 3600 mg dose level.  Symptom data in the Phase 2a study showed a 
decrease in the AUC of symptoms scores for the 3600-mg dose that is consistent 
with the virological results as illustrated in Table 1. 
 
1.3.2.4 
Patient Monitoring and Supervision 
MHAA4549A will be administered to enrolled patients in a hospital environment under 
close medical supervision by physician investigators.  Medical staff will be available for 
prompt evaluation and treatment of any adverse events.  Emergency resuscitation 
equipment and emergency facilities will be readily available.  Patients will undergo 
screening assessments to confirm eligibility, will be closely monitored during the 
administration of MHAA4549A, and will be resident for at least 24 hours following the 
administration of MHAA4549A.  Furthermore, safety laboratory tests relating to the blood 
chemistries, including liver function tests, will be conducted. 
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An internal monitoring committee (IMC) in combination with a scientific oversight 
committee (SOC) will provide safety monitoring for the study in addition to the ongoing 
review of safety by the Medical Monitor and Safety Scientist.  See Section 3.1.2 for more 
information.  
The 120-day follow-up period in the Phase 1 and 2a studies allowed for monitoring of 
subjects for approximately 5 half-lives of MHAA4549A.  No ATAs were detected in the 
Phase 1 study, while one subject in the Phase 2a study tested positive for ATAs at 
baseline and post-baseline timepoints as described in Section 1.2.2.  The Phase 2b 
study will also include a safety follow-up period of 60 days and an unlimited collection of 
all SAEs believed related to MHAA4549A.   
Based on the above data and design of this study, the Sponsor concludes that the 
benefit−risk profile of MHAA4549A in the population with severe influenza is favorable.  
2. 
OBJECTIVES 
2.1 
SAFETY OBJECTIVES 
The safety objectives for this study are as follows: 
• 
To evaluate the safety of MHAA4549A in combination with oseltamivir compared 
with placebo and oseltamivir in patients with severe influenza A, focusing on the 
nature, frequency, and severity of serious and non-serious adverse events as well 
as effects on laboratory values, vital signs, electrocardiogram (ECG) parameters, 
ATAs, or other safety biomarkers 
 
2.2 
PRIMARY EFFICACY OBJECTIVES 
The primary efficacy objective for this study is as follows: 
• 
To determine the time to normalization of respiratory function of patients dosed with 
MHAA4549A in combination with oseltamivir compared to patients dosed with 
placebo and oseltamivir. 
 
2.3 
SECONDARY EFFICACY OBJECTIVES 
The secondary efficacy objectives for this study are as follows: 
• 
To measure clinical failure, as defined in Section 3.3.3, after 24 hours post-infusion 
of study drug  
• 
To determine the time to clinical resolution of vital signs  
• 
To measure mortality in patients  
• 
To determine changes in the extent and duration of viral shedding in upper 
respiratory samples  
• 
To measure the duration of hospital and/or ICU stay 
• 
To measure antibiotic usage for respiratory indications  
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3. 
STUDY DESIGN  
3.1 
DESCRIPTION OF THE STUDY 
3.1.1 
Overview of Study Design 
This is a Phase 2b, randomized, double-blind, placebo-controlled study designed to 
assess the safety and clinical activity of a single intravenous (IV) dose of MHAA4549A in 
hospitalized patients with severe influenza A in combination with oseltamivir versus a 
comparator arm of placebo with oseltamivir.  This study is planned to take place in 
approximately 170 study centers globally. 
Patients will be randomized 1:1 into two treatment groups:  a single IV dose of 3600 mg 
of MHAA4549A with oseltamivir or a single IV dose of placebo with oseltamivir.  All 
patients will receive oseltamivir, a NAI, as standard therapy for a minimum of 5 days 
after study drug administration.  Oseltamivir at doses of 75 mg BID or 150 mg BID is 
permitted in order to be consistent with local standard of care practice.  Treatment for 
longer than 5 days is permitted based on local investigator discretion.  The patient must 
start Sponsor-supplied oseltamivir within 8 hours of study drug administration.  The 
study has a planned enrollment of approximately 334 patients globally. 
Hospitalized patients with an O2 or PPV requirement will be evaluated for influenza A 
infection.  Enrollment in this study requires ongoing treatment within 24 hours of hospital 
admission with one of the following:  
• 
any PPV or  
• 
any supplemental O2 to maintain oxygen saturation (SpO2) >92% (see Section 3.3.2)   
 
Patients on PPV should not exceed 45% of the total patients enrolled. 
A Sponsor-supplied rapid influenza test and/or a local polymerase chain reaction (PCR) 
test must be used as an aid in the diagnosis of influenza A infection.   
 
 
 
 
 
 
  
At the time of randomization, patients who are eligible for enrollment, as described 
above, will be randomized to receive MHAA4549A at a dose of 3600 mg or placebo.  
Patients will be stratified by site, PPV versus supplemental O2 at randomization, and 
suspected or confirmed bacterial pneumonia versus no bacterial pneumonia based on 
the status at randomization. 
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Eligible patients who are enrolled into the study will receive either a single IV infusion of 
MHAA4549A or a single IV infusion of placebo on Day 1.  All patients must have the 
study drug infused within 48 hours of hospital admission or sooner if possible.  All 
patients will receive oseltamivir for a minimum of 5 days (10 doses), starting on Day 1, 
beginning no later than 8 hours after study drug administration.   
All patients will be followed and evaluated at minimum on a daily basis for the duration of 
their hospital stay consistent with the planned schedule of assessments.  Any suspicion 
of bacterial superinfection should be thoroughly evaluated including microbiological 
confirmation, if possible.  A follow-up study visit should occur on Day 14 ± 1 (if 
discharged before Day 14); Day 30 ± 4 days (if discharged before Day 30); and 
Day 60 ± 4 days (if discharged before Day 60). 
Safety evaluations will be provided by an IMC and SOC, as defined in the IMC and SOC 
agreement (see Section 3.1.2). 
A schedule of assessments is provided in Appendix 1a and Appendix 1b.  A diagram of 
the study design is presented in Figure 1.  
Figure 1 Phase 2b Study Design (GV29216) 
 
  
3.1.2 
Independent Monitoring Committee and Scientific Oversight 
Committee 
A combined approach with both an IMC and a SOC is proposed to enhance patient 
safety.  The IMC consists of Sponsor representatives from the following functions: 
Clinical Science, Drug Safety, Biostatistics, and Statistical Programming and Analysis.  
The IMC members will be unblinded to patient treatment and assignment.  The Clinical 
Science representative on the IMC (IMC Chair) will be a person other than the Study 
Medical Monitor and will not be involved in the conduct of the study or have any contact 
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with study investigators or site staff.  The Study Medical Monitor will remain blinded to 
individual treatment assignments, unless, in exceptional cases, specific circumstances 
require Study Medical Monitor unblinding after IMC Chair approval.  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.  The Biostatistician and Statistical Programmer are 
the only IMC members involved in the conduct of the study; however, they do not have 
any contact with study investigators, and all discussion within the IMC are 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 two SOC members are external experts in the field and will be unblinded to 
treatment allocation.  The SOC may be further expanded by the IMC during the course 
of the study to include additional external experts if the need arises.  
A detailed description of the procedures, data flow, and meeting schedule of the IMC 
and SOC will be provided in a separate IMC and SOC agreement. 
3.1.3 
End of Study 
The end of study is defined as the first day when all patients have had a study 
completion visit or early termination visit or have otherwise been discontinued from the 
study. 
3.2 
RATIONALE FOR STUDY DESIGN 
3.2.1 
Rationale for Study Design 
Hospitalized influenza A infection represents a high unmet need, which, when left 
untreated, may progress to a more serious disease that may result in significant 
morbidity and mortality in otherwise healthy adults as well as in vulnerable populations.   
This study is designed to estimate the improvement in outcome of a combination 
regimen of MHAA4549A with oseltamivir compared to a standard of care arm of placebo 
with oseltamivir.  The study population will include hospitalized patients with influenza A 
requiring O2 support and/or PPV support within 24 hours of hospital admission.  
Study GV29216 will be a Phase 2b study involving approximately 334 patients.  The 
sample size was determined based on an expected clinically meaningful difference of 
1 − 2 days improvement in time to normalization of respiratory function between the 
control and treatment arms, assuming a 5-day median time to the time to normalization 
of respiratory function in the standard of care arm (Blackwood 2011; PREMIER 
database).   
This design ensures that all patients in the trial will receive the current NAI treatment, 
oseltamivir, as standard of care at a minimum, and will evaluate the clinical benefit of 
combining MHAA4549A with this standard of care regimen.  Therefore, this study aims 
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to identify a regimen that could deliver maximum benefit in this high unmet need disease, 
while still treating all enrolled patients with the currently accepted standard of care. 
3.2.2 
Rationale for Patient Population and Primary Endpoint 
Severe influenza, for the purpose of this study, is defined as requiring one of the 
following treatments: any supplemental O2 to maintain an SpO2 > 92% or PPV.  PPV is 
defined as any mechanical positive pressure device to maintain oxygenation; this can 
include positive pressure mask and intubation.  A Sponsor-supplied rapid influenza test 
and/or a local PCR must be used as an aid in the diagnosis of influenza A infection. 
This patient population was chosen based on the rationale that respiratory failure is a 
hallmark of influenza and a major driver of morbidity and mortality, as well as 
hospitalization.  The recovery from ventilator support has been shown to be directly 
proportional to time spent in the ICU (Blackwood 2011; PREMIER database).  Based 
upon an analysis of morbidity and mortality, the patient population that requires 
supplemental O2 or ventilation on their first day of admission was determined to have a 
high unmet medical need as they have an estimated mortality of 9%−32%, and 27% 
require admission to the ICU, according to analysis of a database of over 70,000 
hospitalized patients in the US from 2005−2012 (PREMIER database).   
Support for use of the respiratory endpoint in this population comes from recently 
published data demonstrating that a composite endpoint that captured respiratory rate, 
fever, heart rate, and blood pressure resolution was primarily driven by the respiratory 
component of the endpoint (Marty et al. 2014).   
3.2.3 
Rationale for Control Group and Treatment Window  
In this study, the standard of care regimen for the control or comparator group is 
oseltamivir, an NAI.  In the treatment groups, MHAA4549A will be dosed in addition to 
an oseltamivir standard of care regimen.  The oseltamivir dose will be consistent with the 
local investigator practice at each site where the study will be conducted.  Either 75 mg 
or 150 mg orally BID oseltamivir for a minimum of 5 days is permitted following treatment 
with MHAA4549A.  Treatment for longer than 5 days is permitted based on local 
investigator discretion.  The oseltamivir dosing regimen, including the renal dosing 
adjustment, is listed in Table 2.  This control treatment was based on consideration of 
safety, ethics, and efficacy for treatment of severe influenza and is consistent with 
guidelines for antiviral treatment of hospitalized patients with influenza 
(Harper et al. 2009, Fiore 2011).  
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Table 2 
Oseltamivir Dosing Regimen 
Neuraminidase Inhibitor 
Dosing Regimen 
Duration of 
Therapy 
Oseltamivir  
75 mg or 150 mg orally BID a 
75 mg oral once daily for adult patients with 
creatinine clearance (CrCL) between  
10 and 30 mL/minb 
5 days c 
a 75 mg or 150 mg dose at the discretion of the investigator, and dose must be documented.  
Capsules can be opened and the granules administered via nasogastric tube, if required. 
b No recommended dosing regimens are available for patients with end-stage renal disease 
undergoing routine hemodialysis or continuous peritoneal dialysis treatment. 
c Longer treatment times are at the discretion of the investigator. 
  
From a safety standpoint there are no expected drug interactions between MHAA4549A, 
a monoclonal antibody, and any NAI, which are small molecule drugs that bind to a 
different viral protein than MHAA4549A.  In the Phase 2a challenge study, all subjects 
that were dosed with MHAA4549A also received a 5-day course of oseltamivir starting 
on Day 7.  There were no safety effects attributable to the combination when the drugs 
were present concurrently.  The pharmacokinetics of oseltamivir and its potential 
interaction with MHAA4549A are being assessed from this Phase 2a. 
For this Phase 2b study, a combination of MHAA4549A and oseltamivir was determined 
to be the most clinically feasible treatment regimen, both from an ethical as well as a 
practical perspective.  The treatment of all patients with oseltamivir ensures that all 
patients will receive standard of care given the high morbidity and mortality of 
hospitalized patients with influenza A along with guidelines from Centers for Disease 
Control and Prevention (CDC) and Infectious Diseases Society of America (IDSA) 
stating NAIs are the standard of care for hospitalized patients with influenza A 
(Harper et al. 2009 and CDC Website).  Further, pre-clinical efficacy data from a study 
using MHAA4549A and oseltamivir in combination, showed a potential synergistic effect 
of both compounds which may be due to the different and potentially complementary 
mechanisms of action, i.e. targeting viral hemagglutinin and neuraminidase. 
Dosing of MHAA4549A is confined to a treatment window designed for best expected 
treatment success and to ensure that any observed effects can be attributed to the study 
drug with high confidence.  MHAA4549A shall only be dosed within 5 days of symptom 
onset, within 3 days of initial treatment with a NAI, and no later than 48 hours after 
admission to the hospital.  This proposed window is supported by data demonstrating 
that hospitalized influenza patients benefit from NAI treatment even at 5 days from 
symptom onset (Louie et al. 2012).  
3.2.4 
Rationale for MHAA4549A Dosage 
A single IV dose of 3600 mg of MHAA4549A was selected to assess the efficacy of 
MHAA4549A and to provide data for further clinical development.  The selection of dose 
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in this study for severely ill patients was based on the observed human 
pharmacokinetics in Phase 1 and the relationship between the pharmacokinetics, 
pharmacodynamics, and efficacy observed in a Phase 2a human challenge model of 
influenza.  MHAA4549A was shown to be safe and well-tolerated at all dose levels 
(ranging from 1.5 mg/kg to 45 mg/kg for Phase 1 and 400-3600 mg for Phase 2a) 
through a follow-up period of 120 days post-dose in the Phase 1 and Phase 2a study.  
The dose level used in this study was determined following analysis of data from the 
Phase 2a study, GV28985, which demonstrated the following: 
• 
The 3600-mg dose demonstrated a significant decrease in viral shedding in upper 
respiratory samples.  Based on current interim analysis data, there was a 97.5% 
(p = 0.0051) decrease in AUEC and a 77.3% decrease in peak viral load by qPCR 
measurement compared to the placebo group.   
• 
Symptom data in the Phase 2a study showed a decrease in the AUC of symptoms 
scores for the 3600-mg dose, as illustrated in Table 1, which is consistent with the 
virological results. 
• 
The 1200-mg dose level was not efficacious 
• 
There are no safety concerns at the 3600-mg dose level to date. 
• 
Hospitalized patients generally have a longer duration of viral shedding and 
significantly more viral burden in the lower lung compartments; therefore, high 
concentrations of mAb are likely needed to achieve sufficient occupancy of the virus 
binding sites in the upper and lower respiratory compartments.  Furthermore, higher 
concentrations of mAb are necessary to mitigate the risk of resistance for 
MHAA4549A . 
 
The Phase 1 study was conducted using body-weight based dosing followed by a fixed 
dosing strategy that was used in the Phase 2a study.  Thus, the fixed dosing regimen 
that was used in the Phase 2a study will be used for this study, given the practical 
advantages and positive safety profile of MHAA4549A to date.  Further, fixed dosing is 
generally recommended with monoclonal antibodies, due to their minimal PK variability 
(Bai et al. 2012).  The PK variability introduced by different dosing regimens (i.e., 
body-weight based dosing versus fixed dosing) is moderate relative to the variability 
generally observed in pharmacodynamics, efficacy, and safety and would not be 
expected to be clinically meaningful.   
3.2.5 
Rationale for Biomarker Assessments  
 
 
 
 
 
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3.3 
OUTCOME MEASURES  
3.3.1 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
Adverse events and clinical laboratory abnormalities  
• 
Vital signs, physical findings, ATAs, and clinical laboratory results during 
and following administration of MHAA4549A 
 
3.3.2 
Primary Efficacy Outcome Measure 
The primary outcome measure for this study is as follows: 
• 
Time to normalization of respiratory function defined as: 
− 
The time to cessation of O2 support resulting in a stable SpO2 >95% for at least 
24 hours (see Appendix 2 for details) 
 
3.3.3 
Secondary Efficacy Outcome Measures 
The secondary efficacy outcome measures for this study are as follows: 
• 
Clinical failure after 24 hours post-infusion of study drug; defined as: 
− 
Progression to increased O2 requirement defined by an increase in oxygen 
supplementation from low flow oxygen (2 − 6 L/min) to high flow oxygen 
( > 6 L/min) or from oxygen supplementation alone to any PPV 
− 
Progression to ICU 
− 
Prolonged ventilation or O2 support defined by  > 2 weeks, or 
− 
Death 
• 
Time to clinical normalization of vital signs (3/5 criteria must be met): 
− 
SpO2 > 95% without supplemental O2 for at least 24 hours 
− 
Core temperature < 37.2°C immediately prior to receipt of any antipyretic drug, 
and at least 6-8 hours from the last dose of antipyretic or core temperature 
> 36°C in patients who are initially hypothermic 
− 
Heart rate (HR) < 100/minute 
− 
Systolic blood pressure (SBP) > 90 mmHg 
• 
All-cause mortality at Day 14, Day 30, and Day 60 
• 
Influenza A viral load in nasopharyngeal samples   
− 
AUEC 
− 
Peak viral load 
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− 
Time to resolution of infection  
• 
Duration of hospitalization 
• 
Duration of ICU stay 
• 
Antibiotic usage for respiratory infections 
• 
Complications of influenza: 
− 
Pneumonia (HAP/VAP) 
− 
Exacerbations of chronic lung disease 
− 
Myocarditis 
− 
ARDS 
− 
Otitis media 
− 
Other related complications 
• 
All-cause readmission at Day 30 and Day 60 
• 
Duration of ventilation 
 
3.3.4 
Pharmacokinetic Outcome Measures  
The primary PK outcome measures for this study are as follows: 
• 
PK parameters for MHAA4549A in serum including total exposure (i.e., AUC), 
maximum observed concentration (Cmax), clearance, half-life, and volume of 
distribution, when appropriate, as data allow   
The exploratory PK outcome measures for this study are as follows: 
 
 
 
 
 
 
 
 
3.3.5 
Exploratory Outcome Measures  
The exploratory outcome measures for this study are as follows: 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
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Male partners who have had a vasectomy should have the appropriate 
post-vasectomy documentation available of the absence of sperm in the ejaculate.  
The vasectomized male partner should be the sole partner for that subject. 
− 
For male patients:  Use of condoms and refrain from sperm donation until 
30 days after dosing. 
− 
Non-reproductive potential is defined below (but could be superseded by local 
definitions, if they are more stringent): 
Women who are postmenopausal (i.e., spontaneous amenorrhea for the past 
year confirmed by an FSH level greater than 40 mIU/mL unless the patient is 
receiving a hormonal therapy for their menopause)  
Women who are surgically sterile (i.e., hysterectomy, complete bilateral 
oophorectomy) 
Men who are surgically sterile (castration) 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Pregnant or lactating or intending to become pregnant during the study 
− 
Women who are not postmenopausal (≥ 12 months of non-therapy-induced 
amenorrhea) or who are not surgically sterile must have a negative urine or 
serum pregnancy test result within 2 days prior to study treatment. 
• 
Hypersensitivity to monoclonal antibodies or to the active substance or any 
excipients of MHAA4549A study drug 
• 
Hypersensitivity to the active substance or to any excipients of oseltamivir 
• 
Investigational therapy within the 30 days prior to study treatment  
• 
Received prior therapy with any anti-influenza monoclonal antibody therapy 
including MHAA4549A 8 months prior to study treatment 
• 
Current treatment (within 7 days of dosing) with amantadine or rimantidine 
• 
Patients who have taken more than a total of 3 days (6 doses) of approved 
anti-influenza therapy (e.g., oral oseltamivir, inhaled zanamivir, or oral ribavirin) in 
the period from onset of symptoms and prior to enrollment 
• 
Admission > 48 hours prior to study treatment 
• 
Onset of influenza symptoms > 5 days prior to study treatment 
• 
Positive influenza B or influenza A + B infection within 2 weeks prior to study 
treatment 
• 
High probability of mortality in the next 48 hours as determined by the investigator  
• 
Patient requiring home or baseline oxygenation therapy 
• 
Patient with history of chronic lung disease resulting in baseline SpO2 < 95%  
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• 
Patient on a chronic dose of corticosteroids exceeding 10 mg/day of prednisone or 
equivalent steroid dose for a duration of greater than 14 days within 30 days of entry 
into study 
• 
Patients with the following significant immune suppression:  
− 
Bone marrow or solid organ transplant in the previous 12 months 
− 
Cancer chemotherapy in the previous 12 month 
− 
HIV infection with most recent CD4 < 200 cells/mL 
− 
Other significant immune suppression as determined by the investigator in 
discussion with the Sponsor Medical Monitor or representative 
• 
Patient on extracorporeal membrane oxygenation (ECMO) at time of randomization 
• 
Any disease or condition that would, in the opinion of the site investigator or 
Sponsor, place the subject at an unacceptable risk of injury or render the subject 
unable to meet the requirements of the protocol 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
The randomization of patients will be managed by a central Interactive Voice and Web 
Response System (IxRS) through use of a dynamic hierarchical algorithm.  The 
treatment assignments will be unblinded to selected Sponsor personnel to facilitate 
ongoing monitoring of safety and tolerability, including members of the IMC and SOC.  
All patients will be randomly assigned to receive either MHAA4549A 3600 mg or placebo 
at a 1:1 ratio stratified by site, whether patient is on PPV vs supplemental O2 at 
randomization, and whether the patient has suspected or confirmed bacterial pneumonia 
vs no bacterial pneumonia at randomization.  All patients will receive oseltamivir (75 mg 
or 150 mg BID) for a minimum of 5 days.  Treatment for longer than 5 days is permitted 
based on local investigator discretion. 
Blinded personnel at each study site will make appropriate preparations and perform the 
IV infusions of study drug, as described in Section 4.3.3.  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.  
Bioanalytical laboratory 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 (e.g., to evaluate a possible error in study drug administration). 
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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 in IxRS.  
Treatment codes should not be broken except in emergency situations.  If the 
investigator wishes to know the identity of the study drug for any other reason, they 
should 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 suspected unexpected serious adverse 
reactions (SUSAR)(see Section 5.6) that are considered by the investigator or Sponsor 
to be related to study drug. 
4.3 
STUDY TREATMENT  
4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
MHAA4549A and Placebo 
MHAA4549A, matching placebo, and up to 10-day supply of oseltamivir (Tamiflu®) will 
be supplied by the Sponsor.  For information on the formulation, packaging, and 
handling of MHAA4549A and placebo; see the Pharmacy Manual and the 
MHAA4549A Investigator's Brochure. 
The MHAA4549A vial delivers 10 mL (500 mg) of drug product solution, but may contain 
more (approximately 10.3 mL) than the stated volume to enable delivery of the entire 
10 mL volume.  MHAA4549A is formulated as 50 mg/mL in 10 mM sodium succinate, 
240 mM sucrose, and 0.02% (w/v) polysorbate 20 at pH 5.5 and is contained in a 15 mL 
forma vitrum (USP/PH. Eur. Type 1) glass vial.  The drug product is suitable for single 
use only and contains no preservatives. 
Placebo for MHAA4549A has the same composition as the drug product (without 
MHAA4549A) and is supplied in an identical vial configuration.  The placebo contains no 
preservatives and is suitable for single-use only.  Placebo is formulated as 10 mM 
sodium succinate, 240 mM sucrose, and 0.02% polysorbate 20 at pH 5.5 in a total 
volume of 10 mL in a 15 mL forma vitrum (USP/PH. Eur. Type 1) glass vial. 
MHAA4549A and placebo are supplied in identical blinded vials labeled with unique kit 
numbers.  IxRS will assign kit numbers for each treatment arm; all treatment arms will be 
assigned the same total number of vials for each treatment, and the same preparation 
instructions.  Placebo is identical to active MHAA4549A in formulation and appearance 
but does not contain active drug substance. 
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4.3.1.2 
Oseltamivir (Tamiflu) 
Oseltamivir (Tamiflu) is an influenza NAI indicated for treatment of acute, uncomplicated 
influenza.  For information on the formulation, packaging, and handling of oseltamivir; 
see the local prescribing information for oseltamivir. 
Storage: Capsules should be stored at 25°C (77.7°F); excursions permitted to 15° to 
30°C (59° to 86°F). 
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 3600 mg IV 
or placebo IV at a 1:1 ratio.  Oseltamivir will be dispensed via IxRS.  Oseltamivir dosing 
is described in Table 2.  
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 will be on site during study drug administration for all 
patients. 
A single dose of MHAA4549A or placebo will be delivered by IV infusion following 
dilution in 0.9% normal saline over approximately 60 minutes.  Study drug should be 
delivered using a 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 for 
preparation of study drug can be found in the Pharmacy Manual.   
There are no recommended dosage modifications for MHAA4549A since it is a single 
infusion.  Any overdose or incorrect administration of study drug should be noted on the 
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 AEs associated with overdose.  Patients experiencing such AEs 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.  
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4.3.2.2 
Oseltamivir-Neuraminidase Inhibitor (NAI)  
The Sponsor will be providing oseltamivir (Tamiflu®) for this study for up to a 10-day 
course.  Dosage and administration should follow local prescribing information for 
oseltamivir.  Either 75 mg or 150 mg of oseltamivir will be administered twice daily as 
described in Table 2.  Capsules can be opened and the granules administered via 
nasogastric tube, if required.  
Guidelines for dosage modification for renal dosing are presented in Table 2.   
Any overdose or incorrect administration of oseltamivir should be noted on the 
oseltamivir Administration eCRF.  Adverse events associated with an overdose or 
incorrect administration of oseltamivir should be recorded on the Adverse Event eCRF. 
Patients who are discharged from the hospital with oseltamivir will be required to 
complete a medication diary and return the medication diary, empty (used) oseltamivir 
packets and unused oseltamivir capsules to the study site at the next follow up visit.  
Patients will record the date and time when each oseltamivir capsule is administered. 
4.3.3 
Investigational Medicinal Product Accountability 
Investigational medicinal products (IMPs) required for completion of this study (i.e., 
MHAA4549A and oseltamivir) 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 to 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 to 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. 
The total duration from the preparation of dose solutions to the end of infusion should 
not exceed 24 hours.  Vials are intended for single use only; therefore, any remaining 
solution should be discarded (see the Pharmacy Manual).  
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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 or their delegate 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. 
4.4 
POST-TRIAL ACCESS TO MHAA4549A 
As this is single dose administration, Genentech 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. 
4.5 
CONCOMITANT THERAPY AND FOOD 
4.5.1 
Permitted Therapy  
Concomitant medication 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 concomitant medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF.  For any NAIs (e.g., oseltamivir, peramivir, zanamivir, 
laninimavir) that have been taken prior to study drug therapy, the number of doses and 
duration of therapy must be recorded. 
Patients who use oral contraceptives, hormone-replacement therapy, or other 
maintenance therapy should continue their use. 
All therapies required for management of the patient’s acute illness are permitted except 
for those listed below in Section 4.5.2. 
4.5.2 
Prohibited Therapy 
Use of the following therapies is prohibited during the study and for at least 7 days prior 
to study treatment, unless otherwise specified below:  probenecid, amantadine, or 
rimantidine 
Use of other NAIs, including but not limited to oral oseltamivir, inhaled zanamivir, oral 
ribavirin, laninimivir, and peramivir, are prohibited during the study, but allowed up to 
3 days (6 doses) prior to study treatment as outlined in the exclusion criteria.  If 
oseltamivir resistance is highly suspected or identified during treatment then, following 
discussion with the sponsor medical representative, an alternative NAI to oseltamivir 
may be used. 
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4.5.3 
Prohibited Food  
There are no prohibited foods for this study.  
4.6 
STUDY ASSESSMENTS  
Please see Appendix 1a and Appendix 1b for the schedule of assessments performed 
during the study. 
4.6.1 
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.  Informed consent by 
authorized representatives may be obtained only if allowed by and in accordance with 
local regulations and Independent Review Board (IRB)/Independent Ethics Committee 
(IEC) policies and procedures.  Informed Consent Forms (ICF) 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. 
4.6.2 
Diagnostic Testing for Enrollment 
All hospitalized patients with severe influenza A will be assessed for disease 
confirmation and enrollment into the study.  A Sponsor-supplied rapid influenza test is 
required for the diagnosis of influenza A infection and uses a nasopharyngeal swab.  
When the Sponsor-supplied rapid influenza test is negative, the study inclusion criteria 
can be satisfied with a positive local molecular test (PCR) if the result is within the 
48-hour screening window.  Patients may be enrolled based on a positive local 
molecular test (PCR) result within the 48-hour screening window, but the rapid influenza 
test must still be conducted prior to randomization.  Other tests may not be used for 
enrollment in the study unless the Sponsor has reviewed and approved the use of the 
diagnostic. 
4.6.3 
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.  A careful assessment of the patient’s baseline SpO2 should be 
made especially if the patient has a history of severe chronic lung disease. 
Demographic data will include age, sex, and self-reported race/ethnicity. 
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4.6.4 
Priority of Assessments 
When events warrant, or in the opinion of the investigator, safety issues become 
paramount, safety assessments will always have priority over all other measurements 
and procedures.  Under routine circumstances, however, PK, nasal virological, and 
biomarker serum/plasma samples have priority over other measurements.  The timing 
and number of safety measurements may be modified based on clinical evaluations. 
4.6.5 
Physical Examinations 
A complete physical examination 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 protocol designated visits (or as clinically indicated), limited, symptom-directed 
physical examinations should be performed which 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, if appropriate, on the AE 
eCRF. 
4.6.6 
Vital Signs  
Vital signs will include measurements of resting SpO2 (see Section 4.6.7 for 
measurement), respiratory rate, pulse rate, temperature, and systolic and diastolic blood 
pressures after the patient has been in a seated or supine position for at least 
10 minutes.  Patients in intensive care may have vital signs assessed following local 
procedures, but those procedures should be captured in the eCRF in accordance with 
the eCRF instructions.  
4.6.7 
Oxygen Saturation Measurements 
To ensure that the respiratory status is well recorded, the following daily measurements 
will be performed.  Unless clinically contraindicated, all patients will have their SpO2 and 
corresponding respiratory assessments recorded daily in the morning between 
6 am − 12 pm local time.  Patients on low-flow O2 will have a daily trial of their SpO2 
while on and off the supplementation, as outlined in Appendix 2, and both values will be 
recorded.  
If the patient is on oxygen supplementation, SpO2 measured by pulse oximetry and the 
corresponding respiratory assessments (e.g. FiO2, flow rate) will be recorded.  If the 
patient is on PPV, partial pressure of O2 (PaO2) and the corresponding respiratory 
assessments (e.g. FiO2, ventilator mode, ventilator respiratory rate, positive 
end-expiratory pressure) will be recorded. 
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4.6.8 
Laboratory, Biomarker, and Other Biological Samples  
Samples for the laboratory tests listed in Table 3 and Table 4 will be sent to the study 
site's local laboratory for analysis at screening and during the study, respectively. 
Table 3 
Laboratory Tests at Screening 
Hematology: 
Clinical Chemistry: 
Hemoglobin 
Thyroid stimulating hormone (optional) 
Hematocrit 
 
Erythrocyte count (RBC) 
Serology: 
Leukocytes (WBC) 
HIV Serology 
Neutrophils, segmented & bands 
 
Lymphocytes 
Misc: 
Monocytes 
Pregnancy Test (urine or serum; women of 
child-bearing potential) 
Eosinophils 
Basophils 
 
Platelets 
 
Note:  Investigators must document their review of each laboratory report by signing (or 
initialing) and dating each report. 
 
  
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Table 4 
Laboratory Tests During the Study 
Hematology: 
Clinical Chemistry (Blood):  
Hemoglobin 
Sodium 
Hematocrit 
Potassium 
Erythrocyte count (RBC) 
Bicarbonate 
Leukocytes (WBC) 
Chloride 
Neutrophils, segmented & bands 
Calcium 
Lymphocytes 
Phosphorus 
Monocytes 
Magnesium 
Eosinophils 
Glucose  
Basophils 
Urea nitrogen (BUN) or urea 
Platelets 
Creatinine 
Erythrocyte Sedimentation Rate (ESR) (optional) 
Total cholesterol 
 
Total protein 
Coagulation:  
Albumin 
Activated partial thromboplastin time (APTT) 
Total bilirubin 
Prothrombin time (PT) 
Alkaline phosphatase 
International Normalized Ratio (INR) 
Aspartate aminotransferase (AST) 
 
Alanine aminotransferase (ALT) 
Urinalysis: 
Amylase 
pH 
Gamma-glutamyl transpeptidase (GGT) 
 (if clinically indicated) 
Specific gravity 
Glucose 
C-reactive protein (CRP) (optional) 
Protein 
 
Ketones 
Misc:  
Blood 
Pregnancy Test (if clinically indicated) 
Bilirubin 
 
Nitrite 
 
Leukocyte esterase 
 
Microscopic examination (if clinically indicated) 
Note:  Investigators must document their review of each laboratory report by signing (or initialing) 
and dating each report. 
  
The following samples will be sent to the Sponsor or a designee for PK or ATA analysis: 
• 
 
• 
  
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• 
  
 
 
   
 
 
 
 
   
 
 
 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.   
4.6.9 
Electrocardiograms 
Single ECG recordings will be obtained at specified timepoints, as outlined in the 
schedule of assessments (see Appendix 1a and Appendix 1b), 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 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 QTcF 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 QT interval corrected using 
Fridericia’s formula (QTcF) has stabilized on two successive ECGs.  The Medical 
Monitor should be notified.  If QTcF is not available, QTcB may be recorded.  Standard 
of care treatment may be instituted per the discretion of the investigator.  If a PK sample 
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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 4.9.2.  
The investigator should also evaluate the patient for potential concurrent risk factors 
(e.g., electrolyte abnormalities, medications known to prolong the QT interval, severe 
bradycardia). 
4.6.10 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
   
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4.7 
APACHE AND SOFA SCORES 
Acute Physiology and Chronic Health Evaluation (APACHE) and Sequential Organ 
Failure Assessment (SOFA) scores are for patients that are admitted into the ICU.  
These assessments are not required for study conduct or entry but should be collected if 
available.  The initial scores for APACHE and SOFA should be taken within 24 hours of 
entry into the ICU and at specified time points as seen in Appendix 1a. 
For the calculation of the initial APACHE and SOFA scores, the worst values in the first 
24 hours of ICU admission should be used.  SOFA scores are only for patients admitted 
into the ICU that have available data for calculation (i.e., partial pressure of arterial 
oxygen/fraction of inspired oxygen [PaO2/FiO2] in mmHg).  See Appendix 7 for SOFA 
score calculation. 
4.8 
OSELTAMIVIR MEDICATION DIARY 
Patients who are discharged from the hospital with oseltamivir will be required to 
complete a medication diary and return the medication diary, empty (used) oseltamivir 
packets, and unused oseltamivir capsules to the study site at the next follow up visit.  
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Patients will record the date and time when each oseltamivir capsule is administered.  
4.9 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
4.9.1 
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 or 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 from the study will not be replaced. 
4.9.2 
Study Treatment Discontinuation 
Patients must discontinue MHAA4549A infusion and therefore treatment if they 
experience any of the following: 
• 
Infusion related reactions 
Patients must discontinue oseltamivir treatment if they experience any of the following: 
• 
Pregnancy 
• 
Serious skin/hypersensitivity reactions 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.   
The IMC and SOC may recommend to permanently discontinue dosing for all patients 
within one or both study arms in the event of a general safety concern. 
4.9.3 
Study Completion/Early Discontinuation Visit 
Patients who complete all study visits through Day 60 are considered to have completed 
study.  All patients who discontinue from the study early will be asked to complete all 
assessments for the current visit day and for the early discontinuation visit without 
duplication.  Please see Schedule of Assessments provided in Appendix 1a for 
assessments performed at the Study Completion/Early Discontinuation visit. 
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4.9.4 
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 (GCP) 
• 
No further study activity (i.e., all patients have completed and all obligations have 
been fulfilled) 
 
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 (interim) studies and is 
designed to ensure patient safety.  It will include specific eligibility criteria and monitoring 
assessments as detailed below and above in Section 4.1. 
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. 
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 and SOC agreement.  
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5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and non-serious adverse events of special interest; 
measurement of protocol-specified safety laboratory assessments; measurement of 
protocol-specified vital signs; and 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. 
5.2.1 
Adverse Events 
According to the ICH guideline for GCP, an adverse event is any untoward medical 
occurrence in a clinical investigation patient 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 5.3.5.9. 
• 
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 60 
or Early Discontinuation).  If clinically significant signs or laboratory values are observed 
in a study participant, the investigator should repeat an assessment at the earliest 
opportunity.  Only those events or laboratory values that exceed the level of clinical 
significance upon the repeat assessment will be considered an adverse event. 
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: 
• 
Fatal (i.e., the adverse event actually causes or leads to death) 
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• 
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 5.3.5.10) 
• 
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) 
• 
Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
• 
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 
listed above) 
 
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 Division of 
AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS); see 
Section 5.3.3, Appendix 8, and Appendix 9); 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 
Non-Serious Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) 
Non-serious adverse events of special interest (AESI) 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 5.3.5.6) 
• 
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. 
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• 
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 AEs associated with IRR, 
see Section 5.3.5.1 below): 
− 
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 
• 
Anaphylaxis due to IV drugs most often presents with the following signs and 
symptoms:   
− 
Cutaneous symptoms: flushing, itching, urticaria, 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: such as 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 Section 5.4 − 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. 
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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, regardless of relationship to study 
drug, will be reported until the Day 60 visit or Early Discontinuation visit.  After this period, 
the investigator is not required to actively monitor patients for adverse events; however, 
the Sponsor should be notified if the investigator becomes aware of any death or other 
serious adverse event that occurs after discharge, regardless of causality.  The Sponsor 
should also be notified if the investigator becomes aware of a congenital anomaly/birth 
defect in a subsequently conceived offspring of a female patient exposed to study drug 
(see Section 5.6). 
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 AEs, and SAEs, 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 
AE severity (see Table 5). 
Table 5 
Adverse Event Grading (Severity) Scale 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE-
THREATENING 
ESTIMATING SEVERITY GRADE 
Clinical AE 
NOT identified 
elsewhere in 
this DAIDS AE 
Grading Table  
Symptoms 
causing no or 
minimal 
interference with 
usual social and 
functional 
activities 
Symptoms 
causing greater 
than minimal 
interference with 
usual social & 
functional 
activities 
Symptoms 
causing 
inability to 
perform usual 
social & 
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 
 
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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 or 
not 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 6): 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, considering especially 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 6 
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., chronic obstructive pulmonary 
disease [COPD] diagnosed 2 days after first dose of study drug). 
 
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
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. 
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5.3.5.1 
Diagnosis versus Signs and Symptoms 
Infusion-Related Reactions  
Adverse events that occur during or within 24 hours after study drug infusion should be 
captured as individual signs and symptoms rather than a diagnosis of allergic reaction or 
infusion reaction. 
Other Adverse Events 
For adverse events other than infusion-related reactions, 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 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. 
5.3.5.2 
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. 
5.3.5.3 
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.  If a persistent adverse event 
becomes more severe, it should be recorded as a separate event on the Adverse Event 
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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 event became more severe.  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; see Section 5.4.2 for reporting 
instructions).  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 event became 
serious. 
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. 
5.3.5.4 
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 meets any of the following criteria: 
• 
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 
• 
Clinically significant in the investigator’s judgment (laboratory abnormalities should 
be repeated at the first opportunity and only considered clinically significant if they 
persist on repeat assessment) 
 
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. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 × upper limit of normal [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." 
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Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 
5.3.5.5 
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 meets any of the following criteria: 
• 
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 or a change in concomitant therapy 
• 
Clinically significant in the investigator’s judgment.  Abnormal vital sign values 
should be repeated at the first opportunity and only considered clinically significant if 
they persist on repeat assessment) 
 
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 not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 
5.3.5.6 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × baseline value) 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.  
Therefore, investigators must report as an adverse event the occurrence of either of the 
following: 
• 
Treatment-emergent ALT or AST > 3 × baseline value in combination with total 
bilirubin > 2 × ULN (of which ≥ 35% is direct bilirubin) 
• 
Treatment-emergent ALT or AST > 3 × baseline value 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 
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the event) either as a serious adverse event or a non-serious adverse event of special 
interest (see Section 5.4.2). 
5.3.5.7 
Deaths 
For this protocol, mortality is an efficacy endpoint.  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 severe influenza or any related co-morbidities 
should be recorded 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 as an SAE (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 
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. 
5.3.5.8 
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.  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"). 
5.3.5.9 
Lack of Efficacy or Worsening of Influenza A Infection 
Medical occurrences or symptoms of deterioration that are anticipated as part of 
influenza A should only 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 "). 
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5.3.5.10 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization following initial discharge (i.e., in-patient 
admission to a hospital) or prolonged hospitalization (after the current study 
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 
• 
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 that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
5.3.5.11 
Adverse Events Associated with an Overdose 
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 serious 
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 clinical 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. 
5.4 
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: 
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• 
Serious adverse events 
• 
Non-serious adverse events of special interest 
• 
Pregnancies 
 
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 IRB/IEC. 
5.4.1 
Emergency Medical Contacts 
Medical Monitor Contact Information  
 Medical Monitor contact information: 
Primary Medical Monitor: 
 
Telephone Nos.: 
US Office: 
 
 
US Mobile: 
 
 
Secondary Medical Monitor: 
  
Telephone Nos.: 
US Office: 
 
 
US Mobile: 
 
 
Genentech Medical Monitor contact information for all sites if above medical monitor 
cannot be reached: 
Medical Monitor: 
 
Telephone Nos.: 
US Mobile
 
 
US Office 
 
 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Non-Serious 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.  
A paper Serious Adverse Event Reporting Form and fax cover sheet should be 
completed and faxed to the Sponsor's Safety Risk Management department or its 
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designee immediately (i.e., no more than 24 hours after learning of the event), using the 
fax numbers provided below per region: 
Asia Pacific: 
 
Europe: 
 
Latin America: 
 
North America:  
 
 
5.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events and non-serious adverse events of 
special interest will be reported until the patient is at Day 60 or Early Discontinuation.  
Although the investigator is not required to actively monitor patients for adverse events 
after the patient has been discharged from the study, the Sponsor should be notified if 
the investigator becomes aware of any death or other serious adverse event that occurs 
after discharge from the study, if determined to be related to study drug by the 
investigator.  The Sponsor should also be notified if the investigator becomes aware of a 
congenital anomaly/birth defect in a subsequently conceived offspring of a female 
patient exposed to study drug (see Section 5.4.3).   
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, a paper Serious Adverse Event 
Reporting Form and fax cover sheet should be completed and faxed to Safety Risk 
Management or its designee immediately (i.e., no more than 24 hours after learning of 
the event), using the fax numbers provided to investigators (see fax numbers 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 after the last 
dose of study drug.  A Pregnancy Report eCRF should be completed by the investigator 
immediately (i.e., no more than 24 hours after learning of the pregnancy) and submitted 
via the EDC system.  A pregnancy report will automatically be generated and sent to 
Safety Risk Management.  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 
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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 the event that the EDC system is unavailable, a paper Clinical Trial Pregnancy 
Reporting Form and fax cover sheet should be completed and faxed to Safety Risk 
Management or its designee immediately (i.e., no more than 24 hours after learning of 
the pregnancy), using the fax numbers provided to investigators (see fax numbers 
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. 
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 within 30 days after the dose of 
study drug.  A Pregnancy Report eCRF should be completed by the investigator 
immediately (i.e., no more than 24 hours after learning of the pregnancy) and submitted 
via the EDC system.  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.  Once the 
authorization has been signed, the investigator will update the Pregnancy Report eCRF 
with additional information on the course and outcome of the pregnancy.  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. 
In the event that the EDC system is unavailable, follow reporting instructions provided in 
Section 5.4.3.1. 
5.4.3.3 
Congenital Anomalies/Birth Defects and Abortions 
Any congenital anomaly/birth defect in a child born to a female patient or 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).  
5.4.4 
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.  If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF and the 
Investigator document a discharge plan.  
All pregnancies reported during the study should be followed until pregnancy outcome.  
If the EDC system is not available at the time of pregnancy outcome, follow reporting 
instructions provided in Section 5.4.3.1. 
5.4.5 
Sponsor Follow-Up 
For serious adverse events, non-serious 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. 
5.5 
POSTSTUDY ADVERSE EVENTS 
At the time of study completion or study discontinuation, the investigator should instruct 
each patient to report to the investigator any subsequent adverse events that the patient 
or their personal physician believes could be related to prior study drug treatment or 
study procedures.   
The investigator is not required to actively monitor patients for adverse events after the 
end of the adverse event reporting period (defined as 60 days after the dose of study 
drug).  However, the Sponsor should be notified if the investigator becomes aware of 
any death, other serious adverse event, or non-serious adverse event of special interest 
occurring after the end of the adverse event reporting period, regardless of causality.  
The Sponsor should also be notified if the investigator becomes aware of the 
development of cancer or a congenital anomaly/birth defect in a subsequently conceived 
offspring of a female patient or a female partner of a male patient exposed to study drug. 
The investigator should report these events by completing and faxing a paper Serious 
Adverse Event Reporting Form and fax cover sheet to Safety Risk Management using 
the fax numbers provided to investigators (see Section 5.4.2.1). 
5.6 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events including suspected 
unexpected serious adverse reactions (SUSARs) and non-serious adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, IECs, and applicable 
health authorities based on applicable legislation. 
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To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents: 
• 
MHAA4549A Investigator's Brochure 
• 
Local prescribing information for oseltamivir 
 
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. 
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 2006) 
• 
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 
All 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: 
• 
Randomized patients who have confirmed influenza A infection as confirmed by a 
central PCR test from Day 1 samples 
 
Safety analyses will include all patients who were included in the randomization and who 
received at least one dose of study medication, with patients allocated to the treatment 
arm associated with the regimen actually received.  
No formal hypothesis testing will be done in this study.  As a result, no adjustment for 
a type 1 error will be made to account for the multiplicity of analyses. 
Final efficacy and safety analyses of the total study population will be conducted at the 
end of the study after all patients have completed all study assessments and the 
database has been cleaned and closed.  Further details of the analyses, including 
analysis of the exploratory endpoints, will be contained in the statistical analysis plan 
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(SAP) which will be prepared and finalized before the first optional interim analysis (see 
Section 6.7) or the final efficacy and safety analysis, if no interim analysis takes place.   
6.1 
DETERMINATION OF SAMPLE SIZE 
The purpose of this study is estimation of the effect size and hypothesis generation 
regarding the effect of MHAA4549A on the time to normalization of respiratory function 
relative to the standard of care rather than hypothesis testing.  Point and interval 
estimates will be obtained.  A total of 334 patients will be enrolled in this study in order to 
obtain approximately 300 evaluable patients (an estimated dropout rate of 10%).  It is 
assumed that the median time to normalization of respiratory function in the control arm 
is 5 days.  This sample size (approximately 150 patients per arm) provides 75% power 
to detect a treatment difference of 1 day for the primary endpoint assuming a 2-sided 
alpha of 0.2.  
Operating characteristics (power) under other possible assumptions for 2-sided alpha of 
0.05 and true differences of 1 to 2 days are provided in Table 7.   
Table 7 
Operating Characteristics for Proposed Study Design for Several 
Possible True Underlying Median Values 
 
True Underlying Median for MHAA4549A 
 
3 days 
3.5 days 
4 days 
Hazard Ratio 
0.60 
0.70 
0.80 
Power of log-rank test a 
99% 
86% 
48% 
95% confidence interval 
for true hazard ratio b 
(0.48, 0.75) 
(0.56, 0.88) 
(0.64, 1.00) 
Note:  Operating characteristics are based on the following assumptions:  300 evaluable 
patients, event times are exponentially distributed, median time to normalization of respiratory 
function in the control arm is 5 days, and patients are followed for 60 days. 
a Two-sided α = 0.05. 
b Confidence intervals are based on the assumption that the point estimate is equal to the true 
underlying value of the hazard ratio in each column. 
  
It should be noted that the study is underpowered for detection of minimally clinically 
meaningful differences at a 2-sided alpha of 0.05 such as a true hazard ratio of 0.80 
(see third column of Table 7.   
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. 
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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 
EFFICACY ANALYSES 
The primary and secondary 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. 
Time to event data will be computed using Kaplan-Meier methodology and stratified Cox 
proportional hazards models 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. 
6.4.1 
Primary Efficacy Endpoint 
• 
Median time to normalization of respiratory function 
 
6.4.2 
Secondary Efficacy Endpoints 
• 
Proportion of patients with clinical failure after 24 hours post-infusion of study drug 
• 
Median time to clinical resolution of vital signs 
• 
Hazard ratio for mortality at Day 14, Day 30, and Day 60 
• 
Mean and median AUC of viral load 
• 
Mean and median peak viral load 
• 
Median duration of viral shedding in upper respiratory samples 
• 
Median duration of hospitalization 
• 
Median duration of ICU stay 
• 
Proportion of patients requiring antibiotics for respiratory indications during study 
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• 
Proportion of patients with influenza secondary complications 
• 
Median duration of ventilation 
• 
Proportion of patients who are readmitted by Day 30 and Day 60 
 
6.4.3 
Subgroup Analyses 
Subgroup analyses will be performed to examine the consistency of the treatment 
estimates with use of the primary and selected secondary endpoints.  Subgroups will 
include the stratification factors as well as patients who are identified at baseline as 
influenza A positive by the upper, lower, or both airways and by patients with bacterial 
co-infections at admission.  Additional subgroups may be added following assessment of 
baseline characteristics as exploratory analyses. 
6.5 
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 (including SpO2 measurements), 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.  SAEs 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. 
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 
6.6 
PHARMACOKINETIC ANALYSES  
Individual and mean serum MHAA4549A concentration versus time data will be 
tabulated and plotted.  The serum pharmacokinetics of MHAA4549A will be summarized 
by estimating total serum drug exposure (i.e., AUC), Cmax, Cmin, 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).  
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Inter-patient variability will be evaluated.  MHAA4549A serum concentration–time data 
may be compared with available data from other MHAA4549A clinical studies. 
 
 
  
 
 
 
 
 
6.7 
OPTIONAL INTERIM ANALYSIS  
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 I 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. 
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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 
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.  
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 7.5. 
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/IEC review.  The study site must also allow 
inspection by applicable health authorities. 
7.4 
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 
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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. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, 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. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for GCP 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. Food and Drug Administration (FDA) regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the EU Clinical Trial Directive (2001/20/EC). 
8.2 
INFORMED CONSENT 
The Sponsor’s sample ICFs (and ancillary sample ICFs) 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/IEC submission.  The final 
IRB/IEC−approved Consent Forms must be provided to the Sponsor for health authority 
submission purposes according to local requirements. 
The Consent Forms must be signed and dated by the patient or the patient’s authorized 
representative as applicable and in accordance with local regulations, and IRB/IEC 
policies, before his or her participation in the study.  The case history or clinical records 
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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/IEC-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/IEC policy) during their participation in the study.  For any updated or revised 
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 
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. 
For sites in the United States, 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/IEC by the Principal 
Investigator and reviewed and approved by the IRB/IEC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/IEC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/IEC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/IEC.  Investigators are 
also responsible for promptly informing the IRB/IEC of any protocol amendments (see 
Section 9.1).  
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/IEC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
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for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/IEC, 
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 ICF (or separate authorization for use and 
disclosure of personal health information) signed by the patient, unless permitted or 
required by law. 
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. 
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/IEC 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/IEC 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 
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data integrity to the Sponsor and to the IRB/IEC in accordance with established IRB/IEC 
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/IECs to inspect facilities and records relevant to this study. 
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, clinical monitoring and site management, data quality 
support, medical monitoring, and some safety reporting and regulatory activities as 
specified in 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 dynamic hierarchical 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.   
9.5 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/IEC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/IEC 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). 
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10. 
REFERENCES 
Bai S, Jorga K, Xin Y, et al. A guide to rational dosing of monoclonal antibodies. Clin 
Pharmacokinet 2012;51(2):119-35. 
Blackwood B, Alderdice F, Burns K, et al. Use of weaning protocols for reducing duration 
of mechanical ventilation in critically ill adult patients: Cochrane systematic review and 
meta-analysis. BMJ 2011;342(c7237). 
Centers for Disease Control and Prevention (CDC). Antiviral agents for the treatment 
and chemoprophylaxis of influenza: recommendations of the Advisory Committee on 
Immunization Practices (ACIP). MMRW Morb Mortal Weekly Rep 2001;60(RR01):1−24. 
Centers for Disease Control and Prevention (CDC). 2011-2012 Influenza antiviral 
medications [resource on the Internet]. 2012b [Updated 2014, Mar 21; cited 2014 Apr]. 
Available from: http://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm. 
DeMets D, Lan KKG. Interim analysis: the alpha spending function approach. Stat Med 
1994;13:1341−52. 
Doshi S, Kamimoto L, Finellie L, et al. Description of antiviral treatment among adults 
hospitalized with influenza before and during the 2009 pandemic: United States, 
2005−2009. J Inf Dis 2011;204:1848−56. 
Fiore AE, Fry A, Shay D, et al. (2011). Antiviral agents for the treatment and 
chemoprophylaxis of influenza---recommendations of the Advisory Committee on 
Immunization Practices (ACIP). MMWR. Recommendations and reports: Morbidity and 
mortality weekly report. Recommendations and reports/Centers for Disease Control. 
2011; 60(1):1−24. 
Harper SA, Bradley JS, Englund JA, et al. Expert Panel of the Infectious Diseases 
Society of America. Seasonal influenza in adults and children--diagnosis, treatment, 
chemoprophylaxis, and institutional outbreak management: clinical practice guidelines of 
the Infectious Diseases Society of America. Clin Infect Dis 2009 Apr 15;48(8):1003−32. 
 
 
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. 
Lawton MP, Brody EM. Assessment of older people: self-maintaining and instrumental 
activities of daily living. Gerontologist 1969;9:179−86. 
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Lee N, Ison MG. Diagnosis, management and outcomes of adults hospitalized with 
influenza. Antiviral Therapy 2012:17(1 Pt B):143−57. 
Louie JK, Yang S, Acosta M, et al. Treatment with neuraminidase inhibitors for critically 
ill patients with influenza A (H1N1). CID 2012;55:1198−204. 
Marty FM, Man CY, van der Horst C, et al. Safety and pharmacokinetics of intravenous 
zanamivir treatment in hospitalized adults with influenza: an open-label, multicenter, 
single-arm, Phase II study. J Infect Dis 2014;209(4):542−50. 
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. 
Polakos NK, Cornejo JC, Murray DA, et al. Kupffer cell-dependent hepatitis occurs 
during influenza infection. Am J Pathol 2006;168(4):1169−78. 
Thompson WW, Shay DK, Weintraub E, et al. Influenza-associated hospitalizations in 
the United States. JAMA 2004;292(11):1333−40. 
Zhou H, Thompson WW, Vioud CG, et al. Hospitalizations associated with influenza and 
respiratory syncytial virus in the United States 1993−2008. Clin Inf Dis 
2012;54(10):1427−36. 
 
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APPENDIX 1a 
 
Schedule of Assessments:  Hospitalization Days  
Notes: Unless otherwise indicated, all assessments on Day 1 should be performed prior to study drug administration; x’s within 
parentheses, i.e., (x), indicate optional assessments.  Please refer to Follow-up Period table for visits to be completed after patient is 
discharged from hospital prior to Day 60.  
Day (D) 
Screening 
Hospitalized Days (only to be completed while patients are hospitalized) 
Hospital 
Discharge a D30  
D60  
Study Completion or 
Early Discontinuation 
while Hospitalized 
D -2,-1 
D1 
(Randomization) D2 D3 D4 D5 
D6 
D7 
D8 
D9 D10 D14 D20 D25 
Confirm study drug administration can occur within 48 hours of hospital admission 
 
Informed consent b 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rapid influenza A test c 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Local influenza A PCR test d 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and 
demographic data 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm onset of flu symptoms 
(≤ 5 days prior to study drug 
administration on Day 1) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm history of baseline 
SpO2 > 92% 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy screening e 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm O2 requirement f 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Respiratory Assessment g 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant medications h 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vital signs i 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
APACHE score j 
 
(xz) 
 
 
 
 
 
 
 
 
 
(x) 
 
 
(x) 
(x) 
(x) 
SOFA score k 
 
(xz) 
 
 
 
 
 
(x) 
 
 
 
(x) 
 
 
(x) 
(x) 
(x) 
Electrocardiogram (12-lead) l 
 
x 
 
 
 
x 
 
 
 
 
 
x 
 
 
x 
x 
x 
Randomization 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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APPENDIX 1a (cont’d)  
Schedule of Assessments:  Hospitalization Days  
a Assessments to be performed irrespective of day of discharge.  Assessments on discharge day will supersede assessments for matching day 
except for the study completion/early discontinuation visit (e.g., If a patient is discharged from the hospital on Day X, use assessments under 
“hospital discharge” column instead of the Day X column and record under the hospital discharge folder in the eCRF.  If a patient discontinues 
from the study early on Day X, complete all assessments under the Day X column and “early discontinuation” column without duplication, and 
record under the early discontinuation folder in the eCRF).  
b Informed consent must be obtained from all patients.  For patients who are unable to consent, an authorized representative may be used if 
allowed by local regulations and IRB/IEC policy.   
c Sponsor-supplied rapid influenza test using nasopharyngeal swabs.  
d If the Sponsor-supplied rapid influenza test is negative, local influenza PCR testing can be used to confirm influenza A and satisfy entry criteria if 
results are received within screening/hospitalization window (48 hours).  Patients can be enrolled based on a positive local influenza PCR test 
result within the 48 hour screening window, but the rapid influenza test must still be conducted prior to randomization.  
e A urine pregnancy test should be sent only for women considered by the investigator to be of childbearing potential, see exclusion criteria.  This 
result must be available prior to randomization.  If urine testing is not available at the site, blood already collected from an existing sample may 
be tested for pregnancy. 
f Confirm patient requires supplemental O2 or PPV within 24 hours of hospital admission. 
g All patients will have their on-study SpO2 and corresponding respiratory assessments recorded daily in the morning between 6 am − 12 pm local 
time; screening SpO2 may be taken outside this window.  Patients on low flow O2 should have a daily trial of their SpO2 while on and off the 
supplementation and both values will be recorded. If the patient is on oxygen supplementation, SpO2 measured by pulse oximetry and the 
corresponding respiratory assessments (e.g. FiO2, flow rate) will be recorded.  If the patient is on PPV, PaO2 and the corresponding respiratory 
assessments (e.g. FiO2, ventilator mode, ventilator respiratory rate, positive end-expiratory pressure) will be recorded.  
h Concomitant medications should be recorded for 30 days prior to screening, through the study completion/early discontinuation visit.  See 
exclusion criteria in Section 4.5.2 for prohibited therapies. 
i Vital signs will be collected within 1 hour before MHAA4549A infusion and within 1 hour after completion of MHAA4549A infusion  include 
temperature, 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.  In patients who have multiple 
vital signs taken during any day, the most abnormal value should be recorded from that 24-hour period.  Temperature, blood pressure, 
respiratory rate, and heart rate will be completed after the patient has been supine for > 5 minutes.  The worst/most abnormal value from the last 
24-hour period should be recorded for patients who are in the ICU.  
j APACHE scores are optional and only for patients that are in the ICU.  For calculation of the screening APACHE score, the worst values in the 
preceding 24 hours should be used.  APACHE scores are not required for study conduct or entry but should be collected if available.  
k SOFA scores are only for patients in the ICU that have available data such as PaO2/FiO2 (mmHg).  See Appendix 7 for SOFA score calculation. 
l Patient should rest in a supine position for 10 minutes prior. 
m  Patient will be a resident for at least 24 hours following administration of MHAA4549A. 
n Oseltamivir must be given for a minimum of 5 days.  Treatment longer than 5 days is permitted based on the discretion of the investigator 
[indicated by (x)]. 
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APPENDIX 1a (cont’d)  
Schedule of Assessments:  Hospitalization Days  
o 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 adverse events, if appropriate.  
p 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 adverse events, if appropriate. 
q Height will be obtained at screening only.  Weight will be obtained at all indicated visits.  Height and weight will be recorded in centimeters and 
kilograms, respectively.  
r Local laboratory measurements should be utilized. 
s 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. 
 
 
  
 
 
 
v Day 1 serum PK samples are to be drawn 30 (± 5) minutes pre-dose of MHAA4549A, 60 (± 15) minutes after the end of infusion.  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.  
 
 
 
 
x If patient is discharged on or before Day 5, the oseltamivir PK sample should be taken on the discharge day. 
 
 
 
 
z Assessment to be conducted based on entry into ICU; may vary from patient to patient. 
aa For optional thyroid stimulating hormone test. 
bb HIV serology result not needed for randomization. 
cc Patients who are discharged from the hospital with oseltamivir will be required to complete a medication diary and return the medication diary, 
empty (used) oseltamivir packets and unused oseltamivir capsules to the study site at the next follow up visit.  Patients will record the date and 
time when each oseltamivir capsule is administered.  
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APPENDIX 1b 
 
Schedule of Assessments:  Follow-Up Period  
• 
If a patient is discharged prior to Day 14, he/she will need to complete the following assessments for Day 14 ,Day 30, and Day 60 below. 
• 
If a patient is discharged prior to Day 30 and after Day 14, he/she will need to complete the following assessments for Day 30 and Day 60 
below. 
• 
If a patient is discharged prior to Day 60 but after Day 30, he/she will need to complete the following assessments for Day 60 below. 
• 
If patient is hospitalized for Day 14, Day 30, and/or Day 60, please refer to Appendix 1a.  
Day (D) 
D14 ± 1 
(If discharged BEFORE D14) 
D30 ± 4  
(If discharged BEFORE D30)  
Day 60 ± 4 (Study Completion)  
or Early Discontinuation  
Concomitant medications a 
x 
x 
x 
Vital signsb 
x 
x 
x 
Electrocardiogram (12-lead) c 
x 
x 
x 
Weight & height, BMI d 
x 
x 
x 
Adverse events 
x 
x 
x 
Hematology e
 
x 
x 
x 
Chemistry panel e 
x 
x 
x 
Coagulation panel e 
x 
x 
x 
Urinalysis e 
x 
x 
x 
Flu antibodies (HAI) 
x 
x 
x 
 
 
x 
x 
Serum for MHAA4549A PK 
measurements f 
x 
x 
x 
 
 
x 
x 
x 
 
 
x 
x 
x 
  
 
x 
x 
  
 
x 
x 
  
 
x 
x 
  
 
x 
x 
  
; ATA = Anti-therapeutic antibodies; BMI = body mass index; D = day; 
Dx = diagnostics; eCFR = electronic Case Report Form; ECG = electrocardiogram; HAI = hemagglutinin inhibition; 
 
 
; PD = pharmacodynamics; PK = pharmacokinetic. 
a Concomitant medications should be recorded for 30 days prior to screening, through the study completion/early discontinuation visit.  See 
exclusion criteria in Section 4.5.2 for prohibited therapies. 
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APPENDIX 1b (cont’d)  
Schedule of Assessments:  Follow-up Period  
b Vital signs include temperature, 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 study drug administration of any antipyretic drugs.  
In patients who have multiple vital signs taken during any day, the most abnormal value should be recorded from that 24-hour period.  
Temperature, blood pressure, respiratory rate, and heart rate will be completed after the patient has been supine for > 5 minutes.  
c ECG should be recorded after the patient has rested in a supine position for 10 minutes. 
d Height will be obtained at screening only.  Weight will be obtained at all indicated visits.  Height and weight will be recorded in meters and kg, 
respectively.  
e Local laboratory measurements should be used. 
f PK samples should be drawn from the opposite arm from the one used for drug infusion and must be labeled with the exact time of draw.  
 
 
 
 
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APPENDIX 2  
Time to Normalization of Respiratory Function 
For the purposes of this study, the time to normalization of respiratory function will be 
defined as the time to removal of the patient from O2 supplementation in order to 
maintain an SpO2 > 95%.  
Patients who are on low flow O2 (2-6L/min) should receive a daily trial off O2 in the 
morning between 6 am − 12 pm as described below.  
1. Patient should be resting or sitting. 
2. Patient should be fitted with pulse oximeter, and their SpO2 should be checked 
once while on O2 and then again 3 − 5 minutes after turning off O2 
supplementation.  
3. If the SpO2 > 95%, then the time and reading should be recorded.  Notify the 
study doctor so that he/she can make a clinical judgment to determine whether 
the O2 can be removed. 
4. If the patient is off O2 for 24 hours and his/her reading the subsequent day 
is >95%, then the endpoint is considered satisfied.  The recorded time for the 
endpoint corresponds with the initial discontinuation of O2 and reading. 
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APPENDIX 6  
 
  
 
  
 
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APPENDIX 7  
SOFA Score Calculation  
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 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. 
 
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APPENDIX 8  
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. 
MHAA4549A—Genentech, Inc. 
Protocol GV29216, Version 3 (VHP ONLY) 
91 


 
APPENDIX 8 (cont’d)  
DAIDS Toxicity Grading Tables for Clinical Abnormalities 
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 
 
 
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 
 
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92 


 
APPENDIX 9  
DAIDS Toxicity Grading Tables for Laboratory Abnormalities 
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 
Abbreviations used in the table: 
; CPK = creatine phosphokinase; Dec = Decreased; 
IV = Intravenous; LLN = Lower limit of normal; Mod = Moderate; Req = Required; 
Rx = Therapy; SGOT = serum glutamic oxaloacetic transaminase; SGPT = serum 
glutamic pyruvic transaminase; ULN = Upper limit of normal. 
 
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 gm/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 x 
ULN 
1.26 – 1.50 x 
ULN 
1.51 – 3.0 x 
ULN 
>3 x ULN 
Activated Partial 
Thromboplastin 
Time (APTT) 
1.01 – 1.66 x 
ULN 
1.67 – 2.33 x 
ULN 
2.34 – 3 x ULN 
>3 x ULN 
Methemoglobin 
5.0 – 9.9% 
10.0 – 14.9% 
15.0 – 19.9% 
>20.0% 
From the FDA Guidance document ‘Toxicity Grading Scale from Healthy Adult and Adolescent 
Volunteers Enrolled in Preventative Vaccine Clinical Trials’ 
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93 


 
APPENDIX 9 (cont’d)  
DAIDS Toxicity Grading Tables for Laboratory Abnormalities 
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  
Hyperbilirubinemia 
(when accompanied by 
any increase in other 
liver function test) 
1.1 – <1.25 x 
ULN 
1.25 – <1.5 x 
ULN 
1.5 – 1.75 x  
ULN 
>1.75 x ULN 
Hyperbilirubinemia 
(when other liver 
function are in the 
normal range) 
1.1 – <1.5 x 
ULN 
1.5 – <2.0 x 
ULN 
2.0 – 3.0 x  
ULN 
>3.0 x ULN 
MHAA4549A—Genentech, Inc. 
Protocol GV29216, Version 3 (VHP ONLY) 
94 


 
From the FDA Guidance document ‘Toxicity Grading Scale from Healthy Adult and Adolescent 
Volunteers Enrolled in Preventative Vaccine Clinical Trials’ 
 
ENZYMES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
AST (SGOT) 
1.1 - <2.0 x ULN 
2.0 - <3.0 x ULN 
3.0 – 8.0 x ULN 
>8.0 x ULN 
ALT (SGPT) 
1.1 - <2.0 x ULN 
2.0 - <3.0 x ULN 
3.0 – 8.0 x ULN 
>8.0 x ULN 
GGT 
1.1 - <2.0 x ULN 
2.0 - <3.0 x ULN 
3.0 – 8.0 x ULN 
>8.0 x ULN 
Alkaline 
Phosphatase 
1.1 - <2.0 x ULN 
2.0 - <3.0 x ULN 
3.0 – 8.0 x ULN 
>8.0 x ULN 
Amylase 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.1 – 5.0 x ULN 
>5.1 x ULN 
Lipase 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.1 – 5.0 x ULN 
>5.1 x ULN 
*CPK – mg/dL 
1.25 – 1.5 x ULN 
1.6 – 3.0 x ULN 
3.1 – 10.0 x ULN 
>10 x ULN 
*From the FDA Guidance document ‘Toxicity Grading Scale from Healthy Adult and Adolescent 
Volunteers Enrolled in Preventative Vaccine Clinical Trials’ 
  
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 
From the FDA Guidance document ‘Toxicity Grading Scale from Healthy Adult and Adolescent 
Volunteers Enrolled in Preventative Vaccine Clinical Trials’ 
 
 
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Protocol GV29216, Version 3 (VHP ONLY) 
95 




 
MHAA4549A—Genentech, Inc. 
2/Protocol GV29216, Version 5 (Global)   
 
PROTOCOL AMENDMENT RATIONALE 
This Version 5 amendment consolidates elements of two previous country-specific 
amendments and revises the study design to add a third treatment arm (i.e., 8400 mg 
treatment arm).  The rationale for previous amendments (i.e., Version 3 and Version 4) 
is listed for the convenience of sites that did not receive these versions of the protocol.  
RATIONALE FOR VERSION 3 (VHP ONLY) 
Protocol GV29216 was amended in Version 3 was revised to incorporate VHP feedback 
and reflects the following changes: 
 
Male partners of female patients who have had a vasectomy should have 
appropriate post-vasectomy documentation available of the absence of sperm in the 
ejaculate (see Section 4.1.1). 
 
Female patients should use two acceptable methods of contraception throughout 
the trial, including the active treatment phase AND for 120 days after the last dose 
of MHAA4549A (see Section 4.1.1). 
 
Male patients should use condoms and refrain from donating sperm until 30 days 
after dosing (see Section 4.1.1). 
 
Exclusion criteria “hypersensitivity to monoclonal antibodies or to the active 
substance or any excipients of MHAA4549A study drug” and “hypersensitivity to the 
active substance or to any excipients of oseltamivir” (see Section 4.1.2) 
 
RATIONALE FOR VERSION 4 (RUSSIA ONLY) 
Protocol GV29216 was amended in Version 4 (Russia Only) to address comments from 
the Ministry of Healthcare of the Russian Federation, as follows: 
 
 
 
Changed “mAb” to “monoclonal antibody” throughout the protocol 
 
Clarified rationale for biomarker assessments 
 
Updated exclusion criteria to exclude patients with hypersensitivity to monoclonal 
antibodies or to the active substance or any excipients of MHAA4549A study drug, 
hypersensitivity to the active substance or to any excipients of oseltamivir, and 
patients with a creatinine clearance  10 mL/min 
 
 
 
Clarification of repeating any abnormal assessment or clinically significant 
laboratory findings 
 
In addition, changes were made to clarify inclusion/exclusion criteria and study 
procedures, as follows:  
 
Contraception requirements in inclusion criteria  


 
MHAA4549A—Genentech, Inc. 
3/Protocol GV29216, Version 5 (Global)   
 
Exclusion criteria to exclude patients on current treatment with probenecid to stay 
consistent with the prohibited treatments section 
 
Unblinded personnel at each study site will prepare the intravenous infusions of 
study drug and that the Sponsor will provide masking bags and blinded study 
personnel with administer the study drug 
 
Placebo is identical to active MHAA4549A in formulation, but not appearance 
 
The adverse event reporting period 
 
Additionally, updates were made to the protocol, as follows:  
 
Contact information for reporting serious adverse events and non-serious adverse 
events of special interest 
 
Investigator follow-up instructions (Section 5.4.4) 
 
Poststudy adverse events reporting instructions (Section 5.5) 
 
Addition of publication of data and protection of trade secrets instructions 
(Section 9.5) 
 
Replacement of SOFA score calculations (Appendix 7) 
 
Addition of anaphylaxis precautions and management instructions (Appendix 10) 
 
The Sponsor considers that changes in this amendment will increase the safety 
monitoring in this Phase 2b study without any significant impact on the scientific value of 
the trial, nor will they have any significant impact on the safety or mental or physical 
integrity of study patients. 


RATIONALE FOR VERSION 5 (GLOBAL) 
Protocol GV29216 was amended in Version 5 to add a high-dose arm (i.e., 8400 mg 
MHAA4545A) and to harmonize relevant regional feedback into a global amendment.   
GV29216 will assess severely ill patients who may be infected with various influenza A 
strains and who have a higher viral burden and longer duration of viral shedding than the 
healthy volunteers in GV28985.  This population may benefit from doses higher than 
3600 mg.  Therefore, the study design has been updated to include the addition of an 
8400-mg treatment arm for further dose ranging.  A Phase 1 study (GV29609) 
investigating the 8400-mg dose in healthy volunteers has completed dosing, and interim 
safety data is provided in the introduction.  
The addition of the 8400-mg treatment necessitated an adjustment in the infusion rate to 
120 minutes for MHAA4549A and placebo.  In addition, to mitigate any concerns with 
safety monitoring, the study design was expanded to include an initial safety assessment 
by the Internal Monitoring Committee and the Scientific Oversight Committee of a 
sentinel safety cohort consisting of the first 30 patients enrolled or those patients 
enrolled during the first influenza season, whichever occurs first.  
Version 5 also contains revisions to support the changes discussed above as well as 
updates to the background sections, as follows: 
• 
The time to normalization end point was adjusted operationally based on 
investigator feedback to allow greater flexibility to be in line with local standard 
course of clinical care 
• 
The sample size was adjusted to approximately 330 patients.   
• 
The MHAA4549A dosing rationale was updated to support the 8400-mg dose.  
• 
The background clinical safety and efficacy summaries were updated with the most 
current data concerning MHAA4549A.  Preliminary safety data from the Phase 1 
study (GV29609) was included in the clinical safety section to support the use of the 
8400-mg treatment arm in this study (GV29216). 
• 
Sections that previously required a protocol clarification letter were updated:  use of 
unblinded personnel to prepare the IV infusions of study drug and the use of 
masking bags, SOFA score calculation, and anaphylaxis management instructions. 
• 
The contraception language in the inclusion criteria was updated. 
• 
PaO2 conversion table included as an appendix to allow greater flexibility with 
standard clinical practice. 
 
 
MHAA4549A—Genentech, Inc. 
4/Protocol GV29216, Version 5 (Global)   


SUMMARY OF CHANGES:  
VERSION 5 AMENDMENT 
This Version 5 amendment consolidates elements of two previous country-specific 
amendments and revises the study design to add a third treatment arm (i.e., 8400-mg 
treatment arm).  The Summaries of Changes for previous amendments (i.e., Version 3 
and Version 4) relevant to Version 5 are listed in this section for the convenience of sites 
that did not receive these versions of the protocol.  However, only Version 5 revisions 
are presented as italicized text in the body of the protocol. 
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol. 
SUMMARY OF CHANGES:  Version 3 (VHP Only) 
SECTION 4.1.1: 
Inclusion Criteria 
• 
Patients of reproductive potential must agree to use reliable means of contraception 
as described below as a minimum (adherence to more stringent local requirements 
may be required): 
– 
For female patients:  Use of two acceptable methods of contraception 
throughout the trial, including the active treatment phase AND for 120 days 24 
weeks after the last dose of MHAA4549A.  Acceptable methods of 
contraception include:  intrauterine device, systemic hormonal contraception 
(oral or depot), vaginal ring, tubal ligation of the female partner, vasectomy of 
the male partner, use of latex condoms plus spermicide by the male partner, or 
cervical cap plus spermicide (where the spermicide could be foam, vaginal 
suppository, gel, cream, etc.).  Male partners who have had a vasectomy 
should have the appropriate post-vasectomy documentation available of the 
absence of sperm in the ejaculate.  The vasectomized male partner should be 
the sole partner for that patient. 
– 
For male patients:  Use of condoms and refrain from sperm donation until for 
30 days after dosing when circulating drug levels remain high. 
SECTION 4.1.2: 
Exclusion Criteria 
• 
Hypersensitivity to monoclonal antibodies or to the active substance or any 
excipients of MHAA4549A study drug 
• 
Hypersensitivity to the active substance or to any excipients of oseltamivir 
• 
Hypersensitivity to mABs or any constituents of study drug 
 
 
MHAA4549A—Genentech, Inc. 
5/Protocol GV29216, Version 5 (Global)   




SECTION 3.1.1:  Overview of Study Design 
 
   
SECTION 3.2.5:  Rationale for Biomarker Assessments 
 
 
 
 
e 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
SECTION 3.3.3:  Secondary Efficacy Outcome Measures 
• 
Time to clinical normalization resolution of vital signs (3/5 criteria must be met): 
SECTION 3.3.4:  Pharmacokinetic Outcome Measures 
• 
 
 
 
MHAA4549A—Genentech, Inc. 
7/Protocol GV29216, Version 5 (Global)   


SECTION 3.3.5:  Exploratory Outcome Measures 
 
 
 
   
 
 
 
 
SECTION 4.1.1:  Inclusion Criteria 
− For female patients:  Use of two acceptable methods of contraception 
throughout the trial, including the active treatment phase AND for 120 days after 
the last dose of MHAA4549A.  Acceptable methods of contraception 
include:  intrauterine device, systemic hormonal contraception (oral or depot), 
vaginal ring, tubal ligation of the female partner, vasectomy of the male partner, 
use of latex condoms plus spermicide by the male partner, or cervical cap plus 
spermicide (where the spermicide could be foam, vaginal suppository, gel, 
cream, etc.).  Male partners who have had a vasectomy should provide the 
appropriate post-vasectomy documentation of the absence of sperm in the 
ejaculate.  The vasectomized male partner should be the sole partner for that 
subject. 
− 
For male patients:  Use of condoms and refrain from sperm donation until 
30 days after dosing when circulating drug levels remain high. 
SECTION 4.1.2:  Exclusion Criteria 
• 
Hypersensitivity to monoclonal antibodiesmABs or to the active substance or any 
constituents excipients of MHAA4549A study drug 
• 
Hypersensitivity to the active substance or to any excipients of oseltamivir 
• 
Creatinine clearance ≤ 10 mL/min 
SECTION 4.2:  METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
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, as described in Section 4.3.3.  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.   
SECTION 4.3.1.1:  MHAA4549A and Placebo 
Placebo is identical to active MHAA4549A in formulation and appearance but does not 
contain active drug substance. 
 
MHAA4549A—Genentech, Inc. 
8/Protocol GV29216, Version 5 (Global)   


SECTION 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 3600 mg IV or 
placebo IV at a 1:1 ratio.  Oseltamivir will be dispensed via Oseltamivir 75 mg and 
150 mg will be supplied via IxRS.   
A single dose of MHAA4549A or placebo will be delivered by IV infusion following 
dilution in 0.9% normal saline over approximately 60120 minutes.  Compatibility testing 
has shown that MHAA4549A is stable when diluted in 0.9% normal saline in a 
polyvinylchloride bag, polyolefin bag, or ethylene vinyl acetate bag (EVA), at or above a 
combined total concentrationconcentrations of 0.24 mg/mL up to 27.0 mg/mL.   
SECTION 4.3.2.2:  Oseltamivir-Neuraminidase Inhibitor (NAI) 
Oseltamivir 75 mg and 150 mg will be supplied via IxRS.  For renally impaired 
patients requiring the 30-mg dose strength, the Sponsor will supply oseltamivir or 
reimburse sites for oseltamivir per local regulations. 
SECTION 4.6.5:  
 
 
 
 
 
 
 
 
  
SECTION 4.6.6:  
 
 
 
 
 
 
 
 
SECTION 4.6.10:  Laboratory, Biomarker, and Other Biological Samples 
 
 
 
  
 
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9/Protocol GV29216, Version 5 (Global)   


 
   
 
 
 
SECTION 5.2.1:  Adverse Events 
Adverse events will be monitored throughout the entire study (enrollment through Day 60 
or Early Discontinuation).  If clinically significant signs or laboratory values are observed 
in a study participant, the investigator should repeat an assessment at the earliest 
opportunity.  Only those events or laboratory values that exceed the level of clinical 
significance upon the repeat assessment will be considered an adverse event. 
SECTION 5.3.1:  Adverse Event Reporting Period 
After initiation of study drug, all adverse events, regardless of relationship to study 
drug, will be reported until the Day 60 visit or 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 is not required to actively monitor patients for adverse 
events; however, the Sponsor should be notified if the investigator becomes aware of 
any death or other serious adverse event that occurs after discharge, regardless of 
causality.  The Sponsor should also be notified if the investigator becomes aware of a 
congenital anomaly/birth defect in a subsequently conceived offspring of a female 
patient exposed to study drug (see Section 5.5). 
SECTION 5.3.5.4:  Abnormal Laboratory Values 
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. 
SECTION 5.4.1:  Emergency Medical Contacts 
Medical Monitor: 
 
Telephone Nos.: 
US Mobile Office 
 
 
 
US Office Mobile 
 
 
SECTION 5.4.2.1:  Events That Occur Prior to Study Drug Initiation 
A paper Serious Adverse Event / Adverse Event of Special Interest Reporting Form and 
fax cover sheet should be completed and faxed or scanned and emailed to the Sponsor's 
Safety Risk Management department or its designee immediately (i.e., no more than 24 
 
MHAA4549A—Genentech, Inc. 
10/Protocol GV29216, Version 5 (Global)   


hours after learning of the event), using the fax numberscontact information provided 
below per region: 
Region 
Fax Number 
Email Address 
Asia Pacific 
 
 
Europe 
 
Latin America 
 
North America 
 
Asia Pacific: 
 
Europe: 
 
Latin America: 
 
North America:  
 
SECTION 5.4.2.2:  Events that Occur after Study Drug Initiation 
In the event that the EDC system is unavailable, a paper Serious Adverse Event 
Reporting Form and fax cover sheet should be completed and faxed or scanned and 
emailed to Safety Risk Management or its designee immediately (i.e., no more than 
24 hours after learning of the event), using the fax numberscontact information provided 
to investigators (see fax numbers 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.   
SECTION 5.4.3.1:  Pregnancies in Female Patients 
In the event that the EDC system is unavailable, a paper Clinical Trial Pregnancy 
Reporting Form and fax cover sheet should be completed, and faxed, or scanned and 
emailed to Safety Risk Management or its designee immediately (i.e., no more than 
24 hours after learning of the pregnancy), using the fax numberscontact information 
provided to investigators (see fax numbers 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. 
SECTION 5.4.4:  Investigator Follow Up 
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.   If, after follow up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF and the 
Investigator document a discharge plan. 
MHAA4549A—Genentech, Inc. 
11/Protocol GV29216, Version 5 (Global)  


SECTION 5.5:  POSTSTUDY ADVERSE EVENTS 
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 60 days 
after the last dose of study drug (see Section 5.3.1), if the event is believed to be related 
to prior study drug treatment.   
The investigator should report these events directly to Roche 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 (refer to site binder).At the time of study completion or study 
discontinuation, the investigator should instruct each patient to report to the investigator 
any subsequent adverse events that the patient or their personal physician believes 
could be related to prior study drug treatment or study procedures.   
The investigator is not required to actively monitor patients for adverse events after the 
end of the adverse event reporting period (defined as 60 days after the dose of study 
drug).  However, the Sponsor should be notified if the investigator becomes aware of 
any death, other serious adverse event, or non serious adverse event of special interest 
occurring after the end of the adverse event reporting period, regardless of causality.  
The Sponsor should also be notified if the investigator becomes aware of the 
development of cancer or a congenital anomaly/birth defect in a subsequently conceived 
offspring of a female patient or a female partner of a male patient exposed to study drug. 
SECTION 6.4.2:  Secondary Efficacy Endpoints 
• 
Median duration of viral shedding in upper respiratory samplesnasopharyngeal 
samples 
SECTION 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 from 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 website:  
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 
 
MHAA4549A—Genentech, Inc. 
12/Protocol GV29216, Version 5 (Global)   


 
MHAA4549A—Genentech, Inc. 
13/Protocol GV29216, Version 5 (Global)   
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. 
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. 
APPENDIX 1a:  Schedule of Assessments:  Hospitalization Days 
In the list of procedures, “Upper respiratory tract sample (NP sample)” was changed to 
“Nasopharyngeal sample,” and 
 as changed to “
 
 
A footnote for “Oseltamivir administration” was changed as follows: 
n Oseltamivir must be given for a minimum of 5 days.  Treatment longer than 5 days is permitted 
based on the discretion of the investigator [indicated by (x)].  See Table 2 for oseltamivir 
dosing guidelines and recommended renal dose adjustments. 
 
 


APPENDIX 7:  SOFA Score Calculation 
Variables 
SOFA Score 
0 
1 
2 
3 
4 
Respiratory  
(PaO2/FiO2, mmHg) 
> 400 
≤ 400 
≤ 300 
≤ 200a 
≤ 100a 
Coagulation  
(Platelets x 103/µL) b 
> 150 
≤ 150 
≤ 100 
≤ 50 
≤ 20 
Liver  
(Bilirubin, mg/dL) b 
< 1.2 
1.2 − 1.9 
2.0 − 5.9 
6.0 − 11.9 
> 12.0 
Cardiovascular 
(Hypotension) 
No 
hypotension 
MAP < 70 
mmHg 
Dop ≤ 5 or dob 
(any dose) c 
Dop > 5, epi ≤ 0.1, 
or norepi ≤ 0.1c 
Dop > 15, epi > 0.1, 
or norepi > 0.1c 
Central Nervous System 
(Glasgow Coma Score 
Scale) 
15 
13 − 14 
10 − 12 
6 − 9 
< 6 
Renal  
(Creatinine, mg/dL or 
urine output, mL/day) d 
< 1.2 
1.2 − 1.9 
2.0 − 3.4 
3.5 − 4.9 or < 500 
> 5.0 or < 200 
Norepi = norepinephrine; Dob = dobutamine; Dop = dopamine; Epi = epinephrine; FiO2 = fraction of inspired 
oxygen; MAP = mean arterial pressure; PaO2 = partial pressure of arterial oxygen. 
a Values are with respiratory support. 
b To convert bilirubin from mg/dL to µmol/L, multiply by 17.1. 
c Adrenergic agents administered for at least 1 hour (doses given are in µg/kg per minute). 
d To convert creatinine from mg/dL to µmol/L, multiply by 88.4. 
  
References for Appendix 7: 
Ferreira FL, Bota DP, Bross A et al. Serial evaluation of the SOFA score to predict outcome in 
critically ill patients. JAMA 2001; 286(14):1754−1758 
Vincent JL, de Mendonca A, Cantraine F et al. Use of the SOFA score to assess the incidence of 
organ dysfunction/failure in intensive care units: results of a multicenter, prospective study.  
Working group on “sepsis-related problems” of the European Society of Intensive Care 
Medicine. Crit Care Med 1998;26(11): 1793−1800.  
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 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  
 
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• 
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. 
APPENDIX 10:  Anaphylaxis Precautions and Management 
This appendix was added. 
 
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15/Protocol GV29216, Version 5 (Global)   


SUMMARY OF CHANGES:  Version 5 (Global) 
SECTION 1.2.1:  Nonclinical Background 
This antibody binds to a highly conserved epitope on the influenza A hemagglutinin (HA) 
stalk region, which allows broad neutralization of the influenza A virus by blocking the 
hemagglutininHA-mediated, membrane-fusion event in the late endosome. 
SECTION 1.2.2:  Clinical Safety Background 
SECTION 1.2.2.1:  Phase 1 Entry-into-Human Study GV28916 
In addition, the MHAA4549A pharmacokinetics were generally dose proportional, and 
appeared to have a pharmacokinetic (PK) profile consistent with that of a human IgG1 
antibody that lacks known endogenous host targets.  
SECTION 1.2.2.2:  Phase 2a Influenza Nasal Challenge Study GV28985 
The second study was a Phase 2a challenge study (GV28985) in 101 healthy volunteers 
infected with a H3N2 (A/Wisconsin/67/2005) strain of influenza virus.  Fixed dosing was 
selected for this study and is further described in Section.  Sixty subjects received doses 
of 400 mg, 1200 mg, or 3600 mg MHAA4549A, and 4132 subjects received placebo 
following nasal inoculation of influenza A virus one day earlier.  The interim efficacy 
analysis in  includes the Intent to Treat (ITT) infected population who Eight subjects 
received placebo (N = 21), 400 mg MHAA4549A (N = 11), 1200 mg MHAA4549A (N = 13), 
3600 mg MHAA4549A (N=14), and oseltamivir (N = 2).  starting on Day 1.  One subject 
was randomized and inoculated, but not dosed.All subjects have completed dosing, and 
interim PK and efficacy data are available in the Investigator’s Brochure and upon 
request.   
Most AEs appeared to reflect symptoms of an active influenza infection and occurred 
primarily within the first 21 days after patients received their virus inoculation and 
dose of MHAA4549A or placebo (123 of 213: 58%).  Following the resolution of the 
influenza symptoms, even though levels of MHAA4549A remained relatively high, the 
number of AEs dropped and remained low throughout the remainder of the study: 59 of 
213 (28%) of all AEs occurred between Study Days 22 and 60, and 31 of 213 (15%) of 
all AEs occurred between Study Days 61 and 120.  Differences between treatment 
groups in the number and severity of AEs during the first 22 days appeared to reflect 
variability in the extent and severity of the influenza infection.  Throughout the entire 
study, the pattern of AEs did not differ substantially between subjects who received 
placebo and subjects who received any dose of MHAA4549A.  
The percentage of AEs that investigators judged to be related to study drug treatment 
was 12/33 (36%) for the 400-mg group, 10/40 (25%) for the 1200-mg group, 11/52 
(21%) for the 3600-mg group, and 25/88 (28%) for subjects receiving placebo.  Of those 
AEs considered related, however, 15 of 25 (60%) in the placebo cohort and 26 of 33 
 
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16/Protocol GV29216, Version 5 (Global)   


(79%) in all MHAA4549A cohorts consisted of elevations of alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), or amylase.  These laboratory abnormalities 
have been shown to be associated with the influenza infection (Polakos et al 2006; 
Yingying 2011) and were not observed in either the previous or subsequent Phase 1 
studies (GV28916, GV29609) where MHAA4549A was administered to subjects 
without influenza infection.  
There were 3 SAEs in Study GV28985, none of which were assessed as related to 
MHAA4549A.  One was in a subject hospitalized with a depressive psychosis.  Due to 
his previous history of depression and the known association of psychosis with 
influenza infections, the Investigator considered this event unrelated to study drug.  
The other 2 SAEs were in one subject who fell and required a surgical repair of a 
fractured tibial plateau.  This same subject was subsequently hospitalized for her second 
SAE, which was a post-surgical wound infection.  Neither of these events was 
considered related to study treatment.   
During this study, elevated alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), and amylase levels were observed within the first 2 weeks after inoculation with 
A/Wisconsin/67/2005 and dosing with MHAA4549A.  Previous experience with this 
challenge model has shown ALT/AST/amylase elevations to be associated with the 
influenza infection itself (Polakos 2006).  Consistent with previous trials, In GV28985, 
there was no relationship of elevations in AST, ALT, or amylase with either dose or 
exposure (e.g., placebo: 22.0%, 400 mg: 35.0%, 1200 mg: 25.0%, 3600 mg: 20.0%).   
In GV28985, most AEs were Grade 1 or Grade 2 (mild or moderate) and appeared to 
reflect the symptoms of the influenza infection.  
• 
In the 400 mg group, 15 (75.0%), 1 (5.0%), and 2 (10.0%)  subjects reported Grade 
1, 2, and 3 AEs respectively.   
• 
In the 1200 mg group,  9 (45.0%), 6 (30.0%), and 1 (5.0%) subjects reported Grade 
1, 2, and 3 AEs, respectively.   
• 
In the 3600 mg group,  10 (50.0%), 5 (25.0%), 1 (5.0%) subjects reported Grade 1, 
2, and 3 AEs, respectively.   
One (5.0%) subject reported a Grade 4 AE in the 3600 mg group, which was a lower 
limb fracture, not related to MHAA4549A.subjects in the placebo group reported 18 
(56.3%) Grade 1 AEs, 8 (25.0%) Grade 2 AEs, and 2 (6.3%) Grade 3 AEs.  In addition, 
there were no drug related SAEs, deaths, or discontinuations due to AEs.  There were a 
total of 3 SAEs unrelated to MHAA4549A in two subjects.  One subject reported 
depressive psychosis associated with influenza.  There were a total of 3 SAEs unrelated 
to MHAA4549A in two subjects.  One subject reported depressive psychosis associated 
with influenza.  The second subject reported a broken knee with a subsequent SAE of 
infection following a surgical procedure.   The immunogenicity incidence rate amongst 
the 60 subjects who received MHAA4549A was 0%.  
 
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17/Protocol GV29216, Version 5 (Global)   


SECTION 1.2.2.3:  Phase 1 High-Dose Safety Study GV29609 
A Phase 1 (GV29609) study was initiated to evaluate the safety and tolerability of a 
single intravenous (IV) doses of 8400 mg and 10800 mg MHAA4549A as compared to 
placebo when administered to 14 healthy volunteers. The starting dose of 8400 mg was 
based on simulations from a semi-quantitative pharmacokinetic model (Figure 2) 
developed from the Phase 2a challenge study (GV28985), which suggests that the 
8400 mg may be the minimum dose that is expected to show a separation of nasal 
exposure from a dose of 3600 mg.  The simulation assumes that pharmacokinetics can be 
extrapolated at doses above 3600 mg and that the PK profile in severely ill patients is 
similar to the PK profile of healthy volunteers in the Phase 2a challenge study.  The 
highest proposed dose of 10800 mg was chosen in GV29609 to provide safety coverage 
for those exposures that might be reached in a 40-kg individual dosed with a flat dose of 
8400 mg.  
GV29609 is currently on-going, but preliminary analysis of unblinded safety data up to 
day 57 shows that the 8400 mg and 10800 mg treatment groups are safe and well 
tolerated.  
• 
In subjects who revcieved the 8400 mg MHAA4549A (N=4): 
− 3 of 4 subjects reported 12 AEs.  
− 6 AEs were reported as related to 8400 mg MHAA4549A:  3 headaches, 
1 pruritus, 1 peripheral swelling, and 1 nasal congestion 
 
• 
In subjects who received 10800 mg MHAA4549A (N=4): 
− 4 of 4 subjects reported 7 AEs.  
− 3 AEs reported as related to 10800 mg MHAA4549A treatment group: 
1 nausea, 1 headache, and 1 asthenia 
• 
In subjects who received placebo (N=6): 
− 2 of 6 subjects reported 5 AEs 
− 1 AE was reported as related to study drug: 1 headache 
 
All AEs were reported as mild except for an unrelated moderate AE of 
an increase in creatinine kinase in one subject who received 10800 mg 
MHAA4549A.  There were no SAEs and no subjects have discontinued the 
study for any reason.  
As in both previous studies, headache was the most common AE.  Headache was 
reported by 3 subjects (37.5%) who received 8400 mg group MHAA4549A:  1 subject 
(12.5%) who received 10800 mg MHAA4549A and 2 subjects (33.0%) who received 
placebo.   
 
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Based on this data, MHAA4549A is considered generally safe and well tolerated to date 
at all doses tested, including the 3600 mg dose.   
SECTION 1.2.3:  Clinical Efficacy Background 
The Phase 1 study (GV28916) demonstrated that MHAA4549A pharmacokinetics were 
generally dose proportional.  The PK profile appeared consistent with that of a human 
IgG1 antibody that lacks known endogenous host targets. 
In the Phase 2a challenge study (GV28985), 101 healthy volunteers were inoculated 
with influenza virus 24-36 hours prior to dosing with MHAA4549A.  Following 
inoculation, 60 subjects received doses of 400 mg, 1200 mg, or 3600 mg MHAA4549A, 
32 subjects received placebo, 8 subjects received a 5-day course of oseltamivir, and 
1 subject was not dosed.  The interim efficacy analysis presented in Table 1 included the 
Intent-to-Treat (ITT) infected population followed until at least Day 29 who received 
400 mg MHAA4549A (N = 11), 1200 mg MHAA4549A (N = 13), 3600 mg 
MHAA4549A (N = 14), placebo (N = 21), and oseltamivir (N = 2).  Analysis of efficacy 
from the 3600-mg dose level demonstrated a statistically significant decrease in viral 
shedding from the upper respiratory tract as measured by the area under the curve 
(97.5% reduction by quantitative polymerase chain reaction [qPCR]) and peak viral load 
(77% reduction by qPCR).  All subjects have completed dosing, and interim PK and 
efficacy data are available in the Investigator’s Brochure and upon request. ) as shown 
in . 
In thisthe GV28985 study, all subjects received oseltamivir was started on Day 7 for a 
5-day course, and there were no observed AEs or imbalances in safety events that were 
considered attributable to interactions between oseltamivir and MHAA4549A.  The PK 
profile of MHAA4549A and oseltamivir in GV28985 are being analyzed to exclude 
potential drug-drug interactions, and this analysis will be available before the start of this 
study (GV29216.).   
Composite clinical symptom scores from Study GV28985 for the Intent to Treat (ITT) 
infected population who received placebo (N = 21), 400 mg MHAA4549A (N = 11), 
1200 mg MHAA4549A (N = 13), 3600 mg MHAA4549A (N = 14), and oseltamivir 
(N = 2)ITT infected (ITTI) population are shown in Table 1.   
The responses observed in the Phase 2a study (GV28985) suggest that a higher dose 
may provide better efficacy in a population with established infection.  An 8400-mg 
dose will be included in this Phase 2b study for further dose ranging.  The rationale for 
selected dosages is further explained in Section 3.2.4. 
SECTION 1.3.1:  Study Rationale 
The Two Phase 1 (GV28916, GV29609) studies and Phase 2a studies have 
demonstrated that MHAA4549A is safe and well tolerated to date in healthy volunteers 
 
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at doses up to 8400 mg.  including those who were inoculated with influenza A virus.  
Data from a Phase 2a study (GV28985) demonstrates safety in healthy subjects 
inoculated with influenza virus and also provides evidence that the 3600 mg dose of 
MHAA4549A is effective in reducing viral titers in healthy volunteers inoculated with 
influenza A virus. These findings, Wwhen combined with previous nonclinical studies 
that showed MHAA4549A to have in vitro and in vivo efficacy, a well-tolerated safety 
profile, and anti-viral activity, these findings support further clinical development of 
MHAA4549A. 
Initially, this GV29216 Phase 2b study enrolled patients in a two-arm treatment study 
comparing 3600 mg MHAA4549A with oseltamivir versus placebo with oseltamivir.  
This current Phase 2b study has added an additional arm to evaluate been designed to 
estimate the improvement in outcome of a combination therapy of 3600 mg MHAA4549A 
3600 mg with oseltamivir or of 8400 mg MHAA4549A with oseltamivir versus placebo 
with oseltamivir.  All patients will receive oseltamivir, which is part of the recommended 
standard of care.   
This study (GV29216) will assess severely ill patients who may be infected with 
various influenza A strains, have a higher viral burden and longer duration of viral 
shedding than the healthy volunteers in GV28985, and who may, therefore, require 
doses higher than 3600 mg.  A Phase 1 (GV29609) study is currently on-going to 
assess the safety, tolerability, and pharmacokinetics of 8400-mg and 10800-mg doses of 
MHAA4549A.  The starting dose of 8400 mg was selected based on simulations from a 
semi-quantitative PK model developed from the Phase 2a challenge study (GV28985), 
suggesting that 8400 mg MHAA4549A may be the minimum dose that is expected to 
show a separation of nasal exposure from a dose of 3600 mg.  This simulation assumes 
that pharmacokinetics can be extrapolated at doses above 3600 mg and that the PK 
profile in severely ill patients is similar to the PK profile of healthy volunteers in Phase 
2a challenged with influenza A virus.  The 10800-mg dose was chosen to provide 
assurance of safety for the increased MHAA4549A levels that may be reached in 
smaller individuals who received 8400 mg.  
A preliminary, unblended analysis of the safety data from GV29609 up to Day 57 has 
shown that the 8400-mg and 10800-mg treatment groups are safe and well tolerated.  
In subjects who received 8400 mg MHAA4549A, 3 of 4 subjects reported 12 AEs.  In 
subjects who received 10800 mg MHAA4549A, 4 of 4 subjects reported 7 AEs.  In 
subjects who received placebo, 2 of 6 subjects reported 5 AEs.  All AEs were reported as 
mild, except for one unrelated moderate AE of an increase in creatinine kinase in one 
subject who received 10800 mg MHAA4549A.  There were no SAEs and no subjects 
have discontinued the study for any reason.  As in previous studies, headache was the 
most common AE, and was reported by 3 subjects (37.5%) who received 8400 mg 
MHAA4549A, 1 subject (12.5%) who received 10800 mg MHAA4549A, and 
 
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20/Protocol GV29216, Version 5 (Global)   


2 subjects (33.0%) who received placebo.  As a result, the Sponsor feels that the 
8400-mg dose is safe to include in Study GV29216.  
The 8400-mg dose is also expected to be safe based upon previous nonclinical and 
clinical safety assessments.  Nonclinical safety data do not show any expected or 
unexpected toxicity.   
SECTION 1.3.2.1:  Treatment in Combination with Oseltamivir 
In the Phase 2a challenge study (GV28985), study subjects received MHAA4549A 
followed by oseltamivir with no AEs attributable to the combination therapy noted to date.  
In addition, in this Phase 2b study the PK profile of oseltamivir in concomitantly treated 
subjects will be assessed. 
SECTION 1.3.2.3:  Rationale for Selection of Phase 2b Study Population 
• 
Clinical safety data for MHAA4549A demonstrate a well-tolerated safety profile:   
− 
AEs in the Phase 1 study (GV28916) were mild and did not show a dose 
relationship; there were no ATAs detected in patients treated with 
MHAA4549A after 120 day follow-up visit. 
− 
All AEs in GV29609 from a preliminary analysis of unblinded safety data up 
to day 57 were reported as mild except for an unrelated moderate AE of an 
increase in creatinine kinase in one subject who received 10800 mg 
MHAA4549A.  There were no SAEs and no subjects have discontinued the 
study for any reason. 
 
Interim efficacy data in the Phase 2a challenge study (GV28985) demonstrated a 
significant decrease in viral shedding in the upper respiratory tract at the 3600 mg dose.  
There was a 97.5% (p = 0.0051) decrease in the area under viral load time curve 
(AUEC) and a 77% (p = 0.0024) decrease in peak viral load by qPCR measurement in 
comparison to the placebo group, thus confirming proof of antiviral activity at the 
3600 mg dose level.  Symptom data in the Phase 2a study showed a decrease in the 
AUC of symptoms scores for the 3600 mg dose that is consistent with the virological 
results as illustrated in Table 1. 
SECTION 1.3.2.4:  Patient Monitoring and Supervision 
In addition to the regularly scheduled safety reviews of the patient data by the IMC and 
SOC, an additional sentinel safety cohort of the first 30 patients or patients after the 
first influenza season, whichever occurs first, will be assessed by the IMC and SOC. 
No ATAs were detected in the Phase 1 study, while one subject who received placebo in 
the Phase 2a study tested positive for ATAs at baseline and post-baseline timepoints as 
described in Section 1.2.2 
 
MHAA4549A—Genentech, Inc. 
21/Protocol GV29216, Version 5 (Global)   


SECTION 2.3:  SECONDARY EFFICACY OBJECTIVES 
The secondary efficacy objectives for this study are as follows: 
• 
 
• 
To measure antibiotic usage for respiratory indicationsinfections  
 
SECTION 2.5:  EXPLORATORY OBJECTIVES 
 
 
 
 
SECTION 3.1.1:  Overview of Study Design 
This is a Phase 2b, (GV29216), randomized, double-blind, placebo-controlled study 
designed to assess the safety and clinical activity of a single intravenous (IV) dose of 
3600 mg MHAA4549A or a single IV dose of 8400 mg MHAA4549A in hospitalized 
patients with severe influenza A in combination with oseltamivir versus a comparator 
arm of placebo with oseltamivir.  This study is planned to take place in approximately 
170 study centers globally. 
Initially, GV29216 randomized 1:1 targeted enrollment into two treatment groups:  a 
single IV dose of 3600 mg of MHAA4549A with oseltamivir or a single IV dose of 
placebo with oseltamivir.  
In this version of the protocol, patients will be randomized 1:1:1 into three treatment 
groups:  a single IV dose of 3600 mg of MHAA4549A with oseltamivir, a single IV dose 
of 8400 mg of MHAA4549A with oseltamivir, or a single IV dose of placebo with 
oseltamivir.  All patients will receive oseltamivir, a NAI, as standard therapy for a 
minimum of 5 days after study drug administration.  Oseltamivir at doses of 75 mg twice 
daily (BID) or 150 mg BID is permitted in order to be consistent with local standard of 
care practice.  Treatment for longer than 5 days is permitted based on local investigator 
discretion.  The patient must start Sponsor supplied oseltamivir withinno later than 
8 hours after completion of study drug administration.  The study has a planned 
enrollment of approximately 334330 patients globally. 
A Sponsor-supplied rapidapproved influenza test and that includes influenza antigen 
test or a localinfluenza polymerase chain reaction (PCR) test must be used as an aid in 
the diagnosis of influenza A infection.   
 
  
 
 
 
   
 
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At the time of randomization, patients who are eligible for enrollment, as described 
above, will be randomized to receive 3600 mg MHAA4549A at a dose of 3600 or 
8400 mg MHAA4549A or placebo.  Patients will be stratified by sitecountry, PPV 
versus supplemental O2 at randomization, and suspected or confirmed bacterial 
pneumonia versus no bacterial pneumonia based on the status at randomization. 
Eligible patients who are enrolled into the study will receive either a single IV infusion 
of 3600 mg MHAA4549A or a single IV infusion of 8400 mg MHAA4549A or a single 
IV infusion of placebo on Day 1.  All patients must have thebegin study drug 
infusedinfusion within 48 hours of hospital admission or sooner if possible.  All patients 
will receive oseltamivir for a minimum of 5 days (10 doses), starting on Day 1, beginning 
no later than 8 hours after completion of study drug administration.   
Safety evaluations will also be provided by an IMC and SOC, as defined in the IMC and 
SOC agreement (see Section 3.1.2).  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. 
An additional safety cohort of the first 30 patients, or patients from the first influenza 
season, whichever occurs first, will be assessed by the IMC and SOC.  A review of 
chemistry laboratory test results, AEs, SAEs, vital signs, and deaths will be assessed.  
SECTION 3.1.2:  Independent Internal Monitoring Committee and Scientific 
Oversight Committee 
 Section title was changed, but no changes were made within the section text. 
SECTION 3.2.1:  Rationale for Study Design 
Study GV29216 will be a Phase 2b study involving approximately 334330 patients.   
SECTION 3.2.2:  Rationale for Patient Population and Primary Endpoint 
A Sponsor-supplied rapidapproved influenza test and/, which includes influenza antigen 
test or a local PCR test, must be used as an aid in the diagnosis of influenza A infection. 
The proposed primary efficacy outcome measure in this study is “Time to 
normalization of respiratory function,” defined as oxygen saturation >≥ 95% 
without oxygen supplementation.  Support for use of a respiratory endpoint in 
this population comes from recently published data demonstrating that a 
composite endpoint that captured respiratory rate, fever, heart rate, and blood 
pressure resolution was primarily driven by the respiratory component of the 
endpoint (Marty et al. 2014).  Given that influenza infections generally do not cause 
systemic infections and influenza disease is restricted to the respiratory tract, the 
Sponsor believes that the primary endpoint represents a clinically meaningful outcome 
 
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in this patient population (as shown by analysis of PREMIER database) and measures 
an important physiologically relevant pharmacodynamic response parameter of 
MHAA4549A.  This endpoint is a measure of patient function, measures a symptom 
that represents a serious consequence of influenza, and is consistent with clinically 
relevant endpoints discussed in the US Food and Drug Administration (FDA) 
Guidance, “Influenza: Developing Drugs for Treatment and/or Prophylaxis” (FDA 
2011). 
SECTION 3.2.3:  Rationale for Control Group and Treatment Window 
In the treatment groups, MHAA4549A will be dosed in addition to an oseltamivir.  
standard of care regimen.  The oseltamivir dose will be consistent with the local 
investigator practice at each site where the study will be conducted.   
If oseltamivir resistance is highly suspected or identified during treatment then, or 
oseltamivir route of administration challenges are encountered, then following 
discussion with the Sponsor medical representative, an alternative NAI to oseltamivir 
may be used. 
The treatment of all patients with oseltamivir ensures that all patients will receive the 
standard of care.  Ggiven the high morbidity and mortality of hospitalized patients with 
influenza A along with guidelines from Centers for Disease Control and Prevention (CDC) 
and Infectious Diseases Society of America (IDSA), it is recommended that stating NAIs 
are the standard of care for hospitalized patients with influenza A (Harper et al. 2009 and 
CDC Website).   
MHAA4549A shall only be dosed within 5 days of symptom onset, within 3 days of initial 
treatment with a NAI, and symptoms (including fever, chills, malaise, dry cough, loss of 
appetite, myalgias, coryza, or nausea), no later than 48 hours after admission to the 
hospital., and if a subject has taken less than a total of 6 doses (3 doses for peramivir) of 
approved anti-influenza therapy from onset of symptoms.  This proposed window is 
supported by data demonstrating that hospitalized influenza patients benefit from NAI 
treatment even at 5 days from symptom onset of symptoms (Louie et al. 2012).  The 
patient must start the standard-of-care oseltamivir no later than 8 hours after 
completion of MHAA4549A administration. 
SECTION 3.2.4:  Rationale for MHAA4549A Dosage 
A single IV dose of 3600 mg MHAA4549A or a single IV dose of 8400 mg MHAA4549A 
was selected to assess the efficacy of MHAA4549A and to provide data for further 
clinical development.   
 
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The dose level used inlevels selected for this study waswere determined following 
analysis of data from the Phase 2a study,  (GV28985,), which demonstrated the 
following: 
• 
When compared to placebo, a decrease in viral shedding was observed at the 400 mg 
dose but not at the 1200 mg dose, which may be due to variability in the challenge 
model and differences in infection rate, infection peak, virus level in the 
nasopharynx, nasal pharmacokinetics, immune status, and other inter-subject 
differences.  
• 
There arewere no safety concerns at the 3600 mgany dose level to date.associated 
with MHAA4549A.  
• 
Hospitalized patients generally have a longer duration of viral shedding and 
significantly more viral burden in the lower lung compartments; therefore, high 
concentrations of monoclonal antibody are likely needed to achieve sufficient 
occupancy of the virus binding sites in the upper and lower respiratory compartments.  
Furthermore, higher concentrations of monoclonal antibody may mitigate the risk of 
resistance for MHAA4549A, supporting addition of the 8400 mg MHAA4549A 
treatment arm.  
 
• 
Exploratory exposure-response analysis of GV28985 indicated that higher exposure 
appears to be associated with improved efficacy.  Volunteers with nasal maximum 
concentration greater than the median value had shorter time to resolution of viral 
shedding compared with volunteers in the placebo group (median: 75.8 hours vs. 
113.7 hours).  However, volunteers with a nasal maximum concentration less than 
the median value had similar time to resolution of viral shedding compared with 
volunteers in the placebo group (median 113.7 hours vs 112.1 hours). 
 
The Phase 2a challenge study (GV28985) confirmed proof of activity in decreasing area 
under viral load-time curve, consistent with symptom data at the 3600-mg dose level.  
GV29216 will assess severely ill patients who may be infected with various influenza 
strains, have a higher viral burden and longer duration of viral shedding than the 
healthy volunteers in Study GV28985, and who may, therefore, require doses higher 
than 3600-mg.  As a result, an ongoing Phase 1 (GV29609) study was initiated to 
evaluate the safety and tolerability of two single IV doses of 8400 mg and 10800 mg 
MHAA4549A as compared to placebo when administered to 14 healthy volunteers.  The 
starting dose of 8400 mg was selected based on simulations from a semi-quantitative 
PK model (Figure 2) developed from the Phase 2a challenge study, which suggests that 
8400 mg may be the minimum dose that is expected to show a separation of nasal 
exposure from a dose of 3600 mg.  This simulation assumes that pharmacokinetics can 
be extrapolated at doses above 3600 mg and that the PK profile in severely ill patients is 
similar to the PK profile of healthy volunteers in the Phase 2a challenge study.  The 
highest proposed dose of 10800 mg was chosen in GV29609 to provide safety coverage 
for those exposures that might be reached in a 40-kg individual dosed with a flat dose of 
8400 mg.  Preliminary analysis of unblinded safety data up to day 57 shows that the 
8400 mg and 10800 mg treatment groups are safe and well tolerated.  In subjects who 
 
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received 8400 mg MHAA4549A, 3 of 4 subjects reported 12 AEs.  In subjects who 
received 10800 mg MHAA4549A, 4 of 4 subjects reported 7 AEs.  In subjects who 
received placebo, 2 of 6 subjects reported 5 AEs.  All AEs were reported as mild except 
for an unrelated moderate AE of an increase in creatinine kinase in one subject who 
received 10800 mg MHAA4549A.  There were no SAEs and no subjects have 
discontinued the study for any reason.  Headache was the most common adverse event.  
Headache was reported by 3 subjects (37.5%) who received 8400 mg MHAA4549A, 
1 subject (12.5%) who received 10800 mg MHAA4549A, and 2 subjects (33.0%) who 
received placebo. 
Nonclinical safety data do not show any expected or unexpected toxicity.  Weekly 
administration of MHAA4549A (total of 5 doses) in Sprague-Dawley rats was well 
tolerated up to 150 mg/kg (the highest dose tested).  Ex vivo tissue cross-reactivity 
study data showed no specific binding of MHAA4549A to any of the human or rat 
tissues examined.  
Therefore, the 8400-mg dose is expected to be safe based upon previous nonclinical and 
clinical safety assessments and will be included in this Phase 2b study for further dose 
ranging.  
Although Tthe Phase 1 study (GV28916) was conducted using body-weight based 
dosing, the subsequent Phase 2a study GV28985 and high-dose Phase 1 study GV29609 
used followed by a fixed dosing strategy that was used in the Phase 2a study.  Thus, the 
fixed dosing regimen that was used in the Phase 2a study will be used for this study, 
given the comparable MHAA4549A PK profiles, the practical advantages, and the 
positive safety profile of MHAA4549A to date.   
Figure 2, Predictions from a Semi-Quantitative Pharmacokinetic Model of Nasal 
Exposure, was added. 
SECTION 3.3.2:  Primary Efficacy Outcome Measures 
– 
The time to cessation of O2 support resulting in a stable SpO2 >≥ 95% for at 
least 24 hours (see Appendix 2 for details) 
 
SECTION 3.3.3:  Secondary Efficacy Outcome Measures 
• 
Clinical failure after 24 hours post-infusion of study drug; defined as: 
− 
Progression to increased O2 requirement defined by an increase in oxygen 
supplementation from low flow oxygen (2 − 6 L/min) to high flow oxygen 
(> 6 L/min) or from oxygen supplementation alone to any PPV or 
extracorporeal membrane oxygenation (ECMO) 
• 
Time to clinical resolution of vital signs (3/5 criteria must be met): 
– 
SpO2  >≥ 95% without supplemental O2 for at least 24 hours 
 
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– 
Respiratory rate < 24 breaths per minute without supplemental O2  
− 
Heart rate (HR) < 100 beats/minute 
Influenza A viral load in nasopharyngeal samples   
− 
AUEC (qPCR) 
− 
Peak viral load (qPCR) 
− 
Time to resolution of infection (qPCR) 
− 
  
 
SECTION 3.3.5:  Exploratory Outcome Measures 
 
  
 
 
 
 
 
 
 
 
 
SECTION 4.1:  PATIENTS 
This study aims to enroll approximately 334330 men and women and is designed to 
assess the safety and clinical activity of a single IV administration of 3600 mg 
MHAA4549A or a single IV administration of 8400 mg MHAA4549A in adult patients 
hospitalized with severe influenza A.   
SECTION 4.1.1:  Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Diagnosis of influenza A where one or both of the following area Sponsor-approved 
influenza test is used as an aid(s) in diagnosis.  A Sponsor-approved influenza test 
includes: 
− 
A Sponsor supplied rapid influenza test 
− A local Influenza antigen test  − OR −  
− 
Influenza PCR test 
• 
For women who are not postmenopausal (postmenopausal defined as ≥ 12 months of 
non-therapy-induced amenorrhea) or surgically sterile (absence of ovaries and/or 
uterus):  agreement to remain abstinent or use two adequate methods of 
contraception, including at least one method with a failure rate of < 1% per year, 
during the treatment period and for at least 120 days after the last dose of study 
drug 
 
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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. 
Barrier methods must always be supplemented with the use of a spermicide. 
Examples of contraceptive methods with a failure rate of < 1% per year include tubal 
ligation, male sterilization, hormonal implants, proper use of combined oral or 
injected hormonal contraceptives, and certain intrauterine devices. 
Male partners who have had a vasectomy should have the appropriate 
post-vasectomy documentation available of the absence of sperm in the ejaculate.  
The vasectomized male partner should be the sole partner for that patient. 
• 
For men:  agreement to remain abstinent or use a condom during the treatment 
period and for at least 30 days after the last dose of study drug and agreement to 
refrain from donating sperm during this same period 
Men with a pregnant partner must agree to remain abstinent or use a condom for 
the duration of the pregnancy. 
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. 
 
SECTION 4.1.2:  Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Pregnant or lactating or intending to become pregnant during the study 
− Women who are not postmenopausal (postmenopausal defined as ≥ 12 months of 
non-therapy-induced amenorrhea) or who are not surgically sterile must have a 
negative urine or serum pregnancy test result within 2 days prior to study 
treatment. 
• 
Current treatment (within 7 days of dosing) with probenecid, amantadine, or 
rimantidine 
• 
Patients who have taken more than a total of 3 days (6 doses) (3 doses of peramivir) 
of approved anti-influenza therapy (e.g., oral oseltamivir, inhaled zanamivir, , 
peramivir or oral ribavirin) in the period from onset of symptoms and prior to 
enrollmentstudy treatment 
• 
Onset of influenza symptoms (including fever, chills, malaise, dry cough, loss of 
appetite, myalgias, coryza, or nausea) > 5 days prior to study treatment  
• 
Creatinine clearance ≤10 mL/min 
• 
Patients who received nasally administered influenza A vaccine within the last 7 
days 
 
 
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SECTION 4.2:  METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
The randomization of patients will be managed by a central Interactive Voice and Web 
Response System (IxRS) through use of a dynamic hierarchical algorithm. which 
includes a random component.   
All patients will be randomly assigned to receive 3600 mg MHAA4549A 3600, 8400 mg 
MHAA4549A, or placebo at a 1:1:1 ratio stratified by sitecountry, whether patient is on 
PPV vs supplemental O2 at randomization, and whether the patient has suspected or 
confirmed bacterial pneumonia vs no bacterial pneumonia at randomization.  Initially 
GV29216 randomly assigned patients to receive either 3600 mg MHAA4549A, or 
placebo at a 1:1 ratio.  The updated randomization scheme takes into account the 
numbers already allocated to these two arms and strata prior to allocating to the three 
arm design so that by the end of the study there will be an approximate 1:1:1 allocation 
between the three arms.  
All patients will receive oseltamivir (75 mg or 150 mg BIDas described in Table 2) for a 
minimum of 5 days.   
SECTION 4.3.1.1:  MHAA4549A and Placebo 
The Sponsor will supply MHAA4549A,  and matching placebo, and up to 10 day supply 
of oseltamivir (Tamiflu®) will be supplied by the Sponsor..  For information on the 
formulation, packaging, and handling of MHAA4549A and placebo;, see the Pharmacy 
Manual and the MHAA4549A Investigator's Brochure. 
SECTION 4.3.1.2:  Oseltamivir (Tamiflu®) 
Oseltamivir (Tamiflu®) is an influenza NAI indicated for treatment of acute, 
uncomplicated influenza.  The Sponsor will provide oseltamivir capsules for up to a 
10-day treatment course.   
SECTION 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 3600 mg IV or 
MHAA4549A 8400 mg IV or placebo IV at a 1:1:1 ratio.  
A single dose of MHAA4549A or placebo will be delivered by IV infusion following 
dilution in 0.9% normal saline over approximately 60120 minutes.  Compatibility testing 
has shown that MHAA4549A is stable when diluted in 0.9% normal saline in a 
polyvinylchloride bag, polyolefin bag, or ethylene vinyl acetate bag (EVA), at or above a 
combined total concentrationconcentrations of 0.24 mg/mL up to 27.0 mg/mL.   
 
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SECTION 4.3.2.2:  Oseltamivir-Neuraminidase Inhibitor (NAI) 
The Sponsor will supply oseltamivir (Tamiflu®) for this study for up to a 10-day course.  
Dosage and administration should follow local prescribing information for oseltamivir.  
Either 75 mg or 150 mg of oseltamivir will be administered twice daily as described in 
Table 2.  Capsules can be opened and the granules administered via nasogastric tube, if 
required.  Doses should be captured in the eCRF. 
SECTION 4.4:  POST-TRIAL ACCESS TO MHAA4549A 
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 
SECTION 4.5.2:  Prohibited Therapy 
Use of other NAIs, including but not limited to oral oseltamivir, inhaled zanamivir, oral 
ribavirin, laninimivir, and peramivir, are prohibited during the study, but allowed up to 
3 days (a total of 6 doses) (3 doses for peramivir) in the period from onset of symptoms 
and prior to study treatment as outlined in the exclusion criteria.  Patients must start 
standard-of-care oseltamivir no later than 8 hours after completion of MHAA4549A 
administration.  If oseltamivir resistance is highly suspected or identified during 
treatment or if oseltamivir route of administration challenges are encountered, then, 
following discussion with the Sponsor’s medical representative, an alternative NAI to 
oseltamivir may be used. 
SECTION 4.6.2:  Diagnostic Testing for Enrollment 
All hospitalized patients with severe influenza A will must be assessed for disease 
confirmation prior to and enrollment into the study.  A Sponsor-supplied rapid approved 
influenza test is required foras an aid in the diagnosis of influenza A infection and uses.  
This requires a nasopharyngeal swab.  When be introduced into one nostril.  Note that 
the Sponsor supplied rapid influenza antigen test is negative, the study inclusion criteria 
can be satisfied with a positive local molecularor influenza PCR test (PCR) if the result 
ismust be available within the 48-hour screening window.  Patients may be enrolled 
based on a positive local molecular test (PCR) result within the 48 hour screening 
window, but the rapid influenza test must still be conducted prior to randomization.  
Other tests may not be used for enrollment in the study unless the Sponsor has 
reviewed and approved the use of the diagnostic. 
SECTION 4.6.3:  Medical History and Demographic Data 
A careful assessment of the patient’s baseline SpO2 will should be made especially if 
the patient has a history of severe chronic lung disease. 
 


 
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SECTION 4.6.4:  Priority of Assessments 
Assessments on Day 1 must be concluded prior to dosing as specified in Appendix 1a.  
Any screening assessments completed prior to consent as standard of care do not need 
to be repeated if done within the screening period. 
SECTION 4.6.7:  Physical Examinations 
At protocol designated visits (or as clinically indicated), limited, symptom-directed 
physical examinations should be performed which include 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.   
SECTION 4.6.8:  Vital Signs 
Vital signs will include measurements of resting SpO2 (see Section 4.6.7 for 
measurement), respiratory rate, pulse rate, temperature, and systolic and diastolic blood 
pressures after the patient has been in a seated or supine position for at least 
10 minutes.   
SECTION 4.6.9:  Oxygen Saturation Measurements 
If the patient is on oxygen supplementation, SpO2 measured by pulse oximetry and the 
corresponding respiratory assessments (e.g., FiO2, flow rate) will be recorded.  If the 
patient is on PPV, partial pressure of arterial O2 (PaO2) and the corresponding 
respiratory assessments (e.g., FiO2, ventilator mode, ventilator respiratory rate, positive 
end expiratory pressure) will be recorded.  If clinically appropriate (i.e., the patient is 
on non-invasive PPV), the conversion table in Appendix 11 may be used for PaO2.  
SECTION 4.6.10:  Laboratory, Biomarker, and Other Biological Samples 
 
  
 
 
 
SECTION 4.6.12:  
 
 
 
 
 
  
 
 
   


 
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SECTION 4.7:  APACHE AND SOFA SCORES 
The initial scores for APACHE and SOFA should be taken within 24 hours of entry into 
the ICU and at the time points specified in Appendix 1a. 
SECTION 4.9.2:  Study Treatment Discontinuation 
Patients must discontinue MHAA4549A infusion and therefore treatment if they 
experience any of the following: 
 
Infusion Life threatening infusion-related reactions  
 
SECTION 4.9.3:  Study Completion/Early Discontinuation Visit 
All patients who discontinue from the study early will be asked to complete all 
assessments for the current visit day and for the early discontinuation visit without 
duplication..   
Section 5.4.2.2:  Events That Occur after Study Drug Initiation 
In the event that the EDC system is unavailable, a paper Serious Adverse Event / 
Adverse Event of Special Interest Reporting Form should be completed and faxed or 
scanned and emailed to Safety Risk Management or its designee immediately (i.e., no 


 
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more than 24 hours after learning of the event), using the contact information provided to 
investigators (see Section 5.4.2.1).   
SECTION 6:  STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
Results will be presented both for the MHAA4549A 3600 mg and 8400 mg treatment 
groups separately and combined for the purpose of comparison to standard of care. 
SECTION 6.1:  DETERMINATION OF SAMPLE SIZE 
Approximately 330 patients will be enrolled in this study in order to obtain approximately 
300 evaluable patients (an estimated dropout rate of 10%). . It is assumed that the 
median time to normalization of respiratory function in the control arm is 5 days.  This 
sample size (approximately 150110 patients per arm) provides 7571% power to detect a 
treatment difference of 1 day for the primary endpoint in both MHAA4549A arms 
assuming a 2-sided alpha of 0.2.  and no difference in efficacy between the two active 
arms.  If the 3600-mg dose shows a treatment difference of 1 day and the 8400-mg dose 
shows a treatment difference of 1.5 days or more then this sample size provides  86% 
power assuming a 2-sided alpha of 0.2. 
Operating characteristics (power) under other possible assumptions for 2-sided alpha of 
0.052 and true differences of 10.5 to 2 days are provided in Table 7.   
Table 7, Operating Characteristics for Proposed Study Design for Several Possible True 
Underlying Median Values, was modified as follows:  hazard ratios were added, power of 
log-rank test values were added, and footnotes were revised.  In addition, the row 
containing 95% CIs was removed. 
It should be noted that the study is underpowered for detection of minimally clinically 
meaningful differences at a 2-sided alpha of 0.05 such as a true hazard ratio of 0.80 
(see third column of .in both MHAA4549A arms.   
SECTION 6.4.3:  Subgroup Analyses 
Subgroups will include the stratification factors as well as patients who are identified at 
baseline as influenza A positive by the upper, lower, or both airways and by patients with 
bacterial co-infections at admission. as well as by the influenza season during which the 
patient was randomized.   
SECTION 10:  References 
Centers for Disease Control and Prevention (CDC). 20112014-2012 2015 Influenza 
antiviral medications [resource on the Internet]. 2012b 2015 [Updated 20142015, Mar 
21Jan 9; cited 20154 Jan].  Available from: 
http://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm. 


 
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Writing Committee of the World Health Organization (WHO) consultation on human 
influenza A/H5.  Avian influenza A (H5N1) infection in humans. N Engl J Med 2005; 
353: 1374-85. 
Yingying C. Abnormal liver chemistry in patients with influenza A H1N1. Liver Int 
2011; 31(6): 902. 
APPENDIX 1a:  Schedule of Assessments:  Hospitalization Days 
Before the assessment table, the following text was added:  Any screening assessments 
completed prior to consent as standard of care do not need to be repeated if done within 
the screening period.  If a patient is unable to be present at the site for a follow-up visit, 
a telephone visit is permitted. 
In the list of procedures, “Rapid A influenza test” was changed to “Sponsor-approved 
influenza test.”  Table footnotes were updated to match changes in protocol body. 
Footnote designations and order were updated to place them in order. 
 
APPENDIX 1b:  Schedule of Assessments:  Follow-up Period 
 
If a patient is discharged after Day 14 but prior to Day 30, he/she will need to complete the 
following assessments for Day 30 and Day 60 below. 
 
If a patient is discharged after Day 30, but prior to Day 60, he/she will need to complete the 
following assessments for Day 60 below. 
Table footnotes were updated to match changes in protocol body. 
 
APPENDIX 2:  Time to Normalization of Respiratory Function 
For the purposes of this study, the time to normalization of respiratory function will be 
defined as the time to removal of the patient from O2 supplementation in order to 
maintain an SpO2 >≥ 95%.   
 
If the SpO2 >≥ 95%, then the time and reading should be recorded.  Notify the study 
doctor so that he/she can make a clinical judgment to determine whether the O2 can 
be removed. 
 
If the patient is off O2 for 24 hours and his/her reading the subsequent day is >95%, 
then the endpoint is considered satisfied.  The recorded time for the endpoint 
corresponds with the initial discontinuation of O2 and reading. 
 
APPENDIX 3:  
 
 


 
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APPENDIX 4:  
 
 
 
 
 
 
APPENDIX 5:  
 
 
 
 
 
 
 
 
 
 
APPENDIX 6:  
 
 
  
SAMPLE INFORMED CONSENT FORM 
The sample Informed Consent Form has been revised to reflect the changes to the 
protocol. 
Abbreviations were updated throughout the document, and additional minor changes 
have been made to improve clarity and consistency.  The amendment number was 
updated throughout the protocol.  Substantive new information appears in italics.  
Citations were added in the text representing the new reference material.  This 
amendment represents cumulative changes to the original protocol. 
 


 
TABLE OF CONTENTS 
PROTOCOL ACCEPTANCE FORM .................................................................. 42 
PROTOCOL SYNOPSIS .................................................................................... 43 
1. 
BACKGROUND .......................................................................................... 54 
1.1 
Background on Influenza ....................................................... 54 
1.2 
Background on MHAA4549A ................................................. 54 
1.2.1 
Nonclinical Background ......................................................... 54 
1.2.2 
Clinical Safety Background .................................................... 55 
1.2.2.1 
Phase 1 Entry-into-Human Study GV28916 .......................... 55 
1.2.2.2 
Phase 2a Influenza Nasal Challenge Study GV28985 .......... 55 
1.2.2.3 
Phase 1 High Dose Safety Study GV29609 .......................... 56 
1.2.3 
Clinical Efficacy Background ................................................. 57 
1.3 
Study Rationale and Benefit-Risk Assessment ...................... 59 
1.3.1 
Study Rationale ..................................................................... 59 
1.3.2 
Benefit-Risk Assessment ....................................................... 60 
1.3.2.1 
Treatment in Combination with Oseltamivir ........................... 60 
1.3.2.2 
Drug Mechanism and Preclinical Studies .............................. 61 
1.3.2.3 
Rationale for Selection of Phase 2b Study Population .......... 61 
1.3.2.4 
Patient Monitoring and Supervision ....................................... 61 
2. 
OBJECTIVES .............................................................................................. 62 
2.1 
Safety Objectives ................................................................... 62 
2.2 
Primary Efficacy Objectives ................................................... 62 
2.3 
Secondary Efficacy Objectives .............................................. 62 
2.4 
Pharmacokinetic Objectives .................................................. 63 
2.5 
Exploratory Objectives ........................................................... 63 
3. 
STUDY DESIGN ......................................................................................... 64 
3.1 
Description of Study .............................................................. 64 
3.1.1 
Overview of Study Design ..................................................... 64 
3.1.2 
Internal Monitoring Committee and Scientific Oversight 
Committee ............................................................................. 66 
3.1.3 
End of Study .......................................................................... 67 
 
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3.2 
Rationale for Study Design .................................................... 67 
3.2.1 
Rationale for Study Design .................................................... 67 
3.2.2 
Rationale for Patient Population and Primary Endpoint ......... 67 
3.2.3 
Rationale for Control Group and Treatment Window ............. 68 
3.2.4 
Rationale for MHAA4549A Dosage ....................................... 70 
3.2.5 
Rationale for Biomarker Assessments ................................... 72 
3.3 
Outcome Measures ............................................................... 73 
3.3.1 
Safety Outcome Measures .................................................... 73 
3.3.2 
Primary Efficacy Outcome Measures .................................... 73 
3.3.3 
Secondary Efficacy Outcome Measures ................................ 73 
3.3.4 
Pharmacokinetic Outcome Measures .................................... 74 
3.3.5 
Exploratory Outcome Measures ............................................ 75 
4. 
MATERIALS AND METHODS .................................................................... 75 
4.1 
Patients .................................................................................. 75 
4.1.1 
Inclusion Criteria .................................................................... 75 
4.1.2 
Exclusion Criteria ................................................................... 77 
4.2 
Method of Treatment Assignment and Blinding ..................... 78 
4.3 
Study Treatment .................................................................... 79 
4.3.1 
Formulation, Packaging, and Handling .................................. 79 
4.3.1.1 
MHAA4549A and Placebo ..................................................... 79 
4.3.1.2 
Oseltamivir (Tamiflu®) ........................................................... 80 
4.3.2 
Dosage, Administration, and Compliance .............................. 80 
4.3.2.1 
MHAA4549A and Placebo ..................................................... 80 
4.3.2.2 
Oseltamivir-Neuraminidase Inhibitor (NAI) ............................ 81 
4.3.3 
Investigational Medicinal Product Accountability ................... 81 
4.4 
Post-Trial Access to MHAA4549A ......................................... 82 
4.5 
Concomitant Therapy and Food ............................................ 82 
4.5.1 
Permitted Therapy ................................................................. 82 
4.5.2 
Prohibited Therapy ................................................................ 82 
4.5.3 
Prohibited Food ..................................................................... 83 
4.6 
Study Assessments ............................................................... 83 
4.6.1 
Informed Consent Forms and Screening Log ........................ 83 
 
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4.6.2 
Diagnostic Testing for Enrollment .......................................... 83 
4.6.3 
Medical History and Demographic Data ................................ 83 
4.6.4 
Priority of Assessments ......................................................... 84 
4.6.5 
Nasopharyngeal Samples (Upper Respiratory Tract) ............ 84 
4.6.6 
Tracheal Aspirate Samples (Lower Respiratory Tract) .......... 84 
4.6.7 
Physical Examinations ........................................................... 84 
4.6.8 
Vital Signs .............................................................................. 85 
4.6.9 
Oxygen Saturation Measurements ........................................ 85 
4.6.10 
Laboratory, Biomarker, and Other Biological Samples .......... 85 
4.6.11 
Electrocardiograms ................................................................ 87 
4.6.12 
 ............................................ 88 
4.6.12.1 
 ........ 88 
4.6.12.2 
 .................................... 89 
4.6.12.3 
.................................... 89 
4.6.12.4 
 89 
4.7 
Apache And Sofa Scores....................................................... 89 
4.8 
Oseltamivir Medication Diary ................................................. 90 
4.9 
Patient, Treatment, Study, and Site Discontinuation ............. 90 
4.9.1 
Patient Discontinuation .......................................................... 90 
4.9.2 
Study Treatment Discontinuation ........................................... 90 
4.9.3 
Study Completion/Early Discontinuation Visit ........................ 91 
4.9.4 
Study and Site Discontinuation .............................................. 91 
5. 
ASSESSMENT OF SAFETY ....................................................................... 91 
5.1 
Safety Plan ............................................................................ 91 
5.2 
Safety Parameters and Definitions ........................................ 92 
5.2.1 
Adverse Events ..................................................................... 92 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) ................................................................................ 92 
5.2.3 
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) .............................. 93 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ................................................................. 94 
5.3.1 
Adverse Event Reporting Period ........................................... 94 
 
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5.3.2 
Eliciting Adverse Event Information ....................................... 95 
5.3.3 
Assessment of Severity of Adverse Events ........................... 95 
5.3.4 
Assessment of Causality of Adverse Events ......................... 95 
5.3.5 
Procedures for Recording Adverse Events ............................ 96 
5.3.5.1 
Diagnosis versus Signs and Symptoms................................. 96 
5.3.5.2 
Adverse Events That Are Secondary to Other Events ........... 97 
5.3.5.3 
Persistent or Recurrent Adverse Events ................................ 97 
5.3.5.4 
Abnormal Laboratory Values ................................................. 98 
5.3.5.5 
Abnormal Vital Sign Values ................................................... 99 
5.3.5.6 
Abnormal Liver Function Tests .............................................. 99 
5.3.5.7 
Deaths ................................................................................. 100 
5.3.5.8 
Preexisting Medical Conditions ............................................ 100 
5.3.5.9 
Lack of Efficacy or Worsening of Influenza A Infection ........ 100 
5.3.5.10 
Hospitalization or Prolonged Hospitalization ........................ 101 
5.3.5.11 
Adverse Events Associated with an Overdose .................... 101 
5.4 
Immediate Reporting Requirements from Investigator to 
Sponsor ............................................................................... 101 
5.4.1 
Emergency Medical Contacts .............................................. 102 
5.4.2 
Reporting Requirements for Serious Adverse Events 
and Non-Serious Adverse Events of Special Interest .......... 103 
5.4.2.1 
Events That Occur prior to Study Drug Initiation .................. 103 
5.4.2.2 
Events That Occur after Study Drug Initiation ...................... 103 
5.4.3 
Reporting Requirements for Pregnancies ............................ 104 
5.4.3.1 
Pregnancies in Female Patients .......................................... 104 
5.4.3.2 
Pregnancies in Female Partners of Male Patients [If 
Applicable] ........................................................................... 104 
5.4.3.3 
Congenital Anomalies/Birth Defects and Abortions ............. 104 
5.5 
Follow-Up of Patients after Adverse Events ........................ 105 
5.5.1 
Investigator Follow-Up ......................................................... 105 
5.5.2 
Sponsor Follow-Up .............................................................. 105 
5.6 
Post-Study Adverse Events ................................................. 105 
5.7 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees ........... 106 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ..................... 106 
 
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6.1 
Determination of Sample Size ............................................. 107 
6.2 
Summaries of Conduct of Study .......................................... 108 
6.3 
Summaries of Treatment Group Comparability ................... 108 
6.4 
Efficacy Analyses ................................................................ 108 
6.4.1 
Primary Efficacy Endpoint .................................................... 108 
6.4.2 
Secondary Efficacy Endpoints ............................................. 109 
6.4.3 
Subgroup Analyses ............................................................. 109 
6.5 
Safety Analyses ................................................................... 109 
6.6 
Pharmacodynamic Analyses ............................................... 110 
6.7 
Optional Interim Analyses .................................................... 110 
7. 
DATA COLLECTION AND MANAGEMENT ............................................. 111 
7.1 
Data Quality Assurance ....................................................... 111 
7.2 
Electronic Case Report Forms ............................................. 111 
7.3 
Source Data Documentation ................................................ 111 
7.4 
Use of Computerized Systems ............................................ 112 
7.5 
Retention of Records ........................................................... 112 
8. 
ETHICAL CONSIDERATIONS .................................................................. 112 
8.1 
Compliance with Laws and Regulations .............................. 112 
8.2 
Informed Consent ................................................................ 113 
8.3 
Institutional Review Board or Ethics Committee .................. 114 
8.4 
Confidentiality ...................................................................... 114 
8.5 
Financial Disclosure ............................................................ 115 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 115 
9.1 
Study Documentation .......................................................... 115 
9.2 
Protocol Deviations .............................................................. 115 
9.3 
Site Inspections ................................................................... 115 
9.4 
Administrative Structure....................................................... 115 
9.5 
Publication of Data and Protection of Trade Secrets ........... 116 
9.6 
Protocol Amendments ......................................................... 116 
10. REFERENCES ......................................................................................... 118 
 
 
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PROTOCOL ACCEPTANCE FORM 
TITLE: 
A PHASE 2 RANDOMIZED, DOUBLE-BLIND 
PLACEBO CONTROLLED TRIAL OF MHAA4549A, 
A MONOCLONAL ANTIBODY, IN COMBINATION 
WITH OSELTAMIVIR VERSUS OSELTAMIVIR FOR 
TREATMENT OF SEVERE INFLUENZA A 
INFECTION 
PROTOCOL NUMBER: GV29216 
VERSION NUMBER: 
5 (Global) 
EUDRACT NUMBER: 
2014-000461-43 
IND NUMBER: 
117,318 
TEST PRODUCT: 
MHAA4549A 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
Genentech, Inc. 
 
I agree to conduct the study in accordance with the current protocol. 
  
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please return a copy of the signed form as instructed by the CRO.  Please retain the 
original for your study files. 
 
 
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therapy for a minimum of 5 days, starting after study drug administration.  Oseltamivir at doses 
of 75 mg twice daily (BID) or 150 mg BID is permitted in order to be consistent with local 
standard of care practice.  Treatment for longer than 5 days is permitted based on local 
investigator discretion.  The patient must start Sponsor-supplied oseltamivir no later than 8 hours 
after completion of study drug administration. 
Patients hospitalized with an oxygen (O2) or PPV requirement will be evaluated for influenza A 
infection.  Enrollment in this study requires ongoing treatment within 24 hours of hospital 
admission with one of the following: any PPV or any supplemental O2 to maintain oxygen 
saturation (SpO2) > 92%.   
A Sponsor-approved influenza test, which includes influenza antigen test and/or influenza 
polymerase chain reaction (PCR) test must be used as an aid in the diagnosis of influenza A 
infection. 
At the time of randomization, patients who are eligible for enrollment will be randomized to 
receive a single IV infusion of 3600 mg MHAA4549A or 8400 mg MHAA4549A or placebo, which 
will be administered on Day 1.  All patients must begin study drug infusion within 48 hours of 
hospital admission or sooner if possible; therefore, screening must be completed within this 
window.  All patients will receive oseltamivir for a minimum of 5 days (10 doses), starting on 
Day 1 beginning no later than 8 hours after completion of study drug administration.  All patients 
will be followed for 60 days from the time of study drug administration. 
Number of Patients 
The study has a planned enrollment of approximately 330 patients (adult men and women) 
globally.  Patients will receive 3600 mg MHAA4549A, 8400 mg, or placebo in 1:1:1 ratio.  The 
number of patients on PPV should not exceed 45% of the total enrolled patients. 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Men or women ≥ 18 years of age on day of signing informed consent or obtaining surrogate 
consent from an authorized representative 
• 
Diagnosis of influenza A where a Sponsor-approved influenza test is used as an aid in diagnosis.  
A Sponsor-approved influenza test includes: 
– 
Influenza antigen test –OR– 
– 
Influenza polymerase chain reaction (PCR) test  
• 
One of the following markers of severity within 24 hours of hospital admission: 
– 
Requirement for PPV, OR 
– 
Requirement for O2 supplementation to maintain SpO2 > 92% 
• 
A negative urine or serum pregnancy test for women of childbearing potential 
• 
Patients of reproductive potential must agree to use reliable means of contraception as 
described below as a minimum (adherence to more stringent local requirements may be 
required): 
– 
For women who are not postmenopausal (postmenopausal defined as ≥ 12 months of 
non-therapy-induced amenorrhea) or surgically sterile (absence of ovaries and/or 
uterus):  agreement to remain abstinent or use two adequate methods of contraception, 
including at least one method with a failure rate of < 1% per year, during the 
treatment period and for at least 120 days after the last dose of 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 post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
Barrier methods must always be supplemented with the use of a spermicide. 
 
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Examples of contraceptive methods with a failure rate of < 1% per year include tubal 
ligation, male sterilization, hormonal implants, proper use of combined oral or 
injected hormonal contraceptives, and certain intrauterine devices. 
– 
For men:  agreement to remain abstinent or use a condom during the treatment 
period and for at least 30 days after the last dose of study drug and agreement to 
refrain from donating sperm during this same period 
Men with a pregnant partner must agree to remain abstinent or use a condom for the 
duration of the pregnancy. 
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. 
 
Non-reproductive potential is defined below (but could be superseded by local definitions, if they 
are more stringent): 
– 
Women who are postmenopausal (i.e., spontaneous amenorrhea for the past year 
confirmed by an follicle stimulating hormone [FSH] level greater than 40 mIU/mL unless 
the patient is receiving a hormonal therapy for their menopause)  
– 
Women who are surgically sterile (i.e., hysterectomy, complete bilateral oophorectomy) 
– 
Men who are surgically sterile (castration) 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Pregnant or lactating, or intending to become pregnant during the study 
− 
Women who are not postmenopausal (postmenopausal defined as ≥ 12 months of 
non-therapy-induced amenorrhea) or who are not surgically sterile must have a negative 
urine or serum pregnancy test result within 2 days prior to study treatment 
• 
Hypersensitivity to monoclonal antibodies or to the active substance or any excipients of 
MHAA4549A study drug 
• 
Hypersensitivity to the active substance or to any excipients of oseltamivir 
• 
Investigational therapy within the 30 days prior to study treatment  
• 
Received prior therapy with any anti-influenza monoclonal antibody therapy (including 
MHAA4549A) 8 months prior to study treatment 
• 
Current treatment (within 7 days of dosing) with probenecid, amantadine, or rimantidine 
• 
Patients who have taken more than a total of 6 doses (3 doses for peramivir) of 
anti-influenza therapy (e.g., oseltamivir, zanamivir, peramivir) in the period from onset of 
symptoms and prior to study treatment 
• 
Admission > 48 hours prior to study treatment 
• 
Onset of influenza symptoms (including fever, chills, malaise, dry cough, loss of appetite, 
myalgias, coryza, or nausea) > 5 days prior to study treatment 
• 
Positive influenza B or influenza A + B infection within 2 weeks prior to study treatment 
• 
High probability of mortality in the next 48 hours as determined by the investigator  
• 
Patient requiring home or baseline oxygenation therapy 
• 
Patient with history of chronic lung disease resulting in baseline SpO2 < 95%  
• 
Patient on chronic dose of corticosteroids exceeding 10 mg/day of prednisone or equivalent 
steroid dose for a duration of greater than 14 days within 30 days of entry into study 
• 
Creatinine clearance ≤10 mL/min 
• 
Patients who received nasally administered influenza A vaccine within the last 7 days 
• 
Patients with the following significant immune suppression: 
 
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– 
Bone marrow or solid organ transplant in the previous 12 months 
– 
Cancer chemotherapy in the previous 12 month 
– 
Human immunodeficiency virus (HIV) infection with most recent CD4  200 cells/mL 
– 
Other significant immune suppression as determined by the investigator in discussion 
with the Sponsor Medical Monitor or representative 
 
Patient on extracorporeal membrane oxygenation (ECMO) at time of randomization 
 
Any disease or condition that would, in the opinion of the site investigator or Sponsor, place 
the subject at an unacceptable risk of injury or render the subject unable to meet the 
requirements of the protocol 
Length of Study 
This study will consist of the following study periods: 
 
A screening period of 48 hours, beginning at time of hospital admission 
 
A treatment period of 1 day, during which patients will receive a single dose of MHAA4549A 
or placebo and a minimum of 5 days of oseltamivir. 
 
A follow-up period beginning at hospital discharge through 60 days post study drug 
(MHAA4549A/placebo) administration 
End of Study 
The end of the study is defined as the first day when all patients have had a study completion 
visit or early termination visit or have otherwise been discontinued from the study. 
Outcome Measures 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
 
AEs and clinical laboratory abnormalities 
 
Vital signs, physical findings, ATAs, and clinical laboratory results during and following 
administration of MHAA4549A 
Efficacy Outcome Measures 
The primary outcome measure for this study is as follows: 
 
Time to normalization of respiratory function defined as: 
– 
The time to cessation of O2 support resulting in a stable SpO2  95%  
The secondary efficacy outcome measures for this study are as follows: 
 
Clinical failure after 24 hours post-infusion of study drug defined as: 
– 
Progression to increased O2 requirement defined by an increase in oxygen 
supplementation from low flow oxygen (2  6 L/min) to high flow oxygen (  6 L/min) or 
from oxygen supplementation alone to any PPV or ECMO 
– 
Progression to ICU 
– 
Prolonged ventilation or O2 support defined by  2 weeks, or 
– 
Death 
 
Time to clinical resolution of vital signs (3/5 criteria must be met): 
– 
SpO2 95% without supplemental O2  
– 
Respiratory rate  24 breaths per minute without supplemental O2  
– 
Core temperature  37.2°C immediately prior to receipt of any antipyretic drug, and at 
least 6-8 hours from the last dose of antipyretic or core temperature  36°C in patients 
who are initially hypothermic 
– 
Heart rate (HR)  100 beats/minute 
– 
Systolic blood pressure (SBP)  90 mmHg 






 
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 I error penalty of 0.0001 will be taken.  In addition, as discussed below, the 
Sponsor will conduct interim safety analyses separate from and in conjunction with the above. 
Determination of Sample Size   
A total of 330 patients will be enrolled in this study.  It is assumed that the median time to 
normalization of respiratory function in the control arm is 5 days 
 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
 
 
AE 
Adverse event 
AESI 
Adverse events of special interest 
ALT 
Alanine aminotransferase 
APACHE 
Acute Physiology and Chronic Health Evaluation 
ARDS 
Acture respiratory distress syndrome 
AST 
Aspartate aminotransferase 
ATA 
anti-therapeutic antibody 
AUC 
Area under serum concentration-time curve 
AUEC 
Area under viral load-time curve 
BID 
Twice a day 
°C 
Celsius 
CDC 
Centers for Disease Control and Prevention 
Cmax 
Maximum observed concentration 
Cmin 
Minimum observed concentration 
CPK 
Creatine phosphokinase 
CRO 
contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAIDS 
Division of Acquired Immunodeficiency Syndrome 
ECG 
Electrocardiogram 
eCRF 
electronic Case Report Form 
ECMO 
Extracorporeal membrane oxygenation 
EDC 
electronic data capture 
EU 
European Union 
EVA 
Ethylene vinyl acetate 
FDA 
Food and Drug Administration 
FiO2 
Fraction of inspired oxygen 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
HA 
Hemagglutinin 
HAI 
Hemagglutinin inhibition 
HAP 
Hospital Acquired Pneumonia 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
 
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hMPV 
Human metapneumovirus 
HPLC 
High-performance liquid chromatography 
HR 
Heart rate 
HRP 
Horseradish peroxidase 
HRV 
Human rhinovirus 
 
 
IC50 
Concentration required for 50% inhibition 
ICH 
International Conference on Harmonisation 
ICU 
Intensive Care Unit 
IDSA 
Infectious Diseases Society of America 
IEC 
Independent Ethics Committee 
IMC 
Internal Monitoring Committee 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (application) 
IQR 
Interquartile range 
IRB 
Institutional Review Board 
IRR 
Infusion-related reactions 
ITT 
Intent-to-treat 
IV 
Intravenous 
IxRS 
Interactive voice and web response system 
LFTs 
Liver function tests 
LPLV 
last patient, last visit 
NA 
Neuraminidase 
NAI 
Neuraminidase inhibitor 
NIMP 
Non-investigational medicinal product 
NP 
Nasopharyngeal 
O2 
Oxygen 
PaO2 
Partial pressure of arterial oxygen 
PCR 
Polymerase Chain Reaction 
PD 
Pharmacodynamic 
PE 
Paired end 
PK 
Pharmacokinetic 
PIV 
Parainfluenza virus 
PPV 
Positive pressure ventilation 
qPCR 
Quantitative Polymerase Chain Reaction 
QTcB 
QT interval corrected using Bazett’s formula 
QTcF 
QT interval corrected using Fridericia’s formula 
 
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RBC 
Red blood cell 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SOC 
Scientific Oversight Committee 
SOFA 
Sequential Organ Failure Assessment 
SpO2 
Oxygen saturation by pulse oximetry 
SUSAR 
Suspected unexpected serious adverse reactions 
TCID50 
50% tissue culture infectious dose 
ULN 
Upper limit of normal 
US 
United States 
UVTM 
Universal viral transport medium 
VAP 
Ventilation Acquired Pneumonia 
WBC 
White blood cell 
 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON INFLUENZA  
Influenza A is a membrane-enveloped RNA virus that causes significant morbidity and 
mortality.  Currently, there is a great need in hospitalized influenza patients for a 
parenteral therapeutic option that is well tolerated, can rapidly resolve influenza-related 
signs and symptoms, decrease mortality, reduce hospital and intensive care unit (ICU) 
stays, as well as have a prolonged window for initiation of treatment beyond the current 
standard of care (i.e., within 48 hours of the onset of flu symptoms). 
Approximately 200,000 to 278,000 patients are hospitalized with severe influenza 
infections annually in the United States (US) (Thompson et al. 2004; Zhou et al. 2012), 
and assuming the same rate reported in the US, an estimated 319,000 to 
445,000 patients are hospitalized in the European Union (EU).  Hospitalization due to 
severe influenza is associated with high mortality (4%−8%), ICU admission (5%−17%; 
Lee and Ison 2012), mechanical ventilation support in an ICU setting (7%−11%; 
Doshi et al. 2011), and prolonged hospital stays (5−9 days; Lee and Ison 2012).  During 
a pandemic season, the outcomes may be more serious, with up to 34% of patients 
requiring ICU care and a mortality rate as high as 15% (Lee and Ison 2012). 
Influenza infection is an upper and lower respiratory disease with a broad spectrum of 
presentations that can result in fever, shortness-of-breath, pneumonia, respiratory failure, 
secondary respiratory infections, and even death.  The standard of care therapy for 
patients hospitalized with influenza consists of supportive measures and administration 
of available antiviral agents, primarily neuraminidase inhibitors (NAI) that include but are 
not limited to oseltamivir, zanamivir, and peramivir.  However, a significant unmet 
medical need still exists in the severely ill patient population, as evidenced by the 
considerable degree of morbidity and mortality in this setting.  To address this need, the 
Sponsor is developing a highly-specific anti-influenza A (MHAA4549A) antibody therapy 
for treatment of hospitalized patients with severe influenza. 
1.2 
BACKGROUND ON MHAA4549A  
1.2.1 
Nonclinical Background 
MHAA4549A is a human monoclonal IgG1 antibody that binds to the influenza A virus 
and is 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, which allows broad 
neutralization of the influenza A virus by blocking the HA-mediated, membrane-fusion 
event in the late endosome. 
In vitro, MHAA4549A is capable of neutralizing all current clinically relevant influenza A 
strains.  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.  
 
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MHAA4549A specifically targets an epitope on the human influenza A HA glycoprotein, 
which does not appear to be endogenously expressed on human or rat tissues and, 
therefore, is unlikely to be present in the absence of viral infection.  Weekly 
administration of MHAA4549A (total of 5 doses) in Sprague-Dawley rats was well 
tolerated up to the maximum feasible dose of 150 mg/kg.  Ex vivo tissue cross-reactivity 
study data showed no specific binding of MHAA4549A to any of the human or rat tissues 
examined. 
1.2.2 
Clinical Safety Background 
To date, MHAA4549A has been shown to be safe and well tolerated in two clinical 
studies, which altogether enrolled 122 healthy volunteers.   
1.2.2.1 
Phase 1 Entry-into-Human Study GV28916 
The first study was a Phase 1 study (GV28916) in 21 healthy volunteers where single 
doses of 1.5 mg/kg, 5 mg/kg, 15 mg/kg, and 45 mg/kg were tested with an extended 
follow-up period of 120 days.  MHAA4549A was safe and well tolerated with no serious 
adverse events (SAEs).  All adverse events (AEs) were mild or mild to moderate and 
resolved fully before the end of the study’s follow-up period.  No anti-therapeutic 
antibodies (ATAs) were detected in this study.   
1.2.2.2 
Phase 2a Influenza Nasal Challenge Study GV28985 
The second study was a Phase 2a challenge study (GV28985) in 101 healthy volunteers 
infected with a H3N2 (A/Wisconsin/67/2005) strain of influenza virus.  Sixty subjects 
received doses of 400 mg, 1200 mg, or 3600 mg MHAA4549A, and 32 subjects received 
placebo following nasal inoculation of influenza A virus one day earlier.  Eight subjects 
received oseltamivir starting on Day 1.  One subject was randomized and inoculated, but not 
dosed.   
Most AEs appeared to reflect symptoms of an active influenza infection and occurred primarily 
within the first 21 days after patients received their virus inoculation and dose of MHAA4549A 
or placebo (123 of 213: 58%).  Following the resolution of the influenza symptoms, even though 
levels of MHAA4549A remained relatively high, the number of AEs dropped and remained low 
throughout the remainder of the study: 59 of 213 (28%) of all AEs occurred between Study Days 
22 and 60, and 31 of 213 (15%) of all AEs occurred between Study Days 61 and 120.  Differences 
between treatment groups in the number and severity of AEs during the first 22 days appeared to 
reflect variability in the extent and severity of the influenza infection.  Throughout the entire 
study, the pattern of AEs did not differ substantially between subjects who received placebo and 
subjects who received any dose of MHAA4549A.  
The percentage of AEs that investigators judged to be related to study drug treatment was 12/33 
(36%) for the 400-mg group, 10/40 (25%) for the 1200-mg group, 11/52 (21%) for the 3600-mg 
group, and 25/88 (28%) for subjects receiving placebo.  Of those AEs considered related, however, 
15 of 25 (60%) in the placebo cohort and 26 of 33 (79%) in all MHAA4549A cohorts consisted of 
 
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elevations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), or amylase.  
These laboratory abnormalities have been shown to be associated with the influenza infection 
(Polakos et al 2006; Yingying 2011) and were not observed in either the previous or subsequent 
Phase 1 studies (i.e., GV28916, GV29609) where MHAA4549A was administered to subjects 
without influenza infection.  
There were 3 SAEs in Study GV28985, none of which were assessed as related to MHAA4549A.  
One was in a subject hospitalized with a depressive psychosis.  Due to his previous history of 
depression and the known association of psychosis with influenza infections, the Investigator 
considered this event unrelated to study drug.  The other 2 SAEs were in one subject who fell and 
required a surgical repair of a fractured tibial plateau.  This same subject was subsequently 
hospitalized for her second SAE, which was a post-surgical wound infection.  Neither of these 
events was considered related to study treatment.   
In GV28985, the immunogenicity incidence rate amongst the 60 subjects who received 
MHAA4549A was 0%.  One subject tested positive for ATAs.  This subject tested 
positive for ATA at baseline and post baseline.  This subject was in the placebo group, 
which included 32 other subjects, resulting in an immunogenicity prevalence rate 
(ATA-positive rate at baseline) of 3.1% and an immunogenicity incidence rate (ATA titers 
post-baseline) of 3.1%, as well, within the placebo group.  Overall, study GV28985 had 
an immunogenicity prevalence rate of 1%.  
1.2.2.3 
Phase 1 High Dose Safety Study GV29609 
A Phase 1 (GV29609) study was initiated to evaluate the safety and tolerability 
of a single intravenous (IV) doses at 8400 mg or 10800 mg MHAA4549A as 
compared to placebo when administered to 14 healthy volunteers.  The starting 
dose of 8400 mg was based on simulations from a semi-quantitative 
pharmacokinetic model (Figure 2) developed from the Phase 2a challenge study 
(GV28985), which suggests that the 8400 mg may be the minimum dose that is 
expected to show a separation of nasal exposure from a dose of 3600 mg.  The 
simulation assumes that pharmacokinetics can be extrapolated at doses above 
3600 mg and that the PK profile in severely ill patients is similar to the PK 
profile of healthy volunteers in the Phase 2a challenge study.  The highest 
proposed dose of 10800 mg was chosen in GV29609 to provide safety coverage 
for those exposures that might be reached in a 40-kg individual dosed with a 
flat dose of 8400 mg.  
GV29609 is currently on-going, but preliminary analysis of unblinded safety 
data up to day 57 shows that the 8400 mg and 10800 mg treatment groups are 
safe and well tolerated.  
• 
In subjects who received 8400 mg MHAA4549A (N=4): 
− 3 of 4 subjects reported 12 AEs  
 
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− 6 AEs were reported as related to 8400 mg MHAA4549A:  3 headaches, 
1 pruritus, 1 peripheral swelling, and 1 nasal congestion 
• 
In subjects who received 10800 mg MHAA4549A (N=4): 
− 4 of 4 subjects reported 7 AEs  
− 3 AEs reported as related to the 10800 mg MHAA4549A treatment 
group:  1 nausea, 1 headache, and 1 asthenia 
• 
In subjects who received placebo (N=6): 
− 2 of 6 subjects reported 5 AEs 
− 1 AE was reported as related to study drug: 1 headache 
 
All AEs were reported as mild except for an unrelated moderate AE of 
an increase in creatinine kinase in one subject who received 10800 mg 
MHAA4549A.  There were no SAEs and no subjects have discontinued the 
study for any reason.  
As in both previous studies, headache was the most common AE.  Headache was 
reported by 3 subjects (37.5%) who received 8400 mg MHAA4549A:  1 subject 
(12.5%) who received 10800 mg MHAA4549A and 2 subjects (33.0%) who 
received placebo.   
Based on this data, MHAA4549A is considered generally safe and well tolerated.   
1.2.3 
Clinical Efficacy Background 
The Phase 1 study (GV28916) demonstrated that MHAA4549A 
pharmacokinetics were generally dose proportional.  The PK profile appeared 
consistent with that of a human IgG1 antibody that lacks known endogenous 
host targets. 
In the Phase 2a challenge study (GV28985), 101 healthy volunteers were inoculated 
with influenza virus 24-36 hours prior to dosing with MHAA4549A.  Following 
inoculation, 60 subjects received doses of 400 mg, 1200 mg, or 3600 mg MHAA4549A, 
32 subjects received placebo, 8 subjects received a 5-day course of oseltamivir, and 
1 subject was not dosed.  The interim efficacy analysis presented in Table 1 included the 
Intent-to-Treat (ITT) infected population followed until at least Day 29 who received 
400 mg MHAA4549A (N = 11), 1200 mg MHAA4549A (N = 13), 3600 mg 
MHAA4549A (N = 14), placebo (N = 21), and oseltamivir (N = 2).  Analysis of efficacy 
from the 3600-mg dose level demonstrated a statistically significant decrease in viral 
shedding from the upper respiratory tract as measured by the area under the curve 
(97.5% reduction by quantitative polymerase chain reaction [qPCR]) and peak viral load 
(77% reduction by qPCR).  All subjects have completed dosing, and interim PK and 
efficacy data are available in the Investigator’s Brochure and upon request.  
 
MHAA4549A—Genentech, Inc. 
57/Protocol GV29216, Version 5 (Global)   


 
 
MHAA4549A—Genentech, Inc. 
58/Protocol GV29216, Version 5 (Global)   
In the GV28985 study, all subjects received oseltamivir started on Day 7 for a 5-day course, 
and there were no observed AEs or imbalances in safety events that were considered 
attributable to interactions between oseltamivir and MHAA4549A.  The PK profile of 
MHAA4549A and oseltamivir in GV28985 are being analyzed to exclude potential 
drug-drug interactions, and this analysis will be available before the start of this study 
(GV29216).   
Table 1 
Interim Efficacy Results from Phase 2a Challenge Study 
(GV28985) 
Endpoint 
Placebo 
(N=21) 
MHAA4549A 
Oseltamivir 
400 mg 
(N=11) 
% reduction
(p-value)a 
1200 mg 
(N=13) 
% reduction 
(p-value)a 
3600 mg 
(N=14) 
% reduction 
(p-value)a 
75 mg BID 
(N=2) 
% reduction 
(p-value)a 
Median qPCR 
Viral AUEC 
(log10 vc/mL x 
hour) 
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 qPCR 
Peak Viral Load 
(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 Total 
Clinical Symptom 
AUEC 
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) 
AUEC  area under viral loadtime curve; qPCR  quantitative polymerase chain reaction. 
a Comparison of active and placebo using nonparametric Wilcoxon rank-sum test.  All p-values 
are unadjusted for multiple testing. 
  
The A/Wisconsin/67/2005 virus induced mild symptoms that were predominantly 
captured in the upper respiratory tract symptoms that included runny nose, stuffy nose, 
and sneezing. 
The Symptom Diary Cards used 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 from Study GV28985 for the ITT infected (ITTI) population are shown in Table 1.   
Given the variability of the symptom scores the results were not statistically significant.  
However, there was a decrease in the AUEC of symptoms scores for the 3600-mg dose, 
which is consistent with the virological results described in Table 1.  Data from the 
oseltamivir treated group is also shown, but it should be noted that only 2 subjects were 
in the ITT infected population. 
The responses observed in the Phase 2a study (GV28985) suggest that a higher dose 
may provide better efficacy in a population with established infection.  An 8400-mg 


 
dose will be included in this Phase 2b study for further dose ranging.  The rationale for 
selected dosages is further explained in Section 3.2.4. 
See the MHAA4549A Investigator's Brochure for additional details on nonclinical and 
clinical studies. 
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
1.3.1 
Study Rationale 
Two Phase 1 (GV28916, GV29609) studies have demonstrated that MHAA4549A is 
safe and well tolerated to date in healthy volunteers at doses up to 8400 mg.  Data from 
a Phase 2a study (GV28985) demonstrates safety in healthy subjects inoculated with 
influenza virus and provides evidence that the 3600 mg dose of MHAA4549A is 
effective in reducing viral titers in healthy volunteers inoculated with influenza A virus. 
When combined with previous nonclinical studies that showed MHAA4549A to have in 
vitro and in vivo efficacy, a well-tolerated safety profile, and anti-viral activity, these 
findings support further clinical development of MHAA4549A. 
In this Phase 2b study (GV29216), MHAA4549A is being evaluated in combination with 
the current standard of care (oseltamivir), to decrease the severity and duration of viral 
infection with influenza A virus with the ultimate goal of reducing the clinical symptoms of 
infection as compared to oseltamivir with placebo.  There are three primary goals for this 
Phase 2b study:  
• 
Demonstrate the safety and efficacy of MHAA4549A in combination with oseltamivir 
in hospitalized influenza A patients  
• 
Demonstrate a reduction in the extent and duration of viral burden in upper and 
lower lung compartments in order to gain an understanding of the 
PK/pharmacodynamic (PD) and PD/efficacy relationships  
• 
Demonstrate and evaluate the optimal endpoints for study in hospitalized patients 
with influenza A, given the lack of precedence for approval in patients hospitalized 
with influenza infection, an area of high unmet medical need 
 
Initially, this GV29216 Phase 2b study enrolled patients in a two-arm treatment study 
comparing 3600 mg MHAA4549A with oseltamivir versus placebo with oseltamivir.  
This current Phase 2b study has added an additional arm to evaluate the improvement 
in outcome of a combination therapy of 3600 mg MHAA4549A with oseltamivir or of 
8400 mg MHAA4549A with oseltamivir versus placebo with oseltamivir.  All patients will 
receive oseltamivir, which is part of the recommended standard of care.  In addition, and 
as discussed above, MHAA4549A is a human monoclonal antibody that has, to date, 
shown an acceptable safety profile, a PK profile consistent with that of a IgG1 human 
antibody that lacks known endogenous host targets, and demonstrated antiviral activity 
at the planned dose level of 3600 mg.  
 
MHAA4549A—Genentech, Inc. 
59/Protocol GV29216, Version 5 (Global)   


 
This study (GV29216) will assess severely ill patients who may be infected with 
various influenza A strains, have a higher viral burden and longer duration of viral 
shedding than the healthy volunteers in GV28985, and who may, therefore, require 
doses higher than 3600 mg.  A Phase 1 (GV29609) study is currently on-going to 
assess the safety, tolerability, and pharmacokinetics of 8400-mg and 10800-mg doses of 
MHAA4549A.  The starting dose of 8400 mg was selected based on simulations from a 
semi-quantitative PK model developed from the Phase 2a challenge study (GV28985), 
suggesting that 8400 mg MHAA4549A may be the minimum dose that is expected to 
show a separation of nasal exposure from a dose of 3600 mg.  This simulation assumes 
that pharmacokinetics can be extrapolated at doses above 3600 mg and that the PK 
profile in severely ill patients is similar to the PK profile of healthy volunteers in Phase 
2a challenged with influenza A virus.  The 10800-mg dose was chosen to provide 
assurance of safety for the increased MHAA4549A levels that may be reached in 
smaller individuals who received 8400 mg. 
A preliminary, unblinded analysis of the safety data from GV29609 up to Day 57 has 
shown that the 8400-mg and 10800-mg treatment groups are safe and well tolerated.  
In subjects who received 8400 mg MHAA4549A, 3 of 4 subjects reported 12 AEs.  In 
subjects who received 10800 mg MHAA4549A, 4 of 4 subjects reported 7 AEs.  In 
subjects who received placebo, 2 of 6 subjects reported 5 AEs.  All AEs were reported as 
mild, except for one unrelated moderate AE of an increase in creatinine kinase in one 
subject who received 10800 mg MHAA4549A.  There were no SAEs and no subjects 
have discontinued the study for any reason.  As in previous studies, headache was the 
most common AE, and was reported by 3 subjects (37.5%) who received 8400 mg 
MHAA4549A, 1 subject (12.5%) who received 10800 mg MHAA4549A, and 2 subjects 
(33.0%) who received placebo.  As a result, the Sponsor feels that the 8400-mg dose is 
safe to include in Study GV29216.  
The 8400-mg dose is also expected to be safe based upon previous nonclinical and 
clinical safety assessments.  Nonclinical safety data do not show any expected or 
unexpected toxicity.   
1.3.2 
Benefit-Risk Assessment 
1.3.2.1 
Treatment in Combination with Oseltamivir 
All patients in the study will receive oseltamivir as the current standard of care treatment, 
either with or without MHAA4549A.  Therefore, at a minimum, all patients will be treated 
with the standard of care for influenza.  Given that MHAA4549A is an antibody, the 
potential for a drug-drug interaction with oseltamivir is very low.  In the Phase 2a 
challenge study (GV28985), study subjects received MHAA4549A followed by 
oseltamivir with no AEs attributable to the combination therapy noted to date.  In addition, 
in this Phase 2b study the PK profile of oseltamivir in concomitantly treated subjects will 
be assessed. 
 
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60/Protocol GV29216, Version 5 (Global)   


 
1.3.2.2 
Drug Mechanism and Preclinical Studies 
The available pre-clinical data suggest that there is low risk for drug target-related safety 
events in healthy humans since MHAA4549A specifically targets an epitope on a viral 
protein (i.e., the human influenza A virus HA glycoprotein), which is not endogenously 
expressed in human tissues.  Furthermore, there were no adverse MHAA4549A-related 
findings demonstrated in nonclinical studies at doses up to 150 mg/kg administered 
weekly for 5 weeks and no evidence of target present in host tissues.   
1.3.2.3 
Rationale for Selection of Phase 2b Study Population 
The target patient population of hospitalized patients with severe influenza A requiring 
oxygen (O2) or positive pressure ventilation (PPV) is considered an appropriate 
population to test MHAA4549A for the following reasons: 
• 
Nonclinical safety data does not show any expected or unexpected toxicity. 
• 
Clinical safety data for MHAA4549A demonstrate a well-tolerated safety profile:   
– 
AEs in the Phase 1 study (GV28916) were mild and did not show a dose 
relationship; there were no ATAs detected in patients treated with 
MHAA4549A after 120 day follow-up visit. 
– 
All AEs in GV29609 from a preliminary analysis of unblinded safety data up 
to day 57 were reported as mild except for an unrelated moderate AE of an 
increase in creatinine kinase in one subject who received 10800 mg 
MHAA4549A.  There were no SAEs and no subjects have discontinued the 
study for any reason. 
 
In the Phase 2a study (GV28985), MHAA4549A was generally well tolerated.  A few 
subjects in all treatment groups were observed to have transient elevations in ALT, AST, 
and amylase levels.  There was no dose-dependent relationship of the 
ALT/AST/amylase elevations with MHAA4549A and the overall event rate was in line 
with published rates associated with the influenza challenge model regardless of 
treatment arm:  27/100 [27%] in GV28985 vs. approximately 26% in previous challenge 
studies (Polakos 2006, Yingying 2011).  There were no SAEs related to study drug.  
There were a total of 3 SAEs unrelated to MHAA4549A in two subjects.  One subject 
reported depressive psychosis associated with influenza.  The second subject reported a 
broken knee with a subsequent infection following a surgical procedure.   
1.3.2.4 
Patient Monitoring and Supervision 
MHAA4549A will be administered to enrolled patients in a hospital environment under 
close medical supervision by physician investigators.  Medical staff will be available for 
prompt evaluation and treatment of any AEs.  Emergency resuscitation equipment and 
emergency facilities will be readily available.  Patients will undergo screening 
assessments to confirm eligibility, will be closely monitored during the administration of 
MHAA4549A, and will be resident for at least 24 hours following the administration of 
 
MHAA4549A—Genentech, Inc. 
61/Protocol GV29216, Version 5 (Global)   


 
MHAA4549A.  Furthermore, safety laboratory tests relating to the blood chemistries, 
including liver function tests will be conducted. 
An internal monitoring committee (IMC) in combination with a scientific oversight 
committee (SOC) will provide safety monitoring for the study in addition to the ongoing 
review of safety by the Medical Monitor and Safety Scientist.  See Section 3.1.2 for more 
information.  
In addition to the regularly scheduled safety reviews of the patient data by the IMC and 
SOC, an additional sentinel safety cohort of the first 30 patients or patients after the 
first influenza season, whichever occurs first, will be assessed by the IMC and SOC. 
The 120-day follow-up period in the Phase 1 and 2a studies allowed for monitoring of 
subjects for approximately 5 half-lives of MHAA4549A.  No ATAs were detected in the 
Phase 1 study, while one subject who received placebo in the Phase 2a study tested 
positive for ATAs at baseline and post-baseline timepoints as described in Section 1.2.2.  
The Phase 2b study will also include a safety follow-up period of 60 days and an 
unlimited collection of all SAEs believed related to MHAA4549A.   
Based on the above data and design of this study, the Sponsor concludes that the 
benefit−risk profile of MHAA4549A in the population with severe influenza is favorable.  
2. 
OBJECTIVES 
2.1 
SAFETY OBJECTIVES 
The safety objectives for this study are as follows: 
• 
To evaluate the safety of MHAA4549A in combination with oseltamivir compared 
with placebo and oseltamivir in patients with severe influenza A, focusing on the 
nature, frequency, and severity of serious and non-serious AEs as well as effects on 
laboratory values, vital signs, electrocardiogram (ECG) parameters, ATAs, and 
other safety biomarkers 
 
2.2 
PRIMARY EFFICACY OBJECTIVES 
The primary efficacy objective for this study is as follows: 
• 
To determine the time to normalization of respiratory function of patients dosed with 
MHAA4549A in combination with oseltamivir compared to patients dosed with 
placebo and oseltamivir. 
 
2.3 
SECONDARY EFFICACY OBJECTIVES 
The secondary efficacy objectives for this study are as follows: 
• 
To measure clinical failure, as defined in Section 3.3.3, after 24 hours post infusion 
of study drug  
• 
To determine the time to clinical resolution of vital signs  
 
MHAA4549A—Genentech, Inc. 
62/Protocol GV29216, Version 5 (Global)   


 
• 
To measure mortality in patients  
• 
To determine changes in the extent and duration of viral shedding in 
nasopharyngeal samples as a measure of the pharmacodynamic response  
• 
 
 
• 
To measure the duration of hospital and/or ICU stay 
• 
To measure antibiotic usage for respiratory infections  
• 
To measure the frequency and severity of the following secondary complications of 
influenza:  
– 
Pneumonia (hospital acquired pneumonia [HAP]/ ventilator acquired 
pneumonia [VAP]) 
– 
Exacerbations of chronic lung disease 
– 
Myocarditis 
– 
Acute respiratory distress syndrome (ARDS) 
– 
Otitis media 
– 
Other related complications 
– 
Readmission rates at 30 and 60 days after study treatment 
• 
To measure duration of PPV 
• 
To measure readmission rates 
 
2.4 
PHARMACOKINETIC OBJECTIVES  
The pharmacokinetic (PK) objectives for this study are as follows: 
• 
To characterize the PK profile of MHAA4549A in serum 
 
The exploratory PK objectives for this study are as follows: 
 
 
 
 
 
 
2.5 
EXPLORATORY OBJECTIVES 
The exploratory objectives for this study are as follows: 
 
 
 
 
 
 
 
MHAA4549A—Genentech, Inc. 
63/Protocol GV29216, Version 5 (Global)   


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
3.1.1 
Overview of Study Design 
This is a Phase 2b (GV29216), randomized, double-blind, placebo-controlled study 
designed to assess the safety and clinical activity of a single IV dose of 3600 mg 
MHAA4549A or a single IV dose of 8400 mg MHAA4549A in hospitalized patients with 
severe influenza A in combination with oseltamivir versus a comparator arm of placebo 
with oseltamivir.  This study is planned to take place in approximately 170 study centers 
globally. 
Initially, GV29216 targeted enrollment into two treatment groups: a single IV dose of 
3600 mg of MHAA4549A with oseltamivir or a single IV dose of placebo with oseltamivir.  
In this version of the protocol, patients will be randomized 1:1:1 into three treatment 
groups:  a single IV dose of 3600 mg of MHAA4549A with oseltamivir, a single IV dose 
of 8400 mg of MHAA4549A with oseltamivir, or a single IV dose of placebo with 
oseltamivir.  All patients will receive oseltamivir, a NAI, as standard therapy for a 
minimum of 5 days after study drug administration.  Oseltamivir at doses of 75 mg twice 
a day (BID) or 150 mg BID is permitted in order to be consistent with local standard of 
care practice.  Treatment for longer than 5 days is permitted based on local investigator 
discretion.  The patient must start oseltamivir no later than 8 hours after completion of 
study drug administration.  The study has a planned enrollment of approximately 
330 patients globally. 
Hospitalized patients with an O2 or PPV requirement will be evaluated for influenza A 
infection.  Enrollment in this study requires ongoing treatment within 24 hours of hospital 
admission with one of the following:  
• 
any PPV or  
 
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64/Protocol GV29216, Version 5 (Global)   


 
• 
any supplemental O2 to maintain oxygen saturation (SpO2) > 92% (Section 3.3.2)   
 
Patients on PPV should not exceed 45% of the total patients enrolled. 
A Sponsor-approved influenza test that includes influenza antigen test or influenza 
polymerase chain reaction (PCR) test must be used as an aid in the diagnosis of 
influenza A infection.   
 
  
 
 
 
  
At the time of randomization, patients who are eligible for enrollment, as described 
above, will be randomized to receive 3600 mg MHAA4549A or 8400 mg MHAA4549A 
or placebo.  Patients will be stratified by country, PPV versus supplemental O2 at 
randomization, and suspected or confirmed bacterial pneumonia versus no bacterial 
pneumonia based on the status at randomization. 
Eligible patients who are enrolled into the study will receive a single IV infusion of 
3600 mg MHAA4549A or a single IV infusion of 8400 mg MHAA4549A or a single IV 
infusion of placebo on Day 1.  All patients must begin study drug infusion within 
48 hours of hospital admission or sooner if possible.  All patients will receive oseltamivir 
for a minimum of 5 days (10 doses), starting on Day 1, beginning no later than 8 hours 
after completion of study drug administration.   
All patients will be followed and evaluated at minimum on a daily basis for the duration of 
their hospital stay consistent with the planned schedule of assessments.  Any suspicion 
of bacterial superinfection should be thoroughly evaluated including microbiological 
confirmation, if possible.  A follow-up study visit should occur on Day 14 ± 1 (if 
discharged before Day 14); Day 30 ± 4 days (if discharged before Day 30); and Day 
60 ± 4 days (if discharged before Day 60). 
Safety evaluations will also be provided by an IMC and SOC, as defined in the IMC and 
SOC agreement (see Section 3.1.2).  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. 
An additional safety cohort of the first 30 patients, or patients from the first influenza 
season (whichever occurs first), will be assessed by the IMC and SOC.  A review of 
chemistry laboratory test results, AEs, SAEs, vital signs, and deaths will be assessed.  
 
MHAA4549A—Genentech, Inc. 
65/Protocol GV29216, Version 5 (Global)   


 
A schedule of assessments is provided in Appendix 1a and Appendix 1b.  A diagram of 
the study design is presented in Figure 1.  
Figure 1 Phase 2b Study Design (GV29216) 
 
  
3.1.2 
Internal Monitoring Committee and Scientific Oversight 
Committee 
A combined approach with both an IMC and a SOC is proposed to enhance patient 
safety.  The IMC consists of Sponsor representatives from the following functions: 
Clinical Science, Drug Safety, Biostatistics, and Statistical Programming and Analysis.  
The IMC members will be unblinded to patient treatment and assignment.  The Clinical 
Science representative on the IMC (IMC Chair) will be a person other than the Study 
Medical Monitor and will not be involved in the conduct of the study or have any contact 
with study investigators or site staff.  The Study Medical Monitor will remain blinded to 
individual treatment assignments, unless, in exceptional cases, specific circumstances 
require Study Medical Monitor unblinding after IMC Chair approval.  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.  The Biostatistician and Statistical Programmer are 
the only IMC members involved in the conduct of the study; however, they do not have 
any contact with study investigators, and all discussion within the IMC are kept 
confidential.  All other Sponsor and Contract Research Organization personnel involved 
in the conduct of the study will remain blinded to individual treatment assignments. 
 
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66/Protocol GV29216, Version 5 (Global)   


 
The two SOC members are external experts in the field and will be unblinded to 
treatment allocation.  The SOC may be further expanded by the IMC during the course 
of the study to include additional external experts if the need arises.  
A detailed description of the procedures, data flow, and meeting schedule of the IMC 
and SOC will be provided in a separate IMC and SOC agreement. 
3.1.3 
End of Study 
The end of study is defined as the first day when all patients have had a study 
completion visit or early termination visit or have otherwise been discontinued from the 
study. 
3.2 
RATIONALE FOR STUDY DESIGN 
3.2.1 
Rationale for Study Design 
Hospitalized influenza A infection represents a high unmet need, which, when left 
untreated, may progress to a more serious disease that may result in significant 
morbidity and mortality in otherwise healthy adults as well as in vulnerable populations.   
This study is designed to estimate the improvement in outcome of a combination 
regimen of MHAA4549A with oseltamivir compared to a standard of care arm of placebo 
with oseltamivir.  The study population will include hospitalized patients with influenza A 
requiring O2 support and/or PPV support within 24 hours of hospital admission.  
Study GV29216 will be a Phase 2b study involving approximately 330 patients.  The 
sample size was determined based on an expected clinically meaningful difference of 
1 − 2 days improvement in time to normalization of respiratory function between the 
control and treatment arms, assuming a 5 day median time to the time to normalization 
of respiratory function in the standard of care arm (Blackwood 2011; Premier Inc, 
Charlotte, NC).   
This design ensures that all patients in the trial will receive the current NAI treatment, 
oseltamivir, as standard of care at a minimum, and will evaluate the clinical benefit of 
combining MHAA4549A with this standard of care regimen.  Therefore, this study aims 
to identify a regimen that could deliver maximum benefit in this high unmet need disease, 
while still treating all enrolled patients with the currently accepted standard of care. 
3.2.2 
Rationale for Patient Population and Primary Endpoint 
Severe influenza, for the purpose of this study, is defined as requiring one of the 
following treatments: any supplemental O2 to maintain an SpO2 > 92% or PPV.  PPV is 
defined as any mechanical positive pressure device to maintain oxygenation; this can 
include positive pressure mask and intubation.  A Sponsor-approved influenza test, 
which includes influenza antigen test or influenza PCR test, must be used as an aid in 
the diagnosis of influenza A infection. 
 
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67/Protocol GV29216, Version 5 (Global)   


 
This patient population was chosen based on the rationale that respiratory failure is a 
hallmark of influenza and a major driver of morbidity and mortality, as well as 
hospitalization.  The recovery from ventilator support has been shown to be directly 
proportional to time spent in the ICU (Blackwood 2011; Premier Inc, Charlotte, NC).  
Based upon an analysis of morbidity and mortality, the patient population that requires 
supplemental O2 or ventilation on their first day of admission was determined to have a 
high unmet medical need as they have an estimated mortality of 9%-32%, and 27% 
require admission to the ICU, according to analysis of a database of over 70,000 
hospitalized patients in the US from 2005-2012 (Premier Inc, Charlotte, NC).   
The proposed primary efficacy outcome measure in this study is “Time to normalization 
of respiratory function,” defined as oxygen saturation ≥ 95% without oxygen 
supplementation.  Support for use of a respiratory endpoint in this population comes 
from recently published data demonstrating that a composite endpoint that captured 
respiratory rate, fever, heart rate, and blood pressure resolution was primarily driven by 
the respiratory component of the endpoint (Marty et al. 2014).  Given that influenza 
infections generally do not cause systemic infections and influenza disease is restricted 
to the respiratory tract, the Sponsor believes that the primary endpoint represents a 
clinically meaningful outcome in this patient population (as shown by analysis of 
PREMIER database) and measures an important physiologically relevant 
pharmacodynamic response parameter of MHAA4549A.  This endpoint is a measure of 
patient function, measures a symptom that represents a serious consequence of 
influenza, and is consistent with clinically relevant endpoints discussed in the US Food 
and Drug Administration (FDA) Guidance, “Influenza: Developing Drugs for 
Treatment and/or Prophylaxis” (FDA 2011).  
3.2.3 
Rationale for Control Group and Treatment Window  
In this study, the standard of care regimen for the control or comparator group is 
oseltamivir, an NAI.  In the treatment groups, MHAA4549A will be dosed in addition to 
oseltamivir.  Either 75 mg or 150 mg orally BID oseltamivir for a minimum of 5 days is 
permitted following treatment with MHAA4549A.  Treatment for longer than 5 days is 
permitted based on local investigator discretion (WHO 2005, Fiore 2011, CDC 2015).  
The oseltamivir dosing regimen is listed in Table 2.  This control treatment was based on 
consideration of safety, ethics, and efficacy for treatment of severe influenza and is 
consistent with guidelines for antiviral treatment of hospitalized patients with influenza 
(Harper et al. 2009, Fiore 2011).  
 
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Table 2 
Oseltamivir Dosing Regimen  
Neuraminidase Inhibitor 
Dosing Regimen 
Duration of Therapy 
Oseltamivir 
75 mg or 150 mg oral twice 
daily a 
5 days b 
 
a 75 mg or 150 mg dose at the discretion of the investigator, and dose must be documented.  
Capsules can be opened and the granules administered via nasogastric tube, if required.  For 
renal dose adjustments, follow local standard of care practice/local package insert and 
document in the eCRF. 
b Longer treatment times are at the discretion of the investigator (WHO 2005, Fiore 2011, CDC 
2015). 
  
If oseltamivir resistance is highly suspected or identified during treatment or oseltamivir 
route of administration challenges are encountered, then following discussion with the 
Sponsor medical representative, an alternative NAI to oseltamivir may be used. 
From a safety standpoint there are no expected drug interactions between MHAA4549A, 
a monoclonal antibody, and any NAI, which are small molecule drugs that bind to a 
different viral protein than MHAA4549A.  In the Phase 2a challenge study, all subjects 
that were dosed with MHAA4549A also received a 5-day course of oseltamivir starting 
on Day 7.  There were no safety effects attributable to the combination when the drugs 
were present concurrently.  The pharmacokinetics of oseltamivir and its potential 
interaction with MHAA4549A are being assessed from the Phase 2a study. 
For this Phase 2b study, a combination of MHAA4549A and oseltamivir was determined 
to be the most clinically feasible treatment regimen, both from an ethical as well as a 
practical perspective.  The treatment of all patients with oseltamivir ensures that all 
patients will receive the standard of care.  Given the high morbidity and mortality of 
hospitalized patients with influenza A along with guidelines from Centers for Disease 
Control and Prevention (CDC) and Infectious Diseases Society of America (IDSA) it is 
recommended that NAIs are the standard of care for hospitalized patients with influenza 
A (Harper et al. 2009; CDC Website).  Furthermore, pre-clinical efficacy data from a 
study using MHAA4549A and oseltamivir in combination showed a potential synergistic 
effect of both compounds which may be due to the different and potentially 
complementary mechanisms of action, i.e. targeting viral HA and neuraminidase (NA). 
Dosing of MHAA4549A is confined to a treatment window designed for best expected 
treatment success and to ensure that any observed effects can be attributed to the study 
drug with high confidence.  MHAA4549A shall only be dosed within 5 days of onset of 
symptoms (including fever, chills, malaise, dry cough, loss of appetite, myalgias, coryza, 
or nausea), no later than 48 hours after admission to the hospital, and if a subject has 
taken less than a total of 6 doses (3 doses for peramivir) of approved anti-influenza 
therapy from onset of symptoms.  This proposed window is supported by data 
demonstrating that hospitalized influenza patients benefit from NAI treatment even at 
5 days from onset of symptoms (Louie et al. 2012).  The patient must start 
 
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standard-of-care oseltamivir no later than 8 hours after completion of MHAA4549A 
administration. 
3.2.4 
Rationale for MHAA4549A Dosage 
A single IV dose of 3600 mg MHAA4549A or a single IV dose of 8400 mg MHAA4549A 
was selected to assess the efficacy of MHAA4549A and to provide data for further 
clinical development.  The selection of dose in this study for severely ill patients was 
based on the observed human pharmacokinetics in Phase 1 and the relationship 
between the pharmacokinetics, pharmacodynamics, and efficacy observed in a Phase 
2a human challenge model of influenza.  MHAA4549A was shown to be safe and 
well-tolerated at all dose levels (ranging from 1.5 mg/kg to 45 mg/kg for Phase 1 and 
400-3600 mg for Phase 2a) through a follow-up period of 120 days post-dose in the 
Phase 1 and Phase 2a study.  The dose levels selected for this study were determined 
following analysis of data from the Phase 2a study (GV28985), which demonstrated the 
following: 
• 
The 3600-mg dose demonstrated a significant decrease in viral shedding in upper 
respiratory samples.  Based on current interim analysis data, there was a 97.5% 
(p = 0.0051) decrease in area under the viral load-time curve (AUEC) and a 77.3% 
decrease in peak viral load by qPCR measurement compared to the placebo group.   
• 
Symptom data in the Phase 2a study showed a decrease in the area under the 
serum concentration-time curve (AUC) of symptoms scores for the 3600-mg dose, 
as illustrated in Table 1, which is consistent with the virological results. 
• 
When compared to placebo, a decrease in viral shedding was observed at the 400 mg 
dose but not at the 1200 mg dose, which may be due to variability in the challenge 
model and differences in infection rate, infection peak, virus level in the 
nasopharynx, nasal pharmacokinetics, immune status, and other inter-subject 
differences.  
• 
There were no safety concerns at any dose level associated with MHAA4549A.  
• 
Hospitalized patients generally have a longer duration of viral shedding and 
significantly more viral burden in the lower lung compartments; therefore, high 
concentrations of monoclonal antibody are likely needed to achieve sufficient 
occupancy of the virus binding sites in the upper and lower respiratory 
compartments.  Furthermore, higher concentrations of monoclonal antibody may 
mitigate the risk of resistance for MHAA4549A, supporting addition of the 8400 mg 
MHAA4549A treatment arm.  
• 
Exploratory exposure-response analysis of GV28985 indicated that higher exposure 
appears to be associated with improved efficacy.  Volunteers with nasal maximum 
concentration greater than the median value had shorter time to resolution of viral 
shedding compared with volunteers in the placebo group (median: 75.8 hours vs. 
113.7 hours).  However, volunteers with a nasal maximum concentration less than 
the median value had similar time to resolution of viral shedding compared with 
volunteers in the placebo group (median 113.7 hours vs 112.1 hours). 
 
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The Phase 2a challenge study (GV28985) confirmed proof of activity in decreasing area 
under viral load-time curve, consistent with symptom data at the 3600-mg dose level.  
GV29216 will assess severely ill patients who may be infected with various influenza 
strains, have a higher viral burden and longer duration of viral shedding than the 
healthy volunteers in Study GV28985, and who may, therefore, require doses higher 
than 3600-mg.  As a result, an ongoing, Phase 1 (GV29609) study was initiated to 
evaluate the safety and tolerability of two single IV doses of 8400 mg and 10800 mg 
MHAA4549A as compared to placebo when administered to 14 healthy volunteers.  The 
starting dose of 8400 mg was selected based on simulations from a semi-quantitative 
PK model (Figure 2) developed from the Phase 2a challenge study, which suggests that 
8400 mg may be the minimum dose that is expected to show a separation of nasal 
exposure from a dose of 3600 mg.  This simulation assumes that pharmacokinetics can 
be extrapolated at doses above 3600 mg and that the PK profile in severely ill patients is 
similar to the PK profile of healthy volunteers in the Phase 2a challenge study.  The 
highest proposed dose of 10800 mg was chosen in GV29609 to provide safety coverage 
for those exposures that might be reached in a 40-kg individual dosed with a flat dose of 
8400 mg.  Preliminary analysis of unblinded safety data up to day 57 shows that the 
8400 mg and 10800 mg treatment groups are safe and well tolerated.  In subjects who 
received 8400 mg MHAA4549A, 3 of 4 subjects reported 12 AEs.  In subjects who 
received 10800 mg MHAA4549A, 4 of 4 subjects reported 7 AEs.  In subjects who 
received placebo, 2 of 6 subjects reported 5 AEs.  All AEs were reported as mild except 
for an unrelated moderate AE of an increase in creatinine kinase in one subject who 
received 10800 mg MHAA4549A.  There were no SAEs and no subjects have 
discontinued the study for any reason.  Headache was the most common adverse event. 
Headache was reported by 3 subjects (37.5%) who received 8400 mg MHAA4549A, 
1 subject (12.5%) who received 10800 mg MHAA4549A, and 2 subjects (33.0%) who 
received placebo. 
Nonclinical safety data do not show any expected or unexpected toxicity.  Weekly 
administration of MHAA4549A (total of 5 doses) in Sprague-Dawley rats was well 
tolerated up to 150 mg/kg (the highest dose tested).  Ex vivo tissue cross-reactivity 
study data showed no specific binding of MHAA4549A to any of the human or rat 
tissues examined.  
Therefore, the 8400-mg dose is expected to be safe based upon previous nonclinical and 
clinical safety assessments and will be included in this Phase 2b study for further dose 
ranging.  
Although the Phase 1 study (GV28916) was conducted using body-weight based dosing, 
the subsequent Phase 2a study (GV28985) and high-dose Phase 1 study GV29609 used 
a fixed dosing strategy.  Thus, the fixed dosing regimen will be used for this study, given 
the comparable MHAA4549A PK profiles, the practical advantages, and the positive 
safety profile of MHAA4549A to date.  Further, fixed dosing is generally recommended 
 
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with monoclonal antibodies, due to their minimal PK variability (Bai et al. 2012).  The PK 
variability introduced by different dosing regimens (i.e., body-weight based dosing 
versus fixed dosing) is moderate relative to the variability generally observed in 
pharmacodynamics, efficacy, and safety and would not be expected to be clinically 
meaningful.   
Figure 2 Predictions from a Semi-Quantitative Pharmacokinetic Model of 
Nasal Exposure 
  
Note:  The bottom and top of the box represent the 25th and 75th percentile, and the band 
inside the box is the median.  The upper whisker is the 1.5 interquartile range (IQR) of 75th 
percentile and the lower whisker is the 1.5 IQR of 25th percentile.  The dot is an outlier. 
  
3.2.5 
Rationale for Biomarker Assessments 
 
  
 
 
 
 
 
 
 
 
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3.3 
OUTCOME MEASURES  
3.3.1 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
AEs and clinical laboratory abnormalities  
• 
Vital signs, physical findings, ATAs, and clinical laboratory results during and 
following administration of MHAA4549A 
 
3.3.2 
Primary Efficacy Outcome Measures 
The primary efficacy outcome measures for this study are as follows: 
• 
Time to normalization of respiratory function defined as: 
– 
The time to cessation of O2 support resulting in a stable SpO2 ≥95% (see 
Appendix 2 for details) 
 
3.3.3 
Secondary Efficacy Outcome Measures 
The secondary efficacy outcome measures for this study are as follows: 
• 
Clinical failure after 24 hours post-infusion of study drug; defined as: 
– 
Progression to increased O2 requirement defined by an increase in oxygen 
supplementation from low flow oxygen (2 − 6 L/min) to high flow oxygen 
(> 6 L/min) or from oxygen supplementation alone to any PPV or extracorporeal 
membrane oxygenation (ECMO) 
– 
Progression to ICU 
– 
Prolonged ventilation or O2 support defined by > 2 weeks, or 
– 
Death 
• 
Time to clinical resolution of vital signs (3/5 criteria must be met): 
– 
SpO2 ≥95% without supplemental O2  
– 
Respiratory rate < 24 breaths per minute without supplemental O2  
 
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– 
Core temperature < 37.2°C immediately prior to receipt of any antipyretic drug, 
and at least 6-8 hours from the last dose of antipyretic or core 
temperature > 36°C in patients who are initially hypothermic 
– 
Heart rate (HR) < 100 beats/minute 
– 
Systolic blood pressure (SBP) > 90 mmHg 
• 
All-cause mortality at Day 14, Day 30, and Day 60 
• 
Influenza A viral load in nasopharyngeal samples   
– 
AUEC (qPCR) 
– 
Peak viral load (qPCR) 
– 
Time to resolution of infection (qPCR) 
– 
  
• 
Duration of hospitalization 
• 
Duration of ICU stay 
• 
Antibiotic usage for respiratory infections 
• 
Complications of influenza: 
– 
Pneumonia (HAP/VAP) 
– 
Exacerbations of chronic lung disease 
– 
Myocarditis 
– 
ARDS 
– 
Otitis media 
– 
Other related complications 
• 
All-cause readmission at Day 30 and Day 60 
• 
Duration of ventilation 
 
3.3.4 
Pharmacokinetic Outcome Measures 
The primary PK outcome measures for this study are as follows: 
• 
PK parameters for MHAA4549A in serum including total exposure (i.e., AUC), 
maximum observed concentration (Cmax), clearance, half-life, and volume of 
distribution, when appropriate, as data allow   
 
The exploratory PK outcome measures for this study are as follows: 
 
 
 
 
 
 
 
 
 
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3.3.5 
Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
This study aims to enroll approximately 330 men and women and is designed to assess 
the safety and clinical activity of a single IV administration of 3600 mg MHAA4549A or a 
single IV administration of 8400 mg MHAA4549A in adult patients hospitalized with severe 
influenza A.   
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Hospitalized men or women ≥ 18 years of age on the day of signing the informed 
consent or obtaining surrogate consent from an authorized representative 
 
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• 
Diagnosis of influenza A where a Sponsor-approved influenza test is used as an aid in 
diagnosis.  A Sponsor-approved influenza test includes: 
– 
Influenza antigen test –OR– 
− 
Influenza PCR test 
• 
One of the following markers of severity within 24 hours of hospital admission: 
– 
Requirement for PPV − OR −  
– 
Requirement for O2 supplementation to maintain SpO2 > 92% 
• 
A negative urine or serum pregnancy test for women of child-bearing potential 
• 
Patients of reproductive potential must agree to use reliable means of contraception 
as described below as a minimum (adherence to more stringent local requirements 
may be required): 
– 
For women who are not postmenopausal (postmenopausal defined as 
≥ 12 months of non-therapy-induced amenorrhea) or surgically sterile 
(absence of ovaries and/or uterus):  agreement to remain abstinent or use two 
adequate methods of contraception, including at least one method with a 
failure rate of < 1% per year, during the treatment period and for at least 120 
days after the last dose of 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. 
Barrier methods must always be supplemented with the use of a spermicide. 
Examples of contraceptive methods with a failure rate of < 1% per year include 
tubal ligation, male sterilization, hormonal implants, proper use of combined 
oral or injected hormonal contraceptives, and certain intrauterine devices. 
Male partners who have had a vasectomy should have the appropriate 
post-vasectomy documentation available of the absence of sperm in the 
ejaculate.  The vasectomized male partner should be the sole partner for that 
patient. 
− 
For men:  agreement to remain abstinent or use a condom during the 
treatment period and for at least 30 days after the last dose of study drug and 
agreement to refrain from donating sperm during this same period 
Men with a pregnant partner must agree to remain abstinent or use a condom 
for the duration of the pregnancy. 
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. 
− 
Non-reproductive potential is defined below (but could be superseded by local 
definitions, if they are more stringent): 
 
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Women who are postmenopausal (i.e., spontaneous amenorrhea for the past 
year confirmed by a follicle stimulating hormone [FSH] level greater than 
40 mIU/mL unless the patient is receiving a hormonal therapy for their 
menopause)  
Women who are surgically sterile (i.e., hysterectomy, complete bilateral 
oophorectomy) 
Men who are surgically sterile (i.e., castration) 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Pregnant or lactating, or intending to become pregnant during the study 
– 
Women who are not postmenopausal (postmenopausal defined as ≥ 12 months 
of non-therapy-induced amenorrhea) or surgically sterile must have a negative 
serum pregnancy test result within 2 days prior to initiation of study drug. 
• 
Hypersensitivity to monoclonal antibodies or to the active substance or any 
excipients of MHAA4549A study drug 
• 
Hypersensitivity to the active substance or to any excipients of oseltamivir 
• 
Investigational therapy within the 30 days prior to study treatment  
• 
Received prior therapy with any anti-influenza monoclonal antibody therapy 
(including MHAA4549A) 8 months prior to study treatment 
• 
Current treatment (within 7 days of dosing) with probenecid, amantadine, or 
rimantidine 
• 
Patients who have taken more than a total of 6 doses (3 doses of peramivir) of 
anti-influenza therapy (e.g., oseltamivir, zanamivir, peramivir) in the period from 
onset of symptoms and prior to study treatment 
• 
Admission > 48 hours prior to study treatment 
• 
Onset of influenza symptoms (including fever, chills, malaise, dry cough, loss of 
appetite, myalgias, coryza, or nausea) > 5 days prior to study treatment  
• 
Positive influenza B or influenza A + B infection within 2 weeks prior to study 
treatment 
• 
High probability of mortality in the next 48 hours as determined by the investigator  
• 
Patient requiring home or baseline oxygenation therapy 
• 
Patient with history of chronic lung disease resulting in baseline SpO2 ≤ 95%  
• 
Patient on a chronic dose of corticosteroids exceeding 10 mg/day of prednisone or 
equivalent steroid dose for a duration of greater than 14 days within 30 days of entry 
into study 
• 
Creatinine clearance ≤10 mL/min 
• 
Patients who received nasally administered influenza A vaccine within the last 
7 days 
 
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 
Patients with the following significant immune suppression:  
– 
Bone marrow or solid organ transplant in the previous 12 months 
– 
Cancer chemotherapy in the previous 12 months 
– 
HIV infection with most recent CD4  200 cells/mL 
– 
Other significant immune suppression as determined by the investigator in 
discussion with the Sponsor Medical Monitor or representative 
 
Patient on ECMO at time of randomization 
 
Any disease or condition that would, in the opinion of the site investigator or 
Sponsor, place the subject at an unacceptable risk of injury or render the subject 
unable to meet the requirements of the protocol 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
The randomization of patients will be managed by a central Interactive Voice and Web 
Response System (IxRS) through use of a dynamic hierarchical algorithm which 
includes a random component.  The treatment assignments will be unblinded to selected 
Sponsor personnel to facilitate ongoing monitoring of safety and tolerability, including 
members of the IMC and SOC.  
All patients will be randomly assigned to receive 3600 mg MHAA4549A, 8400 mg 
MHAA4549A, or placebo at a 1:1:1 ratio stratified by country, whether patient is on 
PPV vs supplemental O2 at randomization, and whether the patient has suspected or 
confirmed bacterial pneumonia vs no bacterial pneumonia at randomization.  Initially 
GV29216 randomly assigned patients to receive either 3600 mg MHAA4549A, or 
placebo at a 1:1 ratio.  The updated randomization scheme takes into account the 
numbers already allocated to these two arms and strata prior to allocating to the three 
arm design so that by the end of the study there will be an approximate 1:1:1 allocation 
between the three arms.  
All patients will receive oseltamivir (as described in Table 2) for a minimum of 5 days.  
Treatment for longer than 5 days is permitted based on local investigator discretion. 
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, 
as described in Section 4.3.3.  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.  


 
Bioanalytical laboratory 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 (e.g., to evaluate a possible error in study drug administration). 
If unblinding is necessary for patient management (e.g., in the case of a SAE for which 
patient management might be affected by knowledge of treatment assignment), the 
investigator will be able to break the treatment code in IxRS.  Treatment codes should 
not be broken except in emergency situations.  If the investigator wishes to know the 
identity of the study drug for any other reason, they should 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 SAE). 
For regulatory reporting purposes, and if required by local health authorities, the 
Sponsor will break the treatment code for all suspected unexpected serious adverse 
reactions (SUSAR)(see Section 5.4) that are considered by the investigator or Sponsor 
to be related to study drug. 
4.3 
STUDY TREATMENT  
4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
MHAA4549A and Placebo 
The Sponsor will supply MHAA4549A and matching placebo.  For information on the 
formulation, packaging, and handling of MHAA4549A and placebo, see the Pharmacy 
Manual and the MHAA4549A Investigator's Brochure. 
The MHAA4549A vial delivers 10 mL (500 mg) of drug product solution, but may contain 
more (approximately 10.3 mL) than the stated volume to enable delivery of the entire 
10 mL volume.  MHAA4549A is formulated as 50 mg/mL in 10 mM sodium succinate, 
240 mM sucrose, and 0.02% (w/v) polysorbate 20 at pH 5.5 and is contained in a 15 mL 
forma vitrum (USP/PH. Eur. Type 1) glass vial.  The drug product is suitable for single 
use only and contains no preservatives. 
Placebo for MHAA4549A has the same composition as the drug product (without 
MHAA4549A) and is supplied in an identical vial configuration.  The placebo contains no 
preservatives and is suitable for single-use only.  Placebo is formulated as 10 mM 
sodium succinate, 240 mM sucrose, and 0.02% polysorbate 20 at pH 5.5 in a total 
volume of 10 mL in a 15 mL forma vitrum (USP/PH. Eur. Type 1) glass vial. 
MHAA4549A and placebo are supplied in identical blinded vials labeled with unique kit 
numbers.  IxRS will assign kit numbers for each treatment arm; all treatment arms will be 
assigned the same total number of vials for each treatment, and the same preparation 
instructions.  Placebo is identical to active MHAA4549A in formulation but does not 
contain active drug substance. 
 
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79/Protocol GV29216, Version 5 (Global)   


 
4.3.1.2 
Oseltamivir (Tamiflu®) 
Oseltamivir (Tamiflu®) is an influenza NAI indicated for treatment of acute, 
uncomplicated influenza.  The Sponsor will provide oseltamivir capsules for up to a 
10-day treatment course.  For information on the formulation, packaging, and handling of 
oseltamivir; see the local prescribing information for oseltamivir. 
Storage: Capsules should be stored at 25°C (77.7°F); excursions permitted to 15° to 
30°C (59° to 86°F). 
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 3600 mg IV or 
MHAA4549A 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 will be on site during study drug administration for all 
patients. 
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 0.22 µm in-line filter.  Compatibility testing has shown that 
MHAA4549A is stable when diluted in 0.9% normal saline in a polyvinylchloride bag, 
polyolefin bag, or ethylene vinyl acetate bag (EVA), at concentrations 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 for preparation of study drug can be found 
in the Pharmacy Manual.   
There are no recommended dosage modifications for MHAA4549A since it is a single 
infusion.  Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  AEs 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 AEs associated 
with overdose.  Patients experiencing such AEs 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.  
 
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80/Protocol GV29216, Version 5 (Global)   


 
4.3.2.2 
Oseltamivir-Neuraminidase Inhibitor (NAI)  
The Sponsor will supply oseltamivir (Tamiflu®) for this study for up to a 10-day course.  
Either 75 mg or 150 mg of oseltamivir will be administered twice daily as described in 
Section 3.1.1.  Capsules can be opened and the granules administered via nasogastric 
tube, if required.  Doses should be captured in the eCRF.  
Any overdose or incorrect administration of oseltamivir should be noted on the 
oseltamivir Administration eCRF.  AEs associated with an overdose or incorrect 
administration of oseltamivir should be recorded on the Adverse Event eCRF. 
Patients who are discharged from the hospital with oseltamivir will be required to 
complete a medication diary and return the medication diary, empty (used) oseltamivir 
packets and unused oseltamivir capsules to the study site at the next follow up visit.  
Patients will record the date and time when each oseltamivir capsule is administered. 
4.3.3 
Investigational Medicinal Product Accountability 
Investigational medicinal products (IMPs) required for completion of this study (i.e., 
MHAA4549A and oseltamivir) 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 to 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 to 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. 
The total duration from the preparation of dose solutions to the end of infusion should 
not exceed 24 hours.  Vials are intended for single use only; therefore, any remaining 
solution should be discarded (see the Pharmacy Manual).  
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 or their delegate with the 
appropriate documentation.  The site's method of IMP destruction must be agreed to by 
 
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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. 
4.4 
POST-TRIAL ACCESS TO MHAA4549A 
As this is single dose administration, Genentech 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 
4.5 
CONCOMITANT THERAPY AND FOOD 
4.5.1 
Permitted Therapy  
Concomitant medication 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 
concomitant medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF.  For any NAIs (e.g., oseltamivir, peramivir, zanamivir, 
laninimavir) that have been taken prior to study drug therapy, the number of doses and 
duration of therapy must be recorded. 
Patients who use oral contraceptives, hormone-replacement therapy, or other 
maintenance therapy should continue their use. 
All therapies required for management of the patient’s acute illness are permitted except 
for those listed below in Section 4.5.2. 
4.5.2 
Prohibited Therapy 
Use of the following therapies is prohibited during the study and for at least 7 days prior 
to study treatment, unless otherwise specified below:  probenecid, amantadine, or 
rimantidine. 
Use of other NAIs, including but not limited to oseltamivir, zanamivir, and peramivir, are 
prohibited during the study, but allowed up to a total of 6 doses (3 doses for peramivir) 
in the period from onset of symptoms and prior to study treatment as outlined in the 
exclusion criteria.  Patients must start standard-of-care oseltamivir no later than 
8 hours after completion of MHAA4549A administration.  If oseltamivir resistance is 
highly suspected or identified during treatment or if oseltamivir route of administration 


 
challenges are encountered then, following discussion with the Sponsor’s medical 
representative, an alternative NAI to oseltamivir may be used. 
 
4.5.3 
Prohibited Food 
There are no prohibited foods for this study.  
4.6 
STUDY ASSESSMENTS  
Please see Appendix 1a and Appendix 1b for the schedule of assessments performed 
during the study. 
4.6.1 
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.  Informed consent by 
authorized representatives may be obtained only if allowed by and in accordance with 
local regulations and Independent Review Board (IRB)/Independent Ethics Committee 
(IEC) policies and procedures.  Informed Consent Forms (ICF) 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. 
4.6.2 
Diagnostic Testing for Enrollment 
All hospitalized patients with severe influenza A must be assessed for disease 
confirmation prior to and enrollment into the study.  A Sponsor-approved influenza test is 
required as an aid in the diagnosis of influenza A infection.  This requires a 
nasopharyngeal swab be introduced into one nostril.  Note that the influenza antigen 
test or influenza PCR test result must be available within the 48 hour screening window.   
4.6.3 
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.  A careful assessment of the patient’s baseline SpO2 will be made 
especially if the patient has a history of severe chronic lung disease. 
Demographic data will include age, sex, and self-reported race/ethnicity. 
 
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4.6.4 
Priority of Assessments 
When events warrant, or in the opinion of the investigator, safety issues become 
paramount, safety assessments will always have priority over all other measurements 
and procedures.  Under routine circumstances, however, PK, nasal virological, and 
biomarker serum/plasma samples have priority over other measurements.  The timing 
and number of safety measurements may be modified based on clinical evaluations. 
Assessments on Day 1 must be concluded prior to dosing as specified in Appendix 1a.  
Any screening assessments completed prior to consent as standard of care do not need 
to be repeated if done within the screening period. 
4.6.5 
 
 
 
  
 
  
 
  
4.6.6 
 
 
 
 
 
 
  
 
4.6.7 
Physical Examinations 
A complete physical examination 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 protocol designated visits (or as clinically indicated), limited, symptom-directed 
physical examinations should be performed which include, 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, if appropriate, on the 
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4.6.8 
Vital Signs 
Vital signs will include measurements of respiratory rate, pulse rate, temperature, and 
systolic and diastolic blood pressures after the patient has been in a seated or supine 
position for > 5 minutes.  Patients in intensive care may have vital signs assessed 
following local procedures, but those procedures should be captured in the eCRF in 
accordance with the eCRF instructions. 
4.6.9 
Oxygen Saturation Measurements 
To ensure that the respiratory status is well recorded, the following daily measurements 
will be performed.  Unless clinically contraindicated, all patients will have their SpO2 and 
corresponding respiratory assessments recorded daily in the morning between 
6 am − 12 pm local time.  Patients on low flow O2 will have a daily trial of their SpO2 while 
on and off the supplementation, as outlined in Appendix 2, and both values will be 
recorded.  
If the patient is on oxygen supplementation, SpO2 measured by pulse oximetry and the 
corresponding respiratory assessments (e.g., FiO2, flow rate) will be recorded.  If the 
patient is on PPV, partial pressure of arterial O2 (PaO2) and the corresponding 
respiratory assessments (e.g., FiO2, ventilator mode, ventilator respiratory rate, positive 
end expiratory pressure) will be recorded.  If clinically appropriate (i.e., the patient is 
on non-invasive PPV), the conversion table in Appendix 11 may be used for PaO2.  
4.6.10 
Laboratory, Biomarker, and Other Biological Samples 
Samples for the laboratory tests listed in Table 3 and Table 4 will be sent to the study 
site's local laboratory for analysis at screening and during the study, respectively. 
Table 3 
Laboratory Tests at Screening 
Hematology: 
Clinical Chemistry: 
Hemoglobin 
Thyroid stimulating hormone (optional) 
Hematocrit 
 
Erythrocyte count (RBC) 
Serology: 
Leukocytes (WBC) 
HIV Serology 
Neutrophils, segmented & bands 
 
Lymphocytes 
Misc: 
Monocytes 
Pregnancy Test (urine or serum; women of 
child-bearing potential) 
Eosinophils 
Basophils 
 
Platelets 
 
Note:  Investigators must document their review of each laboratory report by signing (or 
initialing) and dating each report. 
  
 
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Table 4 
Laboratory Tests During the Study 
Hematology: 
Clinical Chemistry (Blood):  
Hemoglobin 
Sodium 
Hematocrit 
Potassium 
Erythrocyte count (RBC) 
Bicarbonate 
Leukocytes (WBC) 
Chloride 
Neutrophils, segmented & bands 
Calcium 
Lymphocytes 
Phosphorus 
Monocytes 
Magnesium 
Eosinophils 
Glucose  
Basophils 
Urea nitrogen (BUN) or urea 
Platelets 
Creatinine 
 
Total cholesterol 
 
Total protein 
Coagulation:  
Albumin 
Activated partial thromboplastin time (APTT) 
Total bilirubin 
Prothrombin time (PT) 
Alkaline phosphatase 
International Normalized Ratio (INR) 
Aspartate aminotransferase (AST) 
 
Alanine aminotransferase (ALT) 
Urinalysis: 
Amylase 
pH 
Gamma-glutamyl transpeptidase (GGT) 
 (if clinically indicated) 
Specific gravity 
Glucose 
C-reactive protein (CRP) (optional) 
Protein 
Erythrocyte Sedimentation Rate (ESR) 
(optional) 
Ketones 
Blood 
 
Bilirubin 
Misc:  
Nitrite 
Pregnancy Test (if clinically indicated) 
Leukocyte esterase 
 
Microscopic examination (if clinically indicated) 
Note:  Investigators must document their review of each laboratory report by signing (or initialing) 
and dating each report. 
  
The following samples will be sent to the Sponsor or a designee for PK or ATA analysis: 
• 
 
• 
Serum samples for ATA testing (see Appendix 1a and Appendix 1b)  
 
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 
 
 
 
Samples for exploratory research assays will be collected as described in the Schedule 
of Assessment (see Appendix 1a and Appendix 1b).   
 
 
 
 
   
 
 
 
 
 
 
 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.   
4.6.11 
Electrocardiograms 
Single ECG recordings will be obtained at specified timepoints, as outlined in the 
schedule of assessments (see Appendix 1a and Appendix 1b), 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 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:  HR, 
RR interval, QRS interval, PR duration, uncorrected QT interval, and QTcF 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 QT interval corrected using 
Fridericia’s formula (QTcF) has stabilized on two successive ECGs.  The Medical 
Monitor should be notified.  If QTcF is not available, QTcB may be recorded.  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 4.9.2.  
The investigator should also evaluate the patient for potential concurrent risk factors 
(e.g., electrolyte abnormalities, medications known to prolong the QT interval, severe 
bradycardia). 
4.6.12 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.6.12.1 
 
 
 
 
 
 
 
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4.6.12.2 
  
 
 
 
 
 
 
 
 
 
  
4.6.12.3 
 
 
 
 
 
 
 
 
 
  
4.6.12.4 
 
 
 
4.7 
APACHE AND SOFA SCORES 
Acute Physiology and Chronic Health Evaluation (APACHE) and Sequential Organ 
Failure Assessment (SOFA) scores are for patients that are admitted into the ICU.  
These assessments are not required for study conduct or entry but should be collected if 
available.  The initial scores for APACHE and SOFA should be taken within 24 hours of 
entry into the ICU and at the time points specified in Appendix 1a. 
 
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For the calculation of the initial APACHE and SOFA scores, the worst values in the first 
24 hours of ICU admission should be used.  SOFA scores are only for patients admitted 
into the ICU that have available data for calculation (i.e., partial pressure of arterial 
oxygen/fraction of inspired oxygen [PaO2/FiO2] in mmHg).  See Appendix 7 for SOFA 
score calculation. 
4.8 
OSELTAMIVIR MEDICATION DIARY 
Patients who are discharged from the hospital with oseltamivir will be required to 
complete a medication diary and return the medication diary, empty (used) oseltamivir 
packets, and unused oseltamivir capsules to the study site at the next follow up visit.  
Patients will record the date and time when each oseltamivir capsule is administered.  
4.9 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
4.9.1 
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 or 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 from the study will not be replaced. 
4.9.2 
Study Treatment Discontinuation 
Patients must discontinue MHAA4549A infusion and therefore treatment if they 
experience any of the following: 
• 
Life threatening infusion-related reactions  
 
Patients must discontinue oseltamivir treatment if they experience any of the following: 
• 
Pregnancy 
• 
Serious skin/hypersensitivity reactions 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.   
The IMC and SOC may recommend to permanently discontinue dosing for all patients 
within one or both study arms in the event of a general safety concern. 
 
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4.9.3 
Study Completion/Early Discontinuation Visit 
Patients who complete all study visits through Day 60 are considered to have completed 
study.  All patients who discontinue from the study early will be asked to complete all 
assessments for the early discontinuation visit.  Please see Schedule of Assessments 
provided in Appendix 1a for assessments performed at the Study Completion/Early 
Discontinuation visit. 
4.9.4 
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 AEs 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 (GCP) 
• 
No further study activity (i.e., all patients have completed and all obligations have 
been fulfilled) 
 
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 (interim) studies and is 
designed to ensure patient safety.  It will include specific eligibility criteria and monitoring 
assessments as detailed below and in Section 4.1. 
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. 
 
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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 and SOC agreement.  
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and non-serious adverse events of special interest; 
measurement of protocol specified safety laboratory assessments; measurement of 
protocol-specified vital signs; and 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. 
5.2.1 
Adverse Events 
According to the ICH guideline for GCP, an adverse event is any untoward medical 
occurrence in a clinical investigation patient 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 5.3.5.9. 
• 
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 60 
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: 
• 
Fatal (i.e., the adverse event actually causes or leads to death) 
 
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• 
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 5.3.5.10) 
• 
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) 
• 
Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
• 
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 
listed above) 
 
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 Division of 
AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS); see 
Section 5.3.3, Appendix 8, and Appendix 9); 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 
Non-Serious Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) 
Non-serious adverse events of special interest (AESI) 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 5.3.5.6) 
• 
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 
 
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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 AEs 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 
 
Anaphylaxis due to IV drugs most often presents with the following signs and symptoms:   
• 
Cutaneous symptoms: flushing, itching, urticaria, 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: such as 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 Section 5.4− 5.5.  
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. 
 
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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, regardless of relationship to study 
drug, will be reported until the Day 60 visit or 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 5.5). 
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 5). 
Table 5 
Adverse Event Grading (Severity) Scale 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE-
THREATENING 
ESTIMATING SEVERITY GRADE 
Clinical AE 
NOT identified 
elsewhere in 
this DAIDS AE 
Grading Table  
Symptoms 
causing no or 
minimal 
interference with 
usual social and 
functional 
activities 
Symptoms 
causing greater 
than minimal 
interference with 
usual social & 
functional 
activities 
Symptoms 
causing 
inability to 
perform usual 
social & 
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 
AE = adverse event; 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 or 
 
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not 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 6): 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, considering especially 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 6 
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., chronic obstructive pulmonary disease [COPD] 
diagnosed 2 days after first dose of study drug). 
 
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
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 
Diagnosis versus Signs and Symptoms 
Infusion-Related Reactions  
Adverse events that occur during or within 24 hours after study drug infusion should be 
captured as individual signs and symptoms rather than a diagnosis of allergic reaction or 
infusion reaction. 
 
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Other Adverse Events 
For adverse events other than infusion-related reactions, 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 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. 
5.3.5.2 
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. 
5.3.5.3 
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.  If a persistent adverse event 
becomes more severe, it should be recorded 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 event became more severe.  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; see Section 5.4.2 for reporting 
 
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instructions).  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 event became 
serious. 
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. 
5.3.5.4 
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 meets any of the following criteria: 
• 
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 
• 
Clinically significant in the investigator’s judgment (laboratory abnormalities should 
be repeated at the first opportunity and only considered clinically significant if they 
persist on repeat assessment) 
 
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 × upper limit of normal [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 not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
 
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changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 
5.3.5.5 
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 meets any of the following criteria: 
• 
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 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). 
5.3.5.6 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × baseline value) 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.  
Therefore, investigators must report as an adverse event the occurrence of either of the 
following: 
• 
Treatment-emergent ALT or AST > 3 × baseline value in combination with total 
bilirubin > 2 × ULN (of which  ≥ 35% is direct bilirubin) 
• 
Treatment-emergent ALT or AST > 3 × baseline value 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 a non-serious adverse event of special 
interest (see Section 5.4.2). 
 
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5.3.5.7 
Deaths 
For this protocol, mortality is an efficacy endpoint.  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 severe influenza or any related co-morbidities 
should be recorded 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 as an SAE (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 
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. 
5.3.5.8 
Preexisting 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.  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"). 
5.3.5.9 
Lack of Efficacy or Worsening of Influenza A Infection 
Medical occurrences or symptoms of deterioration that are anticipated as part of 
influenza A should only 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 "). 
 
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5.3.5.10 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization following initial discharge (i.e., in-patient 
admission to a hospital) or prolonged hospitalization (after the current study 
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 
• 
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 that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
5.3.5.11 
Adverse Events Associated with an Overdose 
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 serious 
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 clinical 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. 
5.4 
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) 
• 
Non-serious adverse events of special interest (see Section 5.4.2 for further details) 
 
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• 
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 IRB/EC. 
5.4.1 
Emergency Medical Contacts 
Medical Monitor Contact Information  
 Medical Monitor contact information: 
Primary Medical Monitor: 
 
Telephone Nos.: 
US Office: 
 
 
US Mobile: 
 
 
Secondary Medical Monitor: 
  
Telephone Nos.: 
US Office: 
 
 
US Mobile: 
 
 
Genentech Medical Monitor contact information for all sites if above medical monitor 
cannot be reached: 
Medical Monitor: 
 
Telephone Nos.: 
US Office 
 
 
US Mobile 
 
 
 
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5.4.2 
Reporting Requirements for Serious Adverse Events and 
Non-Serious 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.  
A paper Serious Adverse Event / Adverse Event of Special Interest Reporting Form 
should be completed and faxed or scanned and emailed to the Sponsor's Safety Risk 
Management department or its designee immediately (i.e., no more than 24 hours after 
learning of the event), using the contact information below per region: 
Region 
Fax Number 
Email Address 
Asia Pacific 
 
 
Europe 
 
Latin America 
 
North America 
 
5.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events and non-serious adverse events of 
special interest will be reported until the patient is at Day 60 or Early Discontinuation.  
Although the investigator is not required to actively monitor patients for adverse events 
after the patient has been discharged from the study, the Sponsor should be notified if 
the investigator becomes aware of any death or other serious adverse event that occurs 
after discharge from the study, if determined to be related to study drug by the 
investigator.  The Sponsor should also be notified if the investigator becomes aware of a 
congenital anomaly/birth defect in a subsequently conceived offspring of a female 
patient exposed to study drug (see Section 5.4.3.3).   
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, a paper Serious Adverse Event / 
Adverse Event of Special Interest Reporting Form should be completed and faxed or 
scanned and emailed to Safety Risk Management or its designee immediately (i.e., no 
more than 24 hours after learning of the event), using the contact information provided to 
investigators (see 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 5.4. 
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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 after the last 
dose of study drug.  A Pregnancy Report eCRF should be completed by the investigator 
immediately (i.e., no more than 24 hours after learning of the pregnancy) and submitted 
via the EDC system.  A pregnancy report will automatically be generated and sent to 
Safety Risk Management.  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 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 the event that the EDC system is unavailable, a paper Clinical Trial Pregnancy 
Reporting Form should be completed, faxed, or scanned and emailed to Safety Risk 
Management or its designee immediately (i.e., no more than 24 hours after learning of 
the pregnancy), using the contact information provided to investigators (see 
Section 5.4.2.1).  Once the EDC system is available, all information will need to be 
entered and submitted via the EDC system. 
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 within 30 days after the dose of 
study drug.  A Pregnancy Report eCRF should be completed by the investigator 
immediately (i.e., no more than 24 hours after learning of the pregnancy) and submitted 
via the EDC system.  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.  Once the 
authorization has been signed, the investigator will update the Pregnancy Report eCRF 
with additional information on the course and outcome of the pregnancy.  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. 
In the event that the EDC system is unavailable, follow reporting instructions provided in 
Section 5.4.2.1. 
5.4.3.3 
Congenital Anomalies/Birth Defects and Abortions 
Any congenital anomaly/birth defect in a child born to a female patient or female partner 
of a male patient exposed to study drug should be classified as a serious adverse event, 
 
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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. 
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.  
If the EDC system is not available at the time of pregnancy outcome, follow reporting 
instructions provided in Section 5.4.3. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, non-serious 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 
POST-STUDY ADVERSE EVENTS 
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 
60 days (see Section 5.3.1) after the last dose of study drug), if the event is believed to 
be related to prior study drug treatment.   
The investigator should report these events directly to Roche, 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 
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5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events including suspected 
unexpected serious adverse reactions (SUSARs) and non-serious adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, IECs, 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 documents: 
• 
MHAA4549A Investigator's Brochure 
• 
Local prescribing information for oseltamivir 
 
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. 
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 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 
All 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: 
• 
Randomized patients who have confirmed influenza A infection as confirmed by a 
central PCR test from Day 1 samples 
 
Safety analyses will include all patients who were included in the randomization and who 
received at least one dose of study medication, with patients allocated to the treatment 
arm associated with the regimen actually received.  
 
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No formal hypothesis testing will be done in this study.  As a result, no adjustment for a 
type 1 error will be made to account for the multiplicity of analyses. 
Results will be presented both for the MHAA4549A 3600 mg and 8400 mg treatment 
groups separately and combined for the purpose of comparison to standard of care. 
Final efficacy and safety analyses of the total study population will be conducted at the 
end of the study after all patients have completed all study assessments and the 
database has been cleaned and closed.  Further details of the analyses, including 
analysis of the exploratory endpoints, will be contained in the statistical analysis plan 
(SAP) which will be prepared and finalized before the first optional interim analysis (see 
Section 6.7) or the final efficacy and safety analysis, if no interim analysis takes place.   
6.1 
DETERMINATION OF SAMPLE SIZE 
The purpose of this study is estimation of the effect size and hypothesis generation 
regarding the effect of MHAA4549A on the time to normalization of respiratory function 
relative to the standard of care rather than hypothesis testing.  Point and interval 
estimates will be obtained.  Approximately 330 patients will be enrolled.  It is assumed 
that the median time to normalization of respiratory function in the control arm is 5 days.  
This sample size (approximately 110 patients per arm) provides 71% power to detect a 
treatment difference of 1 day for the primary endpoint in both MHAA4549A arms 
assuming a 2-sided alpha of 0.2 and no difference in efficacy between the two active 
arms.  If the 3600-mg dose shows a treatment difference of 1 day and the 8400-mg dose 
shows a treatment difference of 1.5 days or more then this sample size provides  86% 
power assuming a 2-sided alpha of 0.2. 
Operating characteristics (power) under other possible assumptions for 2-sided alpha of 
0.2 and true differences of 0.5 to 2 days are provided in Table 7.   
Table 7 
Operating Characteristics for Proposed Study Design for Several 
Possible True Underlying Median Values 
 
True Underlying Median for MHAA4549A 
3600 mg 8400 mg 3600 mg 8400 mg 3600 mg 8400 mg 3600 mg 8400 mg
4 days 
4 days 
4 days 
3.5 days
4 days 
3 days 
4.5 days
4 days 
Hazard Ratio 
0.8 
0.8 
0.8 
0.7 
0.8 
0.6 
0.9 
0.8 
Power of log-rank test a 
71.4% 
86.6% 
98.8% 
56.2% 
Note:  Operating characteristics are based on the following assumptions:  330 evaluable 
patients, event times are exponentially distributed, median time to normalization of 
respiratory function in the control arm is 5 days, and patients are followed for 60 days. 
a Two-sided   0.20. 
  


 
It should be noted that the study is underpowered for detection of minimally clinically 
meaningful differences at a 2-sided alpha of 0.05 such as a true hazard ratio of 0.80 in 
both MHAA4549A arms.   
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 
EFFICACY ANALYSES 
The primary and secondary 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. 
Time to event data will be computed using Kaplan-Meier methodology and stratified Cox 
proportional hazards models 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. 
6.4.1 
Primary Efficacy Endpoint 
• 
Median time to normalization of respiratory function. 
 
 
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6.4.2 
Secondary Efficacy Endpoints 
• 
Proportion of patients with clinical failure after 24 hours post-infusion of study drug 
• 
Median time to clinical resolution of vital signs 
• 
Hazard ratio for mortality at Day 14, Day 30, and Day 60 
• 
Mean and median AUC of viral load 
• 
Mean and median peak viral load 
• 
Median duration of viral shedding in nasopharyngeal samples 
• 
Median duration of hospitalization 
• 
Median duration of ICU stay 
• 
Proportion of patients requiring antibiotics for respiratory indications during study 
• 
Proportion of patients with influenza secondary complications 
• 
Median duration of ventilation 
• 
Proportion of patients who are readmitted by Day 30 and Day 60 
 
6.4.3 
Subgroup Analyses 
Subgroup analyses will be performed to examine the consistency of the treatment 
estimates with use of the primary and selected secondary endpoints.  Subgroups will 
include the stratification factors as well as patients who are identified at baseline as 
influenza A positive by the upper, lower, or both airways and by patients with bacterial 
co-infections at admission as well as by the influenza season during which the patient 
was randomized.  Additional subgroups may be added following assessment of baseline 
characteristics as exploratory analyses. 
6.5 
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 AEs (including deaths, SAEs, discontinuations due to AEs, and the 
incidence and severity of AEs), clinical laboratory tests, vital signs (including SpO2 
measurements), and ECGs. 
All collected AE event data will be listed by study site and patient number.  All AEs 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 SAEs, including deaths, will be listed 
separately and summarized.  SAEs 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 
6.6 
PHARMACODYNAMIC ANALYSES 
Individual and mean serum MHAA4549A concentration versus time data will be 
tabulated and plotted.  The serum pharmacokinetics of MHAA4549A will be summarized 
by estimating total serum drug exposure (i.e., AUC), Cmax, Cmin, 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. 
 
 
  
 
 
 
 
 
6.7 
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 I error penalty of 0.0001 will be taken. 
 
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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. 
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 
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.  
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. 
 
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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 7.5. 
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/IEC review.  The study site must also allow 
inspection by applicable health authorities. 
7.4 
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. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, 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. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for GCP 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 
 
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MHAA4549A—Genentech, Inc. 
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(Clinical Safety Data Management:  Definitions and Standards for Expedited Reporting).  
Studies conducted in the United States or under a US Investigational New Drug (IND) 
application will comply with US FDA regulations and applicable local, state, and federal 
laws.  Studies conducted in the European Union or European Economic Area will comply 
with the EU Clinical Trial Directive (2001/20/EC). 
8.2 
INFORMED CONSENT 
The Sponsor’s sample ICFs (and ancillary sample ICFs) 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/IEC submission.  The final 
IRB/IEC-approved Consent Forms must be provided to the Sponsor for health authority 
submission purposes according to local requirements. 
The Consent Forms must be signed and dated by the patient or the patient’s authorized 
representative as applicable and in accordance with local regulations, and IRB/IEC 
policies, 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/IEC-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/IEC policy) during their participation in the study.  For any updated or revised 
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 
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. 
For sites in the United States, 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/IEC by the Principal 
Investigator and reviewed and approved by the IRB/IEC before the study is initiated.  In 
addition, any patient recruitment materials must be approved by the IRB/IEC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/IEC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/IEC.  Investigators are 
also responsible for promptly informing the IRB/IEC of any protocol amendments (see 
Section 9.1).  
In addition to the requirements for reporting all AEs to the Sponsor, investigators must 
comply with requirements for reporting SAEs to the local health authority and IRB/IEC.  
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/IEC, 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 ICF (or separate authorization for use and 
disclosure of personal health information) signed by the patient, unless permitted or 
required by law. 
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. 
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/IEC for each study site, as 
appropriate. 
 
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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/IEC 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/IEC in accordance with established IRB/IEC 
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/IECs to inspect facilities and records relevant to this study. 
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, clinical monitoring and site management, data quality 
support, medical monitoring, and some safety reporting and regulatory activities as 
specified in 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 dynamic hierarchical algorithm, and 
 
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manage site drug supply.  A central laboratory will be used for sample management and 
storage until shipment to specialty laboratories or Genentech for analysis.   
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 from 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 website:  
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. 
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/IEC and to regulatory authorities in accordance with local 
regulatory requirements. 
 
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Approval must be obtained from the IRB/IEC 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). 
 
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10. 
REFERENCES 
Bai S, Jorga K, Xin Y, et al. A guide to rational dosing of monoclonal antibodies. Clin 
Pharmacokinet 2012;51(2):119 − 135. 
Blackwood B, Alderdice F, Burns K, et al. Use of weaning protocols for reducing duration 
of mechanical ventilation in critically ill adult patients: Cochrane systematic review 
and meta-analysis. BMJ 2011;342(c7237). 
Centers for Disease Control and Prevention (CDC). Antiviral agents for the treatment 
and chemoprophylaxis of influenza: recommendations of the Advisory Committee on 
Immunization Practices (ACIP). MMRW Morb Mortal Weekly Rep 
2001;60(RR01):1 − 24. 
Centers for Disease Control and Prevention (CDC). 2014-2015 Influenza antiviral 
medications [resource on the Internet]. 2015 [Updated 2015, Jan 9; cited 2015 Jan]. 
Available from: http://www.cdc.gov/flu/professionals/antivirals/summary-
clinicians.htm. 
Doshi S, Kamimoto L, Finellie L, et al. Description of antiviral treatment among adults 
hospitalized with influenza before and during the 2009 pandemic: United States, 
2005−2009. J Inf Dis 2011;204:1848 − 1856. 
Fiore AE, Fry A, Shay D, et al. (2011). Antiviral agents for the treatment and 
chemoprophylaxis of influenza---recommendations of the Advisory Committee on 
Immunization Practices (ACIP). MMWR. Recommendations and reports: Morbidity 
and mortality weekly report. Recommendations and reports/Centers for Disease 
Control. 2011; 60(1):1 − 24. 
Harper SA, Bradley JS, Englund JA, et al. Expert Panel of the Infectious Diseases 
Society of America. Seasonal influenza in adults and children--diagnosis, treatment, 
chemoprophylaxis, and institutional outbreak management: clinical practice 
guidelines of the Infectious Diseases Society of America. Clin Infect Dis 2009 Apr 
15;48(8):1003 − 1032. 
 
 
 
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. 
Lawton MP, Brody EM. Assessment of older people: self-maintaining and instrumental 
activities of daily living. Gerontologist 1969;9:179 − 186. 
Lee N, Ison MG. Diagnosis, management and outcomes of adults hospitalized with 
influenza. Antiviral Therapy 2012:17(1 Pt B):143 − 157. 
Louie JK, Yang S, Acosta M, et al. Treatment with neuraminidase inhibitors for critically 
ill patients with influenza A (H1N1). CID 2012;55:1198 − 1204. 
 
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Marty FM, Man CY, van der Horst C, et al. Safety and pharmacokinetics of intravenous 
zanamivir treatment in hospitalized adults with influenza: an open-label, multicenter, 
single-arm, Phase II study. J Infect Dis 2014;209(4):542 − 550. 
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. 
Polakos NK, Cornejo JC, Murray DA, et al. Kupffer cell-dependent hepatitis occurs 
during influenza infection. Am J Pathol 2006;168(4):1169 − 1178. 
Premier Perspective Hospital Database (Premier Inc, Charlotte, NC)   
Thompson WW, Shay DK, Weintraub E, et al. Influenza-associated hospitalizations in 
the United States. JAMA 2004;292(11):1333 − 1340. 
Writing Committee of the World Health Organization (WHO) consultation on 
human influenza A/H5. Avian influenza A (H5N1) infection in humans. N 
Engl J Med 2005; 353: 1374  − 1385. 
Yingying C. Abnormal liver chemistry in patients with influenza A H1N1. 
Liver Int 2011; 31(6):902. 
Zhou H, Thompson WW, Vioud CG, et al. Hospitalizations associated with influenza and 
respiratory syncytial virus in the United States 1993−2008. Clin Inf Dis 
2012;54(10):1427 − 36. 
 
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Appendix 1a  
Schedule of Assessments 
Notes: Unless otherwise indicated, all assessments on Day 1 should be performed prior to study drug administration; x’s within 
parentheses, i.e., (x), indicate optional assessments.  Please refer to Follow-up Period table for visits to be completed after patient is 
discharged from hospital prior to Day 60.  Any screening assessments completed prior to consent as standard of care do not need to be 
repeated if done within the screening period.  If a patient is unable to be present at the site for a follow-up visit, a telephone visit is 
permitted. 
Day (D) 
Screening 
Hospitalized Days (only to be completed while patients are hospitalized) 
Hospital 
Discharge a D30  
D60  
Study Completion or 
Early 
Discontinuation 
while Hospitalized 
D -2,-1 
D1 
(Randomization) D2 D3 D4 D5 
D6 
D7 
D8 
D9 D10 D14 D20 D25 
Confirm study drug administration can occur within 48 hours of hospital admission 
 
Informed consent b 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsor-approved influenza 
test c 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and 
demographic data 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm onset of flu symptoms 
(≤ 5 days prior to study drug 
administration on Day 1) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm history of baseline 
SpO2 > 92% 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy screening d 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm O2 requirement e 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix 1a  
Schedule of Assessments (cont.) 
 
MHAA4549A—Genentech, Inc. 
121/Protocol GV29216, Version 5 (Global)   
Day (D) 
Screening 
Hospitalized Days (only to be completed while patients are hospitalized) 
Hospital 
Discharge a
D30 
D60  
Study Completion or 
Early 
Discontinuation 
while Hospitalized 
D -2,-1 
D1 
(Randomization)
D2 D3 D4 D5
D6
D7
D8
D9 D10 D14 D20 D25
Respiratory Assessment f 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant medications g 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vital signs h 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
APACHE score i 
 
(x j) 
 
 
 
 
 
 
 
 
 
(x) 
 
 
(x) 
(x) 
(x) 
SOFA score  k 
 
(x j) 
 
 
 
 
 
(x) 
 
 
 
(x) 
 
 
(x) 
(x) 
(x) 
Electrocardiogram (12-lead) l 
 
x 
 
 
 
x 
 
 
 
 
 
x 
 
 
x 
x 
x 
Randomization 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MHAA4549A administration m 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Oseltamivir administration n 
 
x 
x 
x 
x 
x 
(x) 
(x) 
(x) 
(x) 
(x) 
 
 
 
 
 
 
Complete physical 
examination o 
x 
(x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Limited, symptom-directed 
physical examination p 
 
 
x 
x 
x 
x 
 
 
 
 
 
x 
 
 
x 
x 
x 
Weight & height q
 
x 
x 
 
 
 
x 
 
 
 
 
 
x 
 
 
x 
x 
x 
Adverse events 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Hematology r 
x 
 
x 
 
 
x 
 
 
 
 
 
x 
 
 
x 
x 
x 
Chemistry panel r 
(x) s 
x 
x 
 
 
x 
 
 
 
 
 
x 
 
 
x 
x 
x 
Coagulation panel r 
 
x 
 
 
 
x 
 
 
 
 
 
x 
 
 
x 
x 
x 




Appendix 1a  
Schedule of Assessments (cont.) 
 
MHAA4549A—Genentech, Inc. 
123/Protocol GV29216, Version 5 (Global)   
Day (D) 
Screening 
Hospitalized Days (only to be completed while patients are hospitalized) 
Hospital 
Discharge a
D30 
D60  
Study Completion or 
Early 
Discontinuation 
while Hospitalized 
D -2,-1 
D1 
(Randomization)
D2 D3 D4 D5
D6
D7
D8
D9 D10 D14 D20 D25
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
  
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
Oseltamivir medication diary dd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
; AE  adverse event; APACHE  Acute Physiology and Chronic Health Evaluation; 
ATA  Anti-therapeutic antibodies; D  day; Dx  diagnostics; eCFR  electronic Case Report Form; ECG  electrocardiogram; HAI  hemagglutinin 
inhibition; 
 
 
; ICU  Intensive Care Unit; IRB/IEC  Independent Review Board/Independent Ethics 
Committee; NAI  neuraminidase inhibitor; NP  nasopharyngeal; O2  oxygen; PaO2/FiO2  partial pressure of oxygen/fraction of inspired oxygen; 
PCR  polymerase chain reaction; PD  pharmacodynamics; PK  pharmacokinetic; PPV  positive pressure ventilation; qPCR  quantitative 
Polymerase Chain Reaction; RBCs  red blood cells; SOFA  Sequential Organ Failure Assessment; SpO2  oxygen saturation measured by pulse 
oximetry; WBCs  white blood cells. 
oxygen/fraction of inspired oxygen; PCR  polymerase chain reaction; PD  pharmacodynamics; PK  pharmacokinetic; PPV  positive pressure 
ventilation; qPCR  quantitative Polymerase Chain Reaction; RBCs  red blood cells; SOFA  Sequential Organ Failure Assessment; SpO2  oxygen 
saturation measured by pulse oximetry; WBCs  white blood cells. 


Appendix 1a  
Schedule of Assessments (cont.) 
 
MHAA4549A—Genentech, Inc. 
124/Protocol GV29216, Version 5 (Global)   
a Assessments to be performed irrespective of day of discharge.  Assessments on discharge day will supersede assessments for matching day 
except for the study completion/early discontinuation visit (e.g., If a patient is discharged from the hospital on Day X, use assessments under 
“hospital discharge” column instead of the Day X column and record under the hospital discharge folder in the eCRF.  If a patient discontinues 
from the study early on Day X, complete all assessments under the “early discontinuation” column and record under the early discontinuation 
folder in the eCRF.  
b Informed consent must be obtained from all patients.  For patients who are unable to consent, an authorized representative may be used if 
allowed by local regulations and IRB/IEC policy.   
c Sponsor-approved influenza test using a nasopharyngeal swab in one nostril.  A Sponsor-approved influenza test includes influenza antigen 
test or influenza polymerase chain reaction (PCR) test.  Result must be available within the 48-hour screening window. 
d A urine pregnancy test should be collected only for women considered by the investigator to be of childbearing potential, see exclusion criteria.  
This result must be available within 2 days prior to study treatment.  If urine testing is not available at the site, blood already collected from an 
existing sample may be tested for pregnancy. 
e Confirm patient requires supplemental O2 or PPV within 24 hours of hospital admission. 
f All patients will have their on-study SpO2 and corresponding respiratory assessments recorded daily in the morning between 6 am  12 pm local 
time; screening SpO2 may be taken outside this window.  From Day 1 onward post-study drug administration, patients on low flow O2 should 
have a daily trial of their SpO2 while on and off the supplementation and both values will be recorded.  If the patient is on oxygen 
supplementation, SpO2 measured by pulse oximetry and the corresponding respiratory assessments (e.g., FiO2, flow rate) will be recorded.  If 
the patient is on PPV, PaO2 and the corresponding respiratory assessments (e.g., FiO2, ventilator mode, ventilator respiratory rate, positive 
end-expiratory pressure) will be recorded.  If clinically appropriate (i.e., the patient is on non-invasive PPV), the conversion table in 
Appendix 11 may be used. 
g Concomitant medications should be recorded for 30 days prior to screening, through the study completion/early discontinuation visit.  See 
exclusion criteria in Section 4.5.2 for prohibited therapies. 
h Vital signs will be collected within 1 hour before MHAA4549A infusion and within 1 hour after completion of MHAA4549A infusion and include 
temperature, 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.  In patients who have multiple 
vital signs taken during any day, the most abnormal value should be recorded from that 24-hour period.  Temperature, blood pressure, 
respiratory rate, and heart rate will be completed after the patient has been in a seated or supine position for  5 minutes.  The worst/most 
abnormal value from the last 24-hour period should be recorded for patients who are in the ICU.  
i APACHE scores are optional and only for patients that are in the ICU.  For calculation of the screening APACHE score, the worst values in the 
preceding 24 hours should be used.  APACHE scores are not required for study conduct or entry but should be collected if available.  




Appendix 1a  
Schedule of Assessments (cont.) 
   
 
 
y Day 1 serum PK samples are to be drawn 30 (± 5) minutes pre-dose of MHAA4549A, 60 (± 15) minutes after the end of infusion.  Serum PK 
samples on Day 2 and after are to be drawn immediately before oseltamivir dosing. 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.  
 
 
aa   If patient is discharged on or before Day 5, the oseltamivir PK samples are to be taken on the discharge day. 
 
 
 
 
 
 
 
 
dd Patients who are discharged from the hospital with oseltamivir will be required to complete a medication diary and return the medication diary, 
empty (used) oseltamivir packets and unused oseltamivir capsules to the study site at the next follow up visit.  Patients will record the date and 
time when each oseltamivir capsule is administered.  
 
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Appendix 1b  
Schedule of Assessments:  Follow-Up Period  
• 
If a patient is discharged prior to Day 14, he/she will need to complete the following assessments for Day 14, Day 30, and Day 60 below. 
• 
If a patient is discharged after Day 14 but prior to Day 30, he/she will need to complete the following assessments for Day 30 and Day 60 
below. 
• 
If a patient is discharged after Day 30, but prior to Day 60, he/she will need to complete the following assessments for Day 60 below. 
• 
If patient is hospitalized for Day 14, Day 30, and/or Day 60, please refer to Appendix 1a.  
Day (D) 
D14 ± 1 
(If discharged  
BEFORE Day 14) 
D30 ± 4  
(If discharged  
BEFORE Day 30)  
Day 60 ± 4 (Study 
Completion)  
or Early Discontinuation  
Concomitant medications a 
x 
x 
x 
Vital signs b 
x 
x 
x 
Electrocardiogram (12-lead) c 
x 
x 
x 
Weight & height, BMI d 
x 
x 
x 
Adverse events 
x 
x 
x 
Hematology e
 
x 
x 
x 
Chemistry panel e 
x 
x 
x 
Coagulation panel e 
x 
x 
x 
Urinalysis e 
x 
x 
x 
Flu antibodies (HAI) 
x 
x 
x 
 
 
x 
x 
Serum for MHAA4549A PK measurements f 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
x 
 
 
x 
x 
  
 
x 
x 
  
 
x 
x 
 
 
x 
x 
 
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Appendix 1b  
Schedule of Assessments:  Follow-Up Period (cont.) 
  
; ATA = Anti-therapeutic antibodies; BMI = body mass index; D = day; 
Dx = diagnostics; eCFR = electronic Case Report Form; ECG = electrocardiogram; HAI = hemagglutinin inhibition; 
 
 
; PD = pharmacodynamics; PK = pharmacokinetic. 
a Concomitant medications should be recorded for 30 days prior to screening, through the study completion/early discontinuation visit.  See 
exclusion criteria in Section 4.1.2 for prohibited therapies. 
b Vital signs include temperature, 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 study drug administration of any antipyretic drugs.  
In patients who have multiple vital signs taken during any day, the most abnormal value should be recorded from that 24-hour period.  
Temperature, blood pressure, respiratory rate, and heart rate will be completed after the patient has been in a seated or supine position for 
> 5 minutes.  
c ECG should be recorded after the patient has rested in a supine position for 10 minutes. 
d Height will be obtained at screening only.  Weight will be obtained at all indicated visits.  Height and weight will be recorded in meters and kg, 
respectively.  
e Local laboratory measurements should be used. 
f PK samples  must be labeled with the exact time of draw.  
 
 
 
 
 
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Appendix 2  
Time to Normalization of Respiratory Function 
For the purposes of this study, the time to normalization of respiratory function will be 
defined as the time to removal of the patient from O2 supplementation in order to 
maintain an SpO2 ≥95%.   
Patients who are on low flow O2 (2-6L/min) should receive a daily trial off O2 in the 
morning between 6 am − 12 pm as described below.  
1. 
Patient should be resting or sitting. 
2. 
Patient should be fitted with pulse oximeter, and their SpO2 should be checked once 
while on O2 and then again 3 − 5 minutes after turning off O2 supplementation.  
3. 
If the SpO2 ≥95%, then the time and reading should be recorded.  Notify the study 
doctor so that he/she can make a clinical judgment to determine whether the O2 can 
be removed. 
4. 
The recorded time for the endpoint corresponds with the initial discontinuation of O2 
and reading. 
 
 
MHAA4549A—Genentech, Inc. 
129/Protocol GV29216, Version 5 (Global)   


 
Appendix 3  
  
 
 
 
 
 
 
 
 
 
 
MHAA4549A—Genentech, Inc. 
130/Protocol GV29216, Version 5 (Global)   


 
 
MHAA4549A—Genentech, Inc. 
131/Protocol GV29216, Version 5 (Global)   
Appendix 4  
  
 
 
 
 
 
 
 
 


 
Appendix 5  
  
 
 
 
 
  
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MHAA4549A—Genentech, Inc. 
132/Protocol GV29216, Version 5 (Global)   


 
Appendix 6  
 
 
  
 
  
 
 
MHAA4549A—Genentech, Inc. 
133/Protocol GV29216, Version 5 (Global)   


 
Appendix 7  
SOFA Score Calculation  
Variables 
SOFA Score 
0 
1 
2 
3 
4 
Respiratory  
(PaO2/FiO2, mmHg) 
> 400 
≤ 400 
≤ 300 
≤ 200a 
≤ 100a 
Coagulation  
(Platelets x 103/µL) b 
> 150 
≤ 150 
≤ 100 
≤ 50 
≤ 20 
Liver  
(Bilirubin, mg/dL) b 
< 1.2 
1.2 − 1.9 
2.0 − 5.9 
6.0 − 11.9 
> 12.0 
Cardiovascular 
(Hypotension) 
No 
hypotension 
MAP < 70 
mmHg 
Dop ≤ 5 or dob 
(any dose) c 
Dop > 5, 
epi ≤ 0.1, or 
norepi ≤ 0.1c 
Dop > 15, 
epi > 0.1, or 
norepi > 0.1c 
Central Nervous System 
(Glasgow Coma Score 
Scale) 
15 
13 − 14 
10 − 12 
6 − 9 
< 6 
Renal  
(Creatinine, mg/dL or 
urine output, mL/day) d 
< 1.2 
1.2 − 1.9 
2.0 − 3.4 
3.5 − 4.9 or 
< 500 
> 5.0 or < 200 
Norepi = norepinephrine; Dob = dobutamine; Dop = dopamine; Epi = epinephrine; FiO2 = fraction of 
inspired oxygen; MAP = mean arterial pressure; PaO2 = partial pressure of arterial oxygen. 
a Values are with respiratory support. 
b To convert bilirubin from mg/dL to µmol/L, multiply by 17.1. 
c Adrenergic agents administered for at least 1 hour (doses given are in µg/kg per minute). 
d To convert creatinine from mg/dL to µmol/L, multiply by 88.4. 
  
References for Appendix 7: 
Ferreira FL, Bota DP, Bross A et al. Serial evaluation of the SOFA score to predict 
outcome in critically ill patients. JAMA 2001; 286(14):1754−1758 
Vincent JL, de Mendonca A, Cantraine F et al. Use of the SOFA score to assess the 
incidence of organ dysfunction/failure in intensive care units: results of a multicenter, 
prospective study.  Working group on “sepsis-related problems” of the European Society 
of Intensive Care Medicine.  Crit Care Med 1998;26(11): 1793−1800. 
 
MHAA4549A—Genentech, Inc. 
134/Protocol GV29216, Version 5 (Global)   


 
Appendix 8  
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. 
 
 
MHAA4549A—Genentech, Inc. 
135/Protocol GV29216, Version 5 (Global)   


Appendix 8 (cont’d) 
 
DAIDS Toxicity Grading Tables for Clinical Abnormalities 
MHAA4549A—Genentech, Inc. 
136/Protocol GV29216, Version 5 (Global)   
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 
 
 
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 
 


 
Appendix 9  
DAIDS Toxicity Grading Tables for Laboratory Abnormalities 
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 
Abbreviations used in the table: 
 
; CPK = creatine phosphokinase; Dec = Decreased; 
IV = Intravenous; LLN = Lower limit of normal; Mod = Moderate; Req = Required; 
Rx = Therapy; SGOT = serum glutamic oxaloacetic transaminase; SGPT = serum glutamic 
pyruvic transaminase; ULN = Upper limit of normal. 
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 gm/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 x 
ULN 
1.26 – 1.50 x 
ULN 
1.51 – 3.0 x 
ULN 
>3 x ULN 
Activated Partial 
Thromboplastin 
Time (APTT) 
1.01 – 1.66 x 
ULN 
1.67 – 2.33 x 
ULN 
2.34 – 3 x ULN 
>3 x ULN 
Methemoglobin 
5.0 – 9.9% 
10.0 – 14.9% 
15.0 – 19.9% 
>20.0% 
From the FDA Guidance document ‘Toxicity Grading Scale from Healthy Adult and Adolescent 
Volunteers Enrolled in Preventative Vaccine Clinical Trials’ 
 
 
MHAA4549A—Genentech, Inc. 
137/Protocol GV29216, Version 5 (Global)   


Appendix 9 (cont’d) 
 
DAIDS Toxicity Grading Tables for Laboratory Abnormalities 
MHAA4549A—Genentech, Inc. 
138/Protocol GV29216, Version 5 (Global)   
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  
Hyperbilirubinemia 
(when accompanied by 
any increase in other 
liver function test) 
1.1 – <1.25 x 
ULN 
1.25 – <1.5 x 
ULN 
1.5 – 1.75 x  
ULN 
>1.75 x ULN 
Hyperbilirubinemia 
(when other liver 
function are in the 
normal range) 
1.1 – <1.5 x 
ULN 
1.5 – <2.0 x 
ULN 
2.0 – 3.0 x  
ULN 
>3.0 x ULN 


Appendix 9 (cont’d) 
 
DAIDS Toxicity Grading Tables for Laboratory Abnormalities 
MHAA4549A—Genentech, Inc. 
139/Protocol GV29216, Version 5 (Global)   
From the FDA Guidance document ‘Toxicity Grading Scale from Healthy Adult and 
Adolescent Volunteers Enrolled in Preventative Vaccine Clinical Trials’ 
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 
* From the FDA Guidance document ‘Toxicity Grading Scale from Healthy Adult and Adolescent 
Volunteers Enrolled in Preventative Vaccine Clinical Trials’ 
  
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 
From the FDA Guidance document ‘Toxicity Grading Scale from Healthy Adult and Adolescent 
Volunteers Enrolled in Preventative Vaccine Clinical Trials’ 
 


 
Appendix 10  
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 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. 
140/Protocol GV29216, Version 5 (Global)   


 
Appendix 11  
Respiratory Conversion Table for PaO2 
Estimating PaO2 from a given oxygen saturation 
Oxygen Saturation (%) 
PaO2 (mmHg) 
80 
44 
81 
45 
82 
46 
83 
47 
84 
49 
85 
50 
86 
52 
87 
53 
88 
55 
89 
57 
90 
60 
91 
62 
92 
65 
93 
69 
94 
73 
95 
79 
96 
86 
97 
96 
98 
112 
99 
145 
From The Extended Study of Prevalence of Infection in Intensive Care: 
http://www.intensive.org/epic2/Documents/Estimation%20of%20PO2%20and%20FiO2.pdf 
 
 
 
MHAA4549A—Genentech, Inc. 
141/Protocol GV29216, Version 5 (Global)   


 
Title
16-May-2016 15:31:18
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 GV29216, Version 7 (Global)   
PROTOCOL 
TITLE: 
A PHASE 2 RANDOMIZED, DOUBLE-BLIND 
PLACEBO-CONTROLLED TRIAL OF MHAA4549A, 
A MONOCLONAL ANTIBODY, IN COMBINATION WITH 
OSELTAMIVIR VERSUS OSELTAMIVIR FOR 
TREATMENT OF SEVERE INFLUENZA A INFECTION 
PROTOCOL NUMBER: GV29216 
VERSION NUMBER: 
7 (Global) 
EUDRACT NUMBER: 
2014-000461-43 
IND NUMBER: 
117,318 
TEST PRODUCT: 
MHAA4549A 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
Genentech, Inc. 
DATE FINAL: 
30 May 2014 
DATES AMENDED: 
Version 2:  14 August 2014 
Version 3 (VHP Only):  25 September 2014  
Version 4 (Russia Only):  5 February 2015 
Version 5 (Global):  20 March 2015 
Version 6 (Russia Only):  11 April 2015 
Version 7 (Global):  See electronic date stamp below. 
 


 
MHAA4549A—Genentech, Inc. 
2/Protocol GV29216, Version 7 (Global)   
PROTOCOL AMENDMENT, VERSION 7: 
RATIONALE 
There are currently no validated clinical endpoints for evaluating clinical efficacy of 
therapeutics for patients hospitalized with severe influenza.  Possible endpoints have 
been proposed which include mortality, duration of hospitalization stay, virology, clinical 
signs and symptoms, time to normalization of vital signs, time to normalization of 
oxygen, and requirements for supplemental oxygen or ventilation.  Each of these 
outcomes will be assessed in this study.  
This Version 7 amendment adds an additional secondary endpoint to compare the 
clinical status of patients using an ordinal outcome with 6 clinical statuses. Patients will 
be categorized into 1 of the following 6 mutually exclusive categories (death; in the 
intensive care unit [ICU]; non-ICU hospitalization, requiring supplemental oxygen; non-
ICU hospitalization, not requiring supplemental oxygen; not hospitalized, but unable to 
resume normal activities; or not hospitalized with full resumption of normal activities) on 
Days 1-7, 14, and 30.  An ordinal outcome is hypothesized to have greater statistical 
power than a binary clinical outcome because it uses more information. Ordinal 
outcomes have been used in other studies of seriously ill patients 
(Roozenbeek B et al. 2011).  
This amendment also contains: 
• 
Updates to MHAA4549A background information 
• 
Updates to clinical safety and efficacy background 
• 
Revised initial oseltamivir dosing from 8 hours to 12 hours after completion of study 
drug administration 
• 
Allowing a medically qualified designee to be present during MHAA4549A 
administration 
• 
Clarification to inclusion criteria of “any supplemental O2 to maintain oxygen 
saturation >92%” 
• 
Expanded Day 60 follow up window from ± 4 to ± 7 days to allow more operational 
flexibility 
• 
Clarification around renal dose adjustments for oseltamivir 
• 
Clarification that only 75 mg oseltamivir capsules are supplied by IxRS for 75 mg 
twice a day (BID) and 150 mg BID regimens  
• 
Removed requirement for FSH test 
• 
Clarification that patients with a history of chronic lung disease with a documented 
SpO2 < 95% off oxygen are excluded 
• 
Clarification that a lower respiratory tract sample may be used if appropriate for the 
sponsor-approved local PCR test for influenza diagnosis 
• 
Clarification of daily trial off oxygen 


 
MHAA4549A—Genentech, Inc. 
3/Protocol GV29216, Version 7 (Global)   
• 
Update to emergency medical contacts 
• 
Update to contact information for reporting serious adverse events and non-serious 
adverse events of special interest 
• 
Update to efficacy analyses in Section 6.4 to support the addition of the new ordinal 
secondary endpoint 
• 
Revision to Schedule of Activities to support the addition of the new ordinal 
secondary endpoint 
• 
Revision to Schedule of Activities to ensure that daily trial off oxygen are captured 
every day up to Day 30 when patients are hospitalized 
• 
Additional appendix on clinical status assessment to aid in assessing the new 
ordinal secondary endpoint 
• 
Updates to remove repetition 
 


 
MHAA4549A—Genentech, Inc. 
4/Protocol GV29216, Version 7 (Global)   
PROTOCOL AMENDMENT, VERSION 7: 
SUMMARY OF CHANGES 
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
SECTION 1.1:  BACKGROUND ON INFLUENZE 
Influenza infection is an upper and lower respiratory disease with a broad spectrum of 
presentations that can result in fever, shortness-of-breath, pneumonia, respiratory 
failure, secondary respiratory infections, and even death.  The standard of care therapy 
for patients hospitalized with influenza consists of supportive measures and 
administration of available antiviral agents, primarily neuraminidase inhibitors (NAI) that 
include but are not limited to oseltamivir, zanamivir, laninamivir, and peramivir.  
However, a significant unmet medical need still exists in the severely ill patient 
population, as evidenced by the considerable degree of morbidity and mortality in this 
setting.  To address this need, the Sponsor is developing a highly-specific 
anti-influenza A (MHAA4549A) antibody therapy for treatment of hospitalized patients 
with severe influenza. 
SECTION 1.2.1:  Nonclinical Background 
MHAA4549A is a human monoclonal IgG1 antibody that binds to the influenza A virus 
and is 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, which allows broad 
neutralization of the influenza A virus by, blocking fusion of the viral envelope with the 
HA mediated,host target cell endosomal membrane fusion event in the late endosome 
and preventing viral replication. 
In vitro, MHAA4549A is capable of neutralizing all current clinically relevanthuman 
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.  MHAA4549A specifically targets an In the absence of 
influenza infection, the epitope on the human influenza A HA glycoprotein, which does  
targeted by MHAA4549A is not appear to be endogenously expressed onin human or 
rat tissues and, therefore, is unlikely to be present in the absence of viral infection. 
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.  Ex vivo tissue cross
reactivity study data showed no specific binding of MHAA4549A to any of the human or 
rat tissues examined mg/kg. 


 
MHAA4549A—Genentech, Inc. 
5/Protocol GV29216, Version 7 (Global)   
SECTION 1.2.2:  Clinical Safety Background 
To date, MHAA4549A has been shown to be safe and well tolerated in twothree clinical 
studies, which altogether enrolled 12284 healthy volunteers who were dosed with 
MHAA4549A. 
SECTION 1.2.2.1:  Phase 1 Entry-into-Human Study (GV28916) 
The first study was a In the Phase 1 entry-into-human (EIH) study (GV28916) in), 21 
healthy volunteers wherewere given single IV doses of placebo (n = 5) or MHAA4549A 
(n = 16) at 1.5, 5, 15, andor 45 mg/kg and followed for 120 days.  
A total of 23 treatment-emergent adverse events (TEAEs) were testedreported 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 four 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 
(four TEAEs per cohort), with an extended follow up period of 120 days.  MHAA4549A 
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 and those who received placebo. 
The most commonly reported TEAEs in subjects receiving MHAA4549A were headache 
(4 subjects) and oropharyngeal pain (2 subjects).  The severity of TEAEs was safe and 
well toleratedprimarily mild, with no only two moderate TEAEs.  No serious adverse 
events (SAEs).  All adverse events (AEs) were mild or mildor dose-limiting toxicities 
were reported.  Two clinical laboratory values were considered TEAEs (an increase in 
ALT in 1 subject who received 5 mg/kg MHAA4549A and an increase in creatinine 
phosphokinase [CK] in 1 subject who received placebo).  Both results returned to 
moderate and resolved fully before the end of the study’s follow up period.  Nonormal 
within 10 days. 
No safety issues were observed with respect to vital signs results or ECG 
measurements.  For all clinical laboratory results, no relevant differences in mean 
values or deviations from baseline over time were observed in subjects receiving 
MHAA4549A doses as compared to placebo.  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 (n = 6) or MHAA4549A (n = 8) at 8400 mg (Cohort A) or 10800 mg 
(Cohort B) and were followed for 120 days. 
A total of 34 TEAEs were reported by 12 of the 14 subjects (85.7%) who received one 
dose of the study medication or placebo (safety population). Of these 34 TEAEs, 24 
TEAEs were reported by 7 of the 8 subjects (87.5%) who had received MHAA4549A 


 
MHAA4549A—Genentech, Inc. 
6/Protocol GV29216, Version 7 (Global)   
and 10 TEAEs were reported by 5 of the 6 subjects (83.3%) who received placebo. 
TEAEs were reported by 3 of the 4 subjects receiving 8400 mg MHAA4549A and all 4 
subjects receiving 10800 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 (4 subjects who received 
MHAA4549A [3 subjects in Cohort A, 1 subject in Cohort B]) and nasopharyngitis 
(3 subjects who received MHAA4549A [1 subject in Cohort A, 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 1 subject who received 8400 mg 
MHAA4549A, and elevations of blood creatine phosphokinase [CK] observed twice in 
1 subject who received 10800 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) 
The second study was a In the Phase 2a challenge study (GV28985) in), 101 healthy 
volunteers infectedwere nasally inoculated with athe H3N2 (A/Wisconsin/67/2005) strain 
of influenza virus.  SixtyAt 24 to 36 hours after inoculation, 60 subjects received single 
IV doses of 400, 1200, or 3600 mg MHAA4549A; 8 subjects received oseltamivir as an 
active comparator; and 32 subjects received placebo following nasal inoculation 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 virus one day earlier.  Eight 
subjects received oseltamivir starting on inoculation (Day 1.  One subject 0).  
Consistent with the Phase 1 studies (GV28916 and GV29609), there was no evidence of 
a dose-related pattern of TEAEs in MHAA4549A-treated subjects.  Expected influenza-
related symptoms and AEs were observed in inoculated subjects; these influenza-related 
AEs were similar in subjects who received MHAA4549A or placebo.  Of the 101 
subjects inoculated and inoculated, but not dosed.  , 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). 


 
MHAA4549A—Genentech, Inc. 
7/Protocol GV29216, Version 7 (Global)   
Following administration of the study drug, there were 207 TEAEs in 86 of the 
100 safety-evaluable subjects (86%), which occurred in a similar pattern across all 
treatment groups.  Thirty-six of the 86 subjects (42%) experienced at least 
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 in 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 subject 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%. 
Most AEs appeared to reflect symptoms of an active influenza infection and occurred 
primarily within the first 21 days after patients received their virus inoculation and dose of 
MHAA4549A or placebo (123 of 213: 58%).  Following the resolution of the influenza 
symptoms, even though levels of MHAA4549A remained relatively high, the number of 
AEs dropped and remained low throughout the remainder of the study: 59 of 213 (28%) 
of all AEs occurred between Study Days 22 and 60, and 31 of 213 (15%) of all AEs 
occurred between Study Days 61 and 120.  Differences between treatment groups in the 
number and severity of AEs during the first 22 days appeared to reflect variability in the 
extent and severity of the influenza infection.  Throughout the entire study, the pattern of 
AEs did not differ substantially between subjects who received placebo and subjects 
who received any dose of MHAA4549A.  
The percentage of AEs that investigators judged to be related to study drug treatment 
was 12/33 (36%) for the 400 mg group, 10/40 (25%) for the 1200 mg group, 11/52 
(21%) for the 3600 mg group, and 25/88 (28%) for subjects receiving placebo.  Of those 
AEs considered related, however, 15 of 25 (60%) in the placebo cohort and 26 of 33 
(79%) in all MHAA4549A cohorts consisted of elevations of alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), or amylase.  These laboratory abnormalities 
have been shown to be associated with the influenza infection (Polakos et al 2006; 


 
MHAA4549A—Genentech, Inc. 
8/Protocol GV29216, Version 7 (Global)   
Yingying 2011) and were not observed in either the previous or subsequent Phase 1 
studies (i.e., GV28916, GV29609) where MHAA4549A was administered to subjects 
without influenza infection.  
There were 3 SAEs in Study GV28985, none of which were assessed as related to 
MHAA4549A.  One was in a subject hospitalized with a depressive psychosis.  Due to 
his previous history of depression and the known association of psychosis with influenza 
infections, the Investigator considered this event unrelated to study drug.  The other 
2 SAEs were in one subject who fell and required a surgical repair of a fractured tibial 
plateau.  This same subject was subsequently hospitalized for her second SAE, which 
was a post surgical wound infection.  Neither of these events was considered related to 
study treatment.   
In GV28985, the immunogenicity incidence rate amongst the 60 subjects who received 
MHAA4549A was 0%.  One subject tested positive for ATAs.  This subject tested 
positive for ATA at baseline and post baseline.  This subject was in the placebo group, 
which included 32 other subjects, resulting in an immunogenicity prevalence rate 
(ATA positive rate at baseline) of 3.1% and an immunogenicity incidence rate (ATA titers 
post baseline) of 3.1%, as well, within the placebo group.  Overall, study GV28985 had 
an immunogenicity prevalence rate of 1%. 
SECTION 1.2.2.4:  Phase 1 High Dose Safety Study GV29609 
A Phase 1 (GV29609) study was initiated to evaluate the safety and tolerability of a 
single intravenous (IV) doses at 8400 mg or 10800 mg MHAA4549A as compared to 
placebo when administered to 14 healthy volunteers.  The starting dose of 8400 mg was 
based on simulations from a semi quantitative pharmacokinetic model (Figure 2) 
developed from the Phase 2a challenge study (GV28985), which suggests that the 8400 
mg may be the minimum dose that is expected to show a separation of nasal exposure 
from a dose of 3600 mg.  The simulation assumes that pharmacokinetics can be 
extrapolated at doses above 3600 mg and that the PK profile in severely ill patients is 
similar to the PK profile of healthy volunteers in the Phase 2a challenge study.  The 
highest proposed dose of 10800 mg was chosen in GV29609 to provide safety coverage 
for those exposures that might be reached in a 40 kg individual dosed with a flat dose of 
8400 mg.  
GV29609 is currently on going, but preliminary analysis of unblinded safety data up to 
day 57 shows that the 8400 mg and 10800 mg treatment groups are safe and well 
tolerated.  
• 
In subjects who received 8400 mg MHAA4549A (N=4): 
3 of 4 subjects reported 12 AEs  
6 AEs were reported as related to 8400 mg MHAA4549A:  3 headaches, pruritus, 
1 peripheral swelling, and 1 nasal congestion 


 
MHAA4549A—Genentech, Inc. 
9/Protocol GV29216, Version 7 (Global)   
• 
In subjects who received 10800 mg MHAA4549A (N=4): 
4 of 4 subjects reported 7 AEs  
3 AEs reported as related to the 10800 mg MHAA4549A treatment group:  1 
nausea, 1 headache, and 1 asthenia 
• 
In subjects who received placebo (N=6): 
2 of 6 subjects reported 5 AEs 
1 AE was reported as related to study drug: 1 headache 
 
All AEs were reported as mild except for an unrelated moderate AE of an increase in 
creatinine kinase in one subject who received 10800 mg MHAA4549A.  There were no 
SAEs and no subjects have discontinued the study for any reason.  
As in both previous studies, headache was the most common AE.  Headache was 
reported by 3 subjects (37.5%) who received 8400 mg MHAA4549A:  1 subject (12.5%) 
who received 10800 mg MHAA4549A and 2 subjects (33.0%) who received placebo.   
Based on this data, MHAA4549A is considered generally safe and well tolerated.   
SECTION 1.2.3:  Clinical Efficacy BackgroundClinical Pharmacokinetics 
The Phase 1 EIH study (GV28916) demonstrated that MHAA4549A serum 
pharmacokinetics were generally dose proportional. with a mean half-life of 
approximately 23 days (range: 21.9−24.6 days).  The pharmacokinetic (PK) profile 
appeared consistent with that of a human IgG1 antibody that lacks known endogenous 
host targets. (Bai et al. 2012; Ishida et al. 2015). 
In the Phase 2a challenge study (GV28985), 101 healthy volunteers were inoculated 
with influenza virus 24 36 hours prior to dosing with MHAA4549A.  Following inoculation, 
60 subjects received doses of 400 mg, 1200 mg, or 3600 mg MHAA4549A, 32 subjects 
received placebo, 8 subjects received a 5 day course of oseltamivir, and 1 subject was 
not dosed.  The interim efficacy analysis 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 
pharmacokinetics.  The group mean maximum observed concentration (Cmax) increased 
in a dose-proportional manner, at 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 18100 day • µg/mL for the 400- and 
3600-mg dose groups, respectively, and was approximately dose proportional.  PK data 
from the Phase 2a study (GV28985) are consistent with those observed in the Phase 1 
EIH study (GV28916), with MHAA4549A demonstrating a mean half-life of 
approximately 23 days (range: 22.5−23.7 days). 


 
MHAA4549A—Genentech, Inc. 
10/Protocol GV29216, Version 7 (Global)   
In the Phase 1 high-dose study (GV29609), MHAA4549A showed linear 
pharmacokinetics, with a mean half-life of approximately 21.5 days 
(range: 21.4−21.6 days).  For the 8400- and 10800-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) is consistent with those observed in the Phase 1 
EIH study (GV28916) and Phase 2a study (GV28985). 
SECTION 1.2.4:  Clinical Efficacy Background 
The virologic efficacy analysis for the Phase 2a influenza nasal challenge study 
(GV28985), presented in Table 1 includedTable 1, includes the Intent-to-Treat infected 
(ITTI) population followed until at least Day 29 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 oseltamivir (N = 2).  Analysishad 
laboratory confirmed evidence of efficacyinfluenza 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 postchallenge virus inoculation 
Or 
• 
At least two positive detections by any quantitative polymerase chain reaction 
(qPCR) assay between virus inoculation and day of discharge from the 
3600 quarantine 
Or 
• 
Seroconversion (≥ 4-fold rise in titer compared to baseline) 
 
SECTION 1.2.4.1:  Virologic Efficacy 
The 400 mg dose level demonstrated a statistically significant decrease in viral shedding 
from the upper respiratory tract as measured by the area under the curve (97.5% 
(reduction in median viral area under the curve [AUC] by quantitative polymerase 
chain reaction [qPCR]) and peak viral load (77% reduction by qPCR).  All subjects have 
completed dosing, and interim PK and efficacy data are available in the Investigator’s 
Brochure and upon request. 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 the variability from the challenge model and 
intersubject differences. 


 
MHAA4549A—Genentech, Inc. 
11/Protocol GV29216, Version 7 (Global)   
In the GV28985 study, all subjects received oseltamivir started on Day 7 for a 5 day 
course, and there were no observed AEs or imbalances in safety events that were 
considered attributable to interactions between oseltamivir and MHAA4549A.  The PK 
profile of MHAA4549A and oseltamivir in GV28985 are being analyzed to exclude 
potential drug drug interactions, and this analysis will be available before the start of this 
study (GV29216).   
SECTION 1.2.4.2:  Symptomatic Efficacy 
The A/Wisconsin/67/2005 virus induced mild symptoms that were predominantly 
captured in the upper respiratory tract symptoms that included runny nose, stuffy nose, 
and sneezing. 
The limited to the upper respiratory tract, including rhinorrhea, nasal congestion, and 
sneezing.  The 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 Cards 
usedCard.  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 from Study GV28985 for the ITT infected (ITTI) population are shown in 
Table 1. 
Given the variability of the symptom scores the results were not statistically significant.  
HoweverConsistent with the virological results, there was a trend toward a decrease in 
the AUEC of symptoms scores for the 3600-mg dose,, which is consistent with the 
virological results described in Table 1.  Data from the oseltamivir treated group is also 
shown, but it should be noted that only 2 subjects were in the ITT infected 
population.with a mean reduction of the composite symptom score of 82% (Table 1).   
The responses observed in the Phase 2a study (GV28985) suggest that a higher 
dosedoses of MHAA4549A may provide betterimprove virological and symptomatic 
efficacy in a population with establishedinfluenza infection.  AnBecause of this, an 8400-
mg dose will be includedassessed in this Phase 2b study for further dose ranging.  The 
rationale for selected dosages is further explained in Section 3.2.4. 
See the MHAA4549A Investigator's Brochure for additional details on nonclinical and 
clinical studies. 
SECTION 1.3.1:  Study Rationale 
Two Phase 1 (GV28916, GV29609) studies have demonstrated that MHAA4549A is safe 
and well tolerated to date in healthy volunteers at doses up to 840010800 mg.  Data 
from a Phase 2a study (GV28985) demonstrates safety in healthy subjects inoculated 
with influenza virus and provides evidencedemonstrated that the3600 mg dose of 
MHAA4549A dose is safe, well tolerated, and effective in reducing viral titers as compared 


 
MHAA4549A—Genentech, Inc. 
12/Protocol GV29216, Version 7 (Global)   
to placebo in healthy volunteers inoculated with influenza A virus.  virus.  No 
MHAA4549A-specific TEAEs have been identified in any of our clinical studies. When 
combined with previous nonclinical studies demonstrating that showed MHAA4549A to 
havehas a well-tolerated safety profile and in vitro and in vivo efficacy, a well tolerated 
safety profile, and anti viral activity against influenza virus, these findings support 
further clinical development of MHAA4549A. 
In this Phase 2b study (GV29216), MHAA4549A is being evaluated in combination with 
the current standard of care (oseltamivir), to decrease the severity and duration of viral 
infection with influenza A virus with the ultimate goal of reducing the clinical symptoms of 
infection as compared to oseltamivir with placebo. Initially, this GV29216 Phase 2b 
study enrolled patients in a two-arm treatment study comparing 3600 mg 
MHAA4549A with oseltamivir versus placebo with oseltamivir.  This current Phase 2b 
study has added an additional arm to evaluate the improvement in outcome of a 
combination therapy of 3600 mg MHAA4549A with oseltamivir or of 8400 mg 
MHAA4549A with oseltamivir versus placebo with oseltamivir for additional 
dose-response information.  All patients will receive oseltamivir, which is part of the 
recommended standard of care for hospitalized influenza patients.  Therefore, at a 
minimum, all patients will be treated with standard of care for influenza.  There are 
three primary goals for this Phase 2b study:  
• 
Demonstrate the safety and efficacy of MHAA4549A in combination with oseltamivir 
in hospitalized influenza A patients  
• 
 
  
• 
Demonstrate and evaluate the optimal endpoints for study in hospitalized patients 
with influenza A, given the lack of precedence for approval in patients hospitalized 
with influenza infection, an area of high unmet medical need 
 
Initially, this GV29216 Phase 2b study enrolled patients in a two arm treatment study 
comparing 3600 mg MHAA4549A with oseltamivir versus placebo with oseltamivir.  
This current Phase 2b study has added an additional arm to evaluate the improvement 
in outcome of a combination therapy of 3600 mg MHAA4549A with oseltamivir or of 
8400 mg MHAA4549A with oseltamivir versus placebo with oseltamivir.  All patients will 
receive oseltamivir, which is part of the recommended standard of care.  In addition, and 
as discussed above, MHAA4549A is a human monoclonal antibody that has, to date, 
shown an acceptable safety profile, a PK profile consistent with that of a IgG1 human 
antibody that lacks known endogenous host targets, and demonstrated antiviral activity 
at the planned dose level of 3600 mg.  


 
MHAA4549A—Genentech, Inc. 
13/Protocol GV29216, Version 7 (Global)   
This study (GV29216) will assess severely ill patients who may be infected with various 
influenza A strains, have a higher viral burden and longer duration of viral shedding than 
the healthy volunteers in GV28985, and who may, therefore, require doses higher than 
3600 mg.  A Phase 1 (GV29609) study is currently on going to assess the safety, 
tolerability, and pharmacokinetics of 8400 mg and 10800 mg doses of MHAA4549A.  
The starting dose of 8400 mg was selected based on simulations from a semi
quantitative PK model developed from the Phase 2a challenge study (GV28985), 
suggesting that 8400 mg MHAA4549A may be the minimum dose that is expected to 
show a separation of nasal exposure from a dose of 3600 mg.  This simulation assumes 
that pharmacokinetics can be extrapolated at doses above 3600 mg and that the PK 
profile in severely ill patients is similar to the PK profile of healthy volunteers in Phase 2a 
challenged with influenza A virus.  The 10800 mg dose was chosen to provide 
assurance of safety for the increased MHAA4549A levels that may be reached in smaller 
individuals who received 8400 mg. 
A preliminary, unblinded analysis of the safety data from GV29609 up to Day 57 has 
shown that the 8400 mg and 10800 mg treatment groups are safe and well tolerated.  In 
subjects who received 8400 mg MHAA4549A, 3 of 4 subjects reported 12 AEs.  In 
subjects who received 10800 mg MHAA4549A, 4 of 4 subjects reported 7 AEs.  In 
subjects who received placebo, 2 of 6 subjects reported 5 AEs.  All AEs were reported 
as mild, except for one unrelated moderate AE of an increase in creatinine kinase in one 
subject who received 10800 mg MHAA4549A.  There were no SAEs and no subjects 
have discontinued the study for any reason.  As in previous studies, headache was the 
most common AE, and was reported by 3 subjects (37.5%) who received 8400 mg 
MHAA4549A, 1 subject (12.5%) who received 10800 mg MHAA4549A, and 2 subjects 
(33.0%) who received placebo.  As a result, the Sponsor feels that the 8400 mg dose is 
safe to include in Study GV29216.  
The 8400 mg dose is also expected to be safe based upon previous nonclinical and 
clinical safety assessments.  Nonclinical safety data do not show any expected or 
unexpected toxicity.   
SECTION 1.3.2.1:  Treatment in Combination with Oseltamivir 
All patients in the study will receive oseltamivir as the current standard of care treatment, 
either with or without MHAA4549A.  Therefore, at a minimum, all patients will be treated 
with the standard of care for influenza.  Given that MHAA4549A is an antibody, the 
potential for a drug drug interaction with oseltamivir is very low.  In the Phase 2a 
challenge study (GV28985), study subjects received MHAA4549A followed by 
oseltamivir with no AEs attributable to the combination therapy noted to date.  In 
addition, in this Phase 2b study the PK profile of oseltamivir in concomitantly treated 
subjects will be assessed. 


 
MHAA4549A—Genentech, Inc. 
14/Protocol GV29216, Version 7 (Global)   
SECTION 1.3.2.2:  Drug Mechanism and Preclinical Studies 
The available pre clinical data suggest that there is low risk for drug target related safety 
events in healthy humans since MHAA4549A specifically targets an epitope on a viral 
protein (i.e., the human influenza A virus HA glycoprotein), which is not endogenously 
expressed in human tissues.  Furthermore, there were no adverse MHAA4549A related 
findings demonstrated in nonclinical studies at doses up to 150 mg/kg administered 
weekly for 5 weeks and no evidence of target present in host tissues.   
SECTION 1.3.2.3:  Rationale for Selection of Phase 2b Study Population 
The target patient population of hospitalized patients with severe influenza A requiring 
oxygen (O2) or positive pressure ventilation (PPV) is considered an appropriate 
population to test MHAA4549A for the following reasons: 
• 
Nonclinical safety data does not show any expected or unexpected toxicity. 
• 
Clinical safety data for MHAA4549A demonstrate a well tolerated safety profile:   
 
AEs in the Phase 1 study (GV28916) were mild and did not show a dose 
relationship; there were no ATAs detected in patients treated with MHAA4549A 
after 120 day follow up visit. 
 
All AEs in GV29609 from a preliminary analysis of unblinded safety data up to 
day 57 were reported as mild except for an unrelated moderate AE of an 
increase in creatinine kinase in one subject who received 10800 mg 
MHAA4549A.  There were no SAEs and no subjects have discontinued the 
study for any reason. 
 
In the Phase 2a study (GV28985), MHAA4549A was generally well tolerated.  A few 
subjects in all treatment groups were observed to have transient elevations in ALT, AST, 
and amylase levels.  There was no dose dependent relationship of the 
ALT/AST/amylase elevations with MHAA4549A and the overall event rate was in line 
with published rates associated with the influenza challenge model regardless of 
treatment arm:  27/100 [27%] in GV28985 vs. approximately 26% in previous challenge 
studies (Polakos 2006, Yingying 2011).  There were no SAEs related to study drug.  
There were a total of 3 SAEs unrelated to MHAA4549A in two subjects.  One subject 
reported depressive psychosis associated with influenza.  The second subject reported a 
broken knee with a subsequent infection following a surgical procedure.   
Although there has been no benefit demonstrated for MHAA4549A in the setting of 
hospitalized influenza, there is a possibility that patients may have improved clinical 
outcomes from this therapy. 
Potential risks of MHAA4549A include immunogenicity and infusion-related 
reactions.  Theoretically, any biologic 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 nonclinical or clinical studies.  In the three 


 
MHAA4549A—Genentech, Inc. 
15/Protocol GV29216, Version 7 (Global)   
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.   
SECTION 1.3.2.1:  Patient Monitoring and Supervision 
MHAA4549A will be administered to enrolled patients in a hospital environment under 
close medical supervision by a physician investigatorsor medically qualified designee.  
Medical staff will be available for prompt evaluation and treatment of any AEs.  
Emergency resuscitation equipment and emergency facilities will be readily available.  
Patients will undergo screening assessments to confirm eligibility, will be closely 
monitored during the administration of MHAA4549A, and will be resident for at least 24 
hours following the administration of MHAA4549A.  Furthermore, safety laboratory tests 
relating to the blood chemistries, including liver function tests will be conducted. 
An internal monitoring committee (IMC) in combination with a scientific oversight 
committee (SOC) will provide safety monitoring for the study in addition to the ongoing 
review of safety by the Medical Monitor and Safety Scientist.  See Section 3.1.2 for more 
information.  
In addition to the regularly scheduled safety reviews of the patient data by the IMC and 
SOC, an additional sentinel safety cohort of the first 30 patients or patients after the first 
influenza season, whichever occurs first, will be assessed by the IMC and SOC. 
The 120-day follow-up period in the Phase 1 and 2a studies allowed for monitoring of 
subjects for approximately 5 half-lives of MHAA4549A.  No treatment-induced ATAs 
were detected in theboth Phase 1 study, while onestudies.  One subject who received 
placebo in the Phase 2a study tested positive for ATAs at baseline and post-baseline 
timepoints as described in Section 1.2.2.  The Phase 2b study will also include a safety 
follow-up period of 60 days and an unlimited collection of all SAEs believed related to 
MHAA4549A. 
Based on the above data and design of this study, the Sponsor concludes that the 
benefit-risk profile of MHAA4549A in the population with severe influenza is favorable.  
SECTION 2.3:  SECONDARY EFFICACY OBJECTIVES 
The secondary efficacy objectives for this study are as follows: 
• 
To compare the clinical status of patients at Days 1−7, 14, and 30 using an ordinal 
outcome with six clinical statuses. Patients will be categorized into one of the 
following six mutually exclusive categories on Days 1−7, 14, and 30 
1. Death; 
2. In the ICU; 
3. Non-ICU hospitalization, requiring supplemental oxygen; 
4. Non-ICU hospitalization, not requiring supplemental oxygen; 




 
MHAA4549A—Genentech, Inc. 
17/Protocol GV29216, Version 7 (Global)   
SECTION 3.1.1:  Overview of Study Design 
This is a Phase 2b (GV29216), randomized, double-blind, placebo-controlled study 
designed to assess the safety and clinical activity of a single IV dose of 3600 mg 
MHAA4549A or a single IV dose of 8400 mg MHAA4549A in hospitalized patients with 
severe influenza A in combination with oseltamivir versus a comparator arm of placebo 
with oseltamivir.  A Sponsor-approved influenza test that includes influenza antigen 
test or influenza polymerase chain reaction (PCR) test must be used to diagnose 
influenza A infection for study eligibility.  This study is planned to take place in 
approximately 170 study centers globally. 
Initially, GV29216 targeted enrollment into two treatment groups: a single IV dose of 
3600 mg of MHAA4549A with oseltamivir or a single IV dose of placebo with oseltamivir.  
In this version of the protocol, patients will be randomized 1:1:1 into three treatment 
groups:  a single IV dose of 3600 mg of MHAA4549A with oseltamivir, a single IV dose 
of 8400 mg of MHAA4549A with oseltamivir, or a single IV dose of placebo with 
oseltamivir.  Patients will be stratified by country, PPV versus supplemental O2 at 
randomization, and suspected or confirmed bacterial pneumonia versus no bacterial 
pneumonia based on the status at randomization.  All patients must begin study drug 
infusion within 48 hours of hospital admission.  In addition, all patients will receive 
oseltamivir, a NAI, as standard therapy for a minimum of 5 days after study drug 
administration.  Oseltamivir at (10 doses of 75 mg twice a day (BID) or 150 mg BID is 
permitted in order to be consistent with local standard of care practice.  ) starting no 
later than 12 hours after completion of study drug administration.  Oseltamivir 
tTreatment for longer than 5 days is permitted based on local investigator discretion.  
The patient must start oseltamivir no later than 8 hours after completion of study drug 
administration.  The study has a planned enrollment of approximately 330 patients 
globally. 
Hospitalized patients with an O2 or PPV requirement will be evaluated for influenza A 
infection.  Enrollment in this study requires ongoing treatment within 24 hours of hospital 
admission with one of the following:  
• 
any PPV or  
• 
any supplemental O2 to maintain oxygen saturation (SpO2) > 92% (Section 3.3.2)  
 
Patients on PPV should not exceed approximately 45% of the total patients enrolled in 
the study. 
A Sponsor approved influenza test that includes influenza antigen test or influenza 
polymerase chain reaction (PCR) test must be used as an aid in the diagnosis of 
influenza A infection.   


 
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At the time of randomization, patients who are eligible for enrollment, as described 
above, will be randomized to receive 3600 mg MHAA4549A or 8400 mg MHAA4549A or 
placebo.  Patients will be stratified by country, PPV versus supplemental O2 at 
randomization, and suspected or confirmed bacterial pneumonia versus no bacterial 
pneumonia based on the status at randomization. 
Eligible patients who are enrolled into the study will receive a single IV infusion of 3600 
mg MHAA4549A or a single IV infusion of 8400 mg MHAA4549A or a single IV infusion 
of placebo on Day 1.  All patients must begin study drug infusion within 48 hours of 
hospital admission or sooner if possible.  All patients will receive oseltamivir for a 
minimum of 5 days (10 doses), starting on Day 1, beginning no later than 8 hours after 
completion of study drug administration.   
All patients will be followed and evaluated at minimum on a daily basis for the duration of 
their hospital stay consistent with the planned schedule of assessmentsactivities.  Any 
suspicion of bacterial superinfection should be thoroughly evaluated including 
microbiological confirmation, if possible.  A follow-up study visit should occur on Day 14 
± 1 (if discharged before Day 14); Day 30 ± 4 days (if discharged before Day 30); and 
Day 60 ± 47 days (if discharged before Day 60). 
Safety evaluations will also be provided by an IMC and SOC, as defined in the IMC and 
SOC agreement (see Section 3.1.2).  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. 
An additional safety cohort of the first 30 patients, or patients from the first influenza 
season (whichever occurs first), will be assessed by the IMC and SOC.  A review of 
chemistry laboratory test results, AEs, SAEs, vital signs, and deaths will be assessed.  
A schedule of assessmentsactivities is provided in Appendix 1a and Appendix 1b.  A 
diagram of the study design is presented in Figure 1.  
SECTION 3.1.2:  Internal Monitoring Committee and Scientific Oversight 
Committee 
A combined approach with both an IMC and a SOC is proposed to enhance patient 
safety.  The IMC consists of Sponsor representatives from the following functions: 
Clinical Science, Drug Safety, Biostatistics, and Statistical Programming and Analysis, 


 
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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 patient treatment and assignment.  The Clinical Science 
representative on the IMC (IMC Chair) will be a person other than the Study Medical 
Monitor and will not be involved in the conduct of the study or have any contact with 
study investigators or site staff.  The Study Medical Monitor will remain blinded to 
individual treatment assignments, unless, in exceptional cases, specific circumstances 
require Study Medical Monitor unblinding after IMC Chair approval.  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.  The Biostatistician and Statistical Programmer are 
the only IMC members involved in the conduct of the study; however, they do not have 
any contact with study investigators, and all discussion within the IMC are kept 
confidential.  All other Sponsor and Contract Research Organization personnel involved 
in the conduct of the study will remain blinded to individual treatment assignments. 
SECTION 3.2.2:  Rationale for Patient Population and Primary Endpoint 
Severe influenza, for the purpose of this study, is defined as requiring one of the 
following treatments: any supplemental O2 to maintain an SpO2 > 92% or PPV.  PPV is 
defined as any mechanical positive pressure device to maintain oxygenation; this can 
include positive pressure mask and intubation.  A Sponsor approved influenza test, 
which includes influenza antigen test or influenza PCR test, must be used as an aid in 
the diagnosis of influenza A infection. 
SECTION 3.2.3:  Rationale for Control Group and Treatment Window 
In this study, the standard of care regimen for the control or comparator group 
(hospitalized influenza A patients) is oseltamivir, an NAI.  In the treatment groups, 
MHAA4549A will be dosed in addition to oseltamivir.  Either 75 mg or 150 mg orally BID 
oseltamivirOseltamivir for a minimum of 5 days is permitted following treatment with 
MHAA4549A.  Treatment for longer than 5 days is permitted based on local investigator 
discretion (WHO 2005; Fiore et al. 2011; CDC 2015CDC 2016).  The oseltamivir dosing 
regimen is listed in Table 2.  This control treatment was based on consideration of 
safety, ethics, and efficacy for treatment of severe influenza and is consistent with 
guidelines for antiviral treatment of hospitalized patients with influenza 
(Harper et al. 2009; Fiore et al. 2011). 
If oseltamivir resistance is highly suspected or identified during treatment or oseltamivir 
route of administration challenges are encountered, then following discussion with the 
Sponsor medical representativeMedical Monitor, an alternative NAI to oseltamivir may 
be used.  For renal dose adjustments, local standard-of-care practice/local package 
insert should be followed and documented in the eCRF.  Capsules other than 75 mg (for 
75 mg twice a day [BID] or 150 mg BID regimens) cannot be provided through the 
study Interactive Voice and Web Response System (IxRS). In these instances, the study 
site may supply the appropriate dose and be reimbursed by the Sponsor.  


 
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From a safety standpoint there are no expected drug interactions between MHAA4549A, 
a monoclonal antibody, and any NAI, which are small molecule drugs that bind to a 
different viral protein than MHAA4549A.  In the Phase 2a challenge study, all subjects 
that were dosed with MHAA4549A also received a 5-day course of oseltamivir starting 
on Day 7.  There were no safety effects attributable to the combination when the drugs 
were present concurrently.  The pharmacokineticsIn the Phase 2a challenge study, 
MHAA4549A treatment did not appear to impact the exposure of oseltamivir and its 
potentialactive metabolite oseltamivir carboxylate. There was no suggestion of PK drug-
drug interaction withbetween MHAA4549A are being assessed from the Phase 2a 
study.and oseltamivir. 
For this Phase 2b study, a combination of MHAA4549A and oseltamivir was determined 
to be the most clinically feasible treatment regimen, both from an ethical as well as a 
practical perspective.  The treatment of all patients with oseltamivir ensures that all 
patients will receive the standard of care.  Given the high morbidity and mortality of 
hospitalized patients with influenza A along with guidelines from Centers for Disease 
Control and Prevention (CDC) and Infectious Diseases Society of America (IDSA) it is 
recommended that NAIs are the standard of care for hospitalized patients with influenza 
A (Harper et al. 2009; CDC 2016CDC Website).  Furthermore, pre-clinical efficacy data 
from a study using MHAA4549A and oseltamivir in combination showed a potential 
synergistic effect of both compounds which may be due to the different and potentially 
complementary mechanisms of action, i.e. targeting viral HA and neuraminidase (NA). 
Dosing of MHAA4549A is confined to a treatment window designed for best expected 
treatment success and to ensure that any observed effects can be attributed to the study 
drug with high confidence.  MHAA4549A shall only be dosed within 5 days of onset of 
symptoms (including fever, chills, malaise, dry cough, loss of appetite, myalgias, coryza, 
or nausea), no later than 48 hours after admission to the hospital, and if a subject has 
taken less than a total of 6 doses (3 doses for peramivir) of approved anti-influenza 
therapy from onset of symptoms.  This proposed window is supported by data 
demonstrating that hospitalized influenza patients benefit from NAI treatment even at 
5 days from onset of symptoms (Louie et al. 2012).  The patient must start 
standard-of-care oseltamivir no later than 812 hours after completion of MHAA4549A 
administration. 
SECTION 3.2.4:  Rationale for MHAA4549A Dosage 
A singleSingle IV dosedoses of 3600 mg MHAA4549A or a single IV dose of and 8400 
mg MHAA4549A was 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 for severely ill patients was based on nonclinical 
efficacy data from the observed humanin vivo mouse influenza A infection models, the 
pharmacokinetics in Phase 1clinical studies, and the relationship between the 
pharmacokinetics, pharmacodynamics, and efficacy observed in athe Phase 2a human 


 
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challenge studymodel of influenza.  MHAA4549A was shown to be safe and 
well tolerated at all dose levels (ranging from 1.5 mg/kg to 45 mg/kg for Phase 1 and 
400 3600 mg for Phase 2a) through a follow up period of 120 days post dose in the 
Phase 1 and Phase 2a study.  in influenza A (GV28985). 
The dose levels selected for this study were determined following analysis of data 
from3600 mg is based on the Phase 2a challenge study (GV28985), which demonstrated 
the following: 
• 
The 3600 mg dose demonstrated both a significant decrease in viral shedding in the 
upper respiratory samples.  Based on current interim analysis data, there was a 
97.5% (p = 0.0051) tract and a decrease in area under the viral load time curve 
(AUEC) and a 77.3% decrease in peak viral load by qPCR measurement compared 
to the placebo group.   
• 
Symptom data in the Phase 2a study showed a decrease in the area under the 
serum concentration time curve (AUC) of symptoms scores forin patients who 
received the 3600-mg dose, of MHAA4549A as illustrated in Table 1, which is 
consistent with the virological results. 
• 
When compared to patients who received placebo, a decrease in viral shedding was 
observed at the 400 mg dose but not at the 1200 mg dose, which may be due to 
variability in the challenge model and differences in infection rate, infection peak, 
virus level in the nasopharynx, nasal pharmacokinetics, immune status, and other 
inter subject differences.  
• 
There were no safety concerns at any dose level associated with MHAA4549A.  
• 
Hospitalized patients generally have a longer duration of viral shedding and 
significantly more viral burden in the lower lung compartments; therefore, high 
concentrations of monoclonal antibody are likely needed to achieve sufficient 
occupancy of the virus binding sites in the upper and lower respiratory 
compartments.  Furthermore, higher concentrations of monoclonal antibody may 
mitigate the risk of resistance for MHAA4549A, supporting addition of the 8400 mg 
MHAA4549A treatment arm.  
• 
Exploratory (see Section 1.2.4).  An exploratory exposure-response analysis of 
GV28985 indicated that higher exposure appears to be associated with improved 
efficacy.  Volunteers with nasal maximum concentrationthis group demonstrated 
that subjects with nasal viral loads greater than the median valueviral load had 
shorter time to resolution of viral shedding as compared with volunteers in the 
placebo group (median:  75.8 hours vs. 113.7 hours).  However, volunteers), 
whereas subjects with a nasal maximum concentrationviral loads less than the 
median valueviral load had similar time to resolution of viral shedding compared 
with volunteers in the placebo group (median:  112.1 hours vs. 113.7 hours vs 
112.1 hours). 
 
The Phase 2a challenge study (GV28985) confirmed proof of activity in decreasing area 
under viral load time curve, consistent with symptom data at the 3600 mg dose level.  


 
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GV29216 will assess severely ill patients who may be infected with various influenza 
strains, have a higher viral burden and longer duration of viral shedding than the healthy 
volunteers in Study GV28985, and who may, therefore, require doses higher than 
3600 mg.  As a result, an ongoing, Phase 1 (GV29609) study was initiated to evaluate 
the safety and tolerability of two single IV   Thus, at higher viral loads, higher doses of 
8400 mg and 10800 mg MHAA4549A as compared to placebo when administered to 14 
healthy volunteers.  The starting dose of 8400 mg was selected based on simulations 
from a semi quantitative PK model (Figure 2) developed from the Phase 2a challenge 
study, which suggests that 8400 mg may be the minimum dose that is expected to show 
a separation of nasal exposure from a dose of 3600 mg.  This simulation assumes that 
pharmacokinetics can be extrapolated at doses above 3600 mg and that the PK profile 
in severely ill patients is similar to the PK profile of healthy volunteers in the Phase 2a 
challenge study.  The highest proposed dose of 10800 mg was chosen in GV29609 to 
provide safety coverage for those exposures that might be reached in a 40 kg individual 
dosed with a flat dose of 8400 mg.  Preliminary analysis of unblinded safety data up to 
day 57 shows that the 8400 mg and 10800 mg treatment groups are safe and well 
tolerated.  In subjects who received 8400 mg MHAA4549A, 3 of 4 subjects reported 12 
AEs.  In subjects who received 10800 mg MHAA4549A, 4 of 4 subjects reported 7 AEs.  
In subjects who received placebo, 2 of 6 subjects reported 5 AEs.  All AEs were reported 
as mild except for an unrelated moderate AE of an increase in creatinine kinase in one 
subject who received 10800 mg MHAA4549A.  There were no SAEs and no subjects 
have discontinued the study for any reason.  Headache was the most common adverse 
event. Headache was reported by 3 subjects (37.5%) who received 8400 mg 
MHAA4549A, 1 subject (12.5%) who received 10800 mg MHAA4549A, and 2 subjects 
(33.0%) who received placebo.MHAA4549A are expected to be more efficacious. 
Nonclinical safety data do not show any expected or unexpected toxicity.  Weekly 
administration of MHAA4549A (total of 5 doses) in Sprague Dawley rats was well 
tolerated up to 150 mg/kg (the highest dose tested).  Ex vivo tissue cross reactivity study 
data showed no specific binding of MHAA4549A to any of the human or rat tissues 
examined.  
Therefore, the 8400 mg dose is 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 
uponon previous nonclinical and clinical safety assessments and will be included in this 
Phase 2b study for further dose ranging.  


 
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Although the Phase 1 study (GV28916) was conducted using body weight based dosing, 
the subsequent Phase 2a study (GV28985) and high dose Phase 1 study GV29609 
used a fixed dosing strategy.  Thus, the fixed dosing regimen will be used for this study, 
given the comparable MHAA4549A PK profiles, the practical advantages, and the 
positive safety profile of MHAA4549A to date.  Further, fixed dosing is generally 
recommended with monoclonal antibodies, due to their minimal PK variability (Bai et al. 
2012).  The PK variability introduced by different dosing regimens (i.e., body weight 
based dosing versus fixed dosing) is moderate relative to the variability generally 
observed in pharmacodynamics, efficacy, and safety and would not be expected to be 
clinically meaningful.  Phase 2a studies. 
SECTION 3.2.5:  Rationale for Biomarker Assessments 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 


 
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SECTION 3.3.3:  Secondary Efficacy Outcome Measures 
The secondary efficacy outcome measures for this study are as follows: 
• 
Clinical status of patient at Days 1−7, 14, and 30.  This is an ordinal outcome with 
six mutually exclusive categories: 
1. 
Death; 
2. 
In the ICU; 
3. 
Non-ICU hospitalization, requiring supplemental oxygen; 
4. 
Non-ICU hospitalization, not requiring supplemental oxygen; 
5. 
Not hospitalized, but unable to resume normal activities; or 
6. 
Not hospitalized with full resumption of normal activities 
• 
Clinical failure after 24 hours post-infusion of study drug; defined as: 
– 
Progression to increased O2 requirement defined by an increase in oxygen 
supplementation from low flow oxygen (i.e., 2−6 L/min) to high flow oxygen 
(>(i.e., > 6 L/min) or from oxygen supplementation alone to any PPV or 
extracorporeal membrane oxygenation (ECMO) 
– 
Progression to ICU 
– 
Prolonged ventilation or O2 support defined by > 2 weeks, or 
– 
Death 
• 
Time to clinical resolution of abnormal vital signs (3/5 criteria must be met): 
– 
SpO2 ≥ 95% without supplemental O2  
– 
Respiratory rate < 24 breaths per minute without supplemental O2  
– 
Core temperature < 37.2°C immediately prior to receipt of any antipyretic drug, 
and at least 6-8 hours from the last dose of antipyretic or core 
temperature > 36°C in patients who are initially hypothermic 
– 
Heart rate (HR) < 100 beats/minute 
– 
Systolic blood pressure (SBP) > 90 mmHg 
• 
All-cause mortality at Day 14, Day 30, and Day 60 
• 
Influenza A viral load in nasopharyngeal samples   
– 
AUEC (qPCR) 
– 
Peak viral load (qPCR) 
– 
Time to resolutionDuration of infection viral shedding (qPCR) 
 
Identification of potential viral resistance  
• 
Duration of hospitalization 
• 
Duration of ICU stay 
• 
Antibiotic usage for respiratory infections 


 
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• 
Complications of influenza: 
– 
Pneumonia (HAP/VAP) 
– 
Exacerbations of chronic lung disease 
– 
Myocarditis 
– 
ARDS 
– 
Otitis media 
– 
Other related complications 
• 
All-cause readmission at Day 30 and Day 60 
• 
Duration of ventilation 
 
SECTION 3.3.5:  Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


 
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• 
 
 
 
 
 
 
SECTION 4.1.1:  Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Hospitalized men or women ≥ 18 years of age on the day of signing the informed 
consent or obtaining surrogate consent from an authorized representative 
• 
Diagnosis of influenza A where a Sponsor-approved influenza test is used as an aid 
in diagnosis.  A Sponsor-approved influenza test includes: 
− 
Influenza antigen test –OR– 
− 
Influenza PCR test 
• 
One of the following markers of severity within 24 hours of hospital admission: 
– 
Requirement for PPV −OR− 
– 
Requirement for O2 supplementation to maintain SpO2 > 92% (Source 
documentation should show that the patient’s SpO2 was less than 92% off 
oxygen.  Source documentation may consist of either a SpO2 off oxygen with a 
value below 92% or a documentation of the Investigator’s rationale in lieu of 
this SpO2 documentation.) 
• 
A negative urine or serum pregnancy test for women of child-bearing potential 
• 
Patients of reproductive potential must agree to use reliable means of contraception 
as described below as a minimum (adherence to more stringent local requirements 
may be required): 
– 
For women who are not postmenopausal (postmenopausal defined as 
≥ 12 months of non-therapy-induced amenorrhea) or surgically sterile (absence 
of ovaries and/or uterus):  agreement to remain abstinent or use two adequate 
methods of contraception, including at least one method with a failure rate of 
< 1% per year, during the treatment period and for at least 120 days after the 
last dose of 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. 
Barrier methods must always be supplemented with the use of a spermicide. 
Examples of contraceptive methods with a failure rate of < 1% per year include 
tubal ligation, male sterilization, hormonal implants, proper use of combined 
oral or injected hormonal contraceptives, and certain intrauterine devices. 


 
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Male partners who have had a vasectomy should have the appropriate 
post-vasectomy documentation available of the absence of sperm in the 
ejaculate.  The vasectomized male partner should be the sole partner for that 
patient. 
– For men:  agreement to remain abstinent or use a condom during the treatment 
period and for at least 30 days after the last dose of study drug and agreement 
to refrain from donating sperm during this same period 
Men with a pregnant partner must agree to remain abstinent or use a condom 
for the duration of the pregnancy. 
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. 
– 
Non-reproductive potential is defined below (but could be superseded by local 
definitions, if they are more stringent): 
Women who are postmenopausal (i.e., spontaneous(≥ 12 months of non-
therapy-induced amenorrhea for the past year confirmed by a follicle 
stimulating hormone [FSH] level greater than 40 mIU/mL unless the patient is 
receiving a hormonal therapy for their menopause) )  
Women who are surgically sterile (i.e., hysterectomy, complete bilateral 
oophorectomy) 
Men who are surgically sterile (i.e., castration) 
 
SECTION 4.1.2:  Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Pregnant or lactating, or intending to become pregnant during the study 
– 
Women who are not postmenopausal (postmenopausal defined as ≥ 12 months 
of non-therapy-induced amenorrhea) or surgically sterile must have a negative 
serum pregnancy test result within 2 days prior to initiation of study drug. 
• 
Hypersensitivity to monoclonal antibodies or to the active substance or any 
excipientsconstituents (sodium succinate, sucrose, polysorbate 20) of MHAA4549A 
study drug 
• 
Hypersensitivity to the active substance or to any excipients of oseltamivir 
• 
Investigational therapy within the 30 days prior to study treatment  
• 
Received prior therapy with any anti-influenza monoclonal antibody therapy 
(including MHAA4549A) within 8 months prior to study treatment 
• 
Current treatment (within 7 days of dosing) with probenecid, amantadine, or 
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• 
Patients who have taken more than a total of 6 doses (3 doses of peramivir) of 
anti-influenza therapy (e.g., oseltamivir, zanamivir, laninamivir, peramivir) in the 
period from onset of symptoms and prior to study treatment 
• 
Admission > 48 hours prior to study treatment 
• 
Onset of influenza symptoms (including fever, chills, malaise, dry cough, loss of 
appetite, myalgias, coryza, or nausea) > 5 days prior to study treatment  
• 
Positive influenza B or influenza A + B infection within 2 weeks prior to study 
treatment 
• 
High probability of mortality in the next 48 hours as determined by the investigator  
• 
Patient requiring home or baseline oxygenation therapy 
• 
Patient with history of chronic lung disease resulting in baselinewith a documented 
SpO2 < 95% off oxygen 
• 
Patient on a chronic dose of corticosteroids exceeding 10 mg/day of prednisone or 
equivalent steroid dose for a duration of greater than 14 days within 30 days of entry 
into study 
• 
Creatinine clearance ≤ 10 mL/min 
• 
Patients who received nasally administered influenza A vaccine within the last 
7 days prior to screening 
• 
Patients with the following significant immune suppression:  
– 
Bone marrow or solid organ transplant in the previous 12 months 
– 
Cancer chemotherapy in the previous 12 months 
– 
HIV infection with most recent CD4 < 200 cells/mL 
– 
Other significant immune suppression as determined by the investigator in 
discussion with the Sponsor Medical Monitor or representative 
• 
Patient on ECMO at time of randomization 
• 
Any disease or condition that would, in the opinion of the site investigator or 
Sponsor, place the subject at an unacceptable risk of injury or render the subject 
unable to meet the requirements of the protocol 
 
SECTION 4.3.1.1:  MHAA4549A and Placebo 
The Sponsor will supply MHAA4549A and matchingwill 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, packaging, and handling of MHAA4549A and 
placebo, see the Pharmacy Manualpharmacy manual and the MHAA4549A 
Investigator'sInvestigator’s Brochure. 


 
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The MHAA4549A vial delivers 10 mL (500 mg) of drug product solution, but may contain 
more (approximately 10.3 mL) than the stated volume to enable delivery of the entire 
10 mL volume.  MHAA4549A is formulated as 50 mg/mL in 10 mM sodium succinate, 
240 mM sucrose, and 0.02% (w/v) polysorbate 20 at pH 5.5 and is contained in a 15 mL 
forma vitrum (USP/PH. Eur. Type 1) glass vial.  The drug product is suitable for single 
use only and contains no preservatives. 
Placebo for MHAA4549A has the same composition as the drug product (without 
MHAA4549A) and is supplied in an identical vial configuration.  The placebo contains no 
preservatives and is suitable for single use only.  Placebo is formulated as 10 mM 
sodium succinate, 240 mM sucrose, and 0.02% polysorbate 20 at pH 5.5 in a total 
volume of 10 mL in a 15 mL forma vitrum (USP/PH. Eur. Type 1) glass vial. 
MHAA4549A and placebo are supplied in identical blinded vials labeled with unique kit 
numbers.  IxRS will assign kit numbers for each treatment arm; all treatment arms will be 
assigned the same total number of vials for each treatment, and the same preparation 
instructions.  Placebo is identical to active MHAA4549A in formulation but does not 
contain active drug substance. 
SECTION 4.3.1.2:  Oseltamivir (Tamiflu®) 
Oseltamivir (Tamiflu®) is an influenza NAI indicated for treatment of acute, 
uncomplicated influenza.  The Sponsor will provide 75-mg capsules of oseltamivir 
capsules for up to a 10-day treatment course.   (for 75- or 150-mg BID regimens).  For 
renal dose adjustments, follow local standard-of-care practice/local package insert and 
document in the eCRF. Capsules other than 75 mg (for 75- or 150-mg BID regimens) 
cannot be provided through the study IxRS.  In these instances, the study site may 
supply the appropriate dose and be reimbursed by the Sponsor. 
SECTION 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 3600 mg IV or 
MHAA4549A 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. 
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- to 0.22-μm in-line filter.  Compatibility testing has shown that 
MHAA4549A is stable when diluted in 0.9% normal saline in a polyvinylchloride bag, 
polyolefin bag, or ethylene vinyl acetate bag (EVA), at concentrations of 0.24 mg/mL up 
to 27.0 mg/mL.  Study drug must be administered within the treatment window outlined 


 
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in Section 3.1.1.  Further detailed instructions for preparation of study drug 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 will be halted until the safety of the drug is assessed. 
SECTION 4.3.2.2:  Oseltamivir-Neuraminidase Inhibitor (NAI) 
The Sponsor will supply 75-mg oseltamivir (Tamiflu®) capsules for this study for up to a 
10-day course.  Either (for 75- or 150-mg of oseltamivirBID regimens).  Oseltamivir will 
be administered twice daily as described in Section 3.1.1.  Capsules can be opened and 
the granules administered via nasogastric tube, if required.  Doses should be captured in 
the eCRF.  For renal dose adjustments, follow local standard-of-care practice/local 
package insert and document in the eCRF.  Capsules other than 75 mg (for 75- or 150-
mg BID regimens) cannot be provided through the study IxRS.  In these instances, the 
study site may supply the appropriate dose and be reimbursed by the Sponsor. 
SECTION 4.3.3:  Investigational Medicinal Product Accountability 
Investigational medicinal products (IMPs) required for completion of this study 
(i.e., MHAA4549A and 75-mg oseltamivir capsules) 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.  
SECTION 4.5:  CONCOMITANT THERAPY AND FOOD 
Concomitant medication 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/early discontinuation 
visit.  All concomitant medications should be reported to the investigator and recorded 
on the Concomitant Medications eCRF.  For any NAIs (e.g., oseltamivir, peramivir, 
zanamivir, laninamivir) that have been taken prior to study drug therapy, the number of 
doses and duration of therapy must be recorded. 
SECTION 4.5.2:  Prohibited Therapy 
Use of other NAIs, including but not limited to oseltamivir, zanamivir, laninamivir, and 
peramivir, are prohibited during the study, but allowed up to a total of 6 doses (3 doses 
for peramivir) in the period from onset of symptoms and prior to study treatment as 
outlined in the exclusion criteria.  Patients must start standard-of-care oseltamivir no 
later than 812 hours after completion of MHAA4549A administration.  If oseltamivir 
resistance is highly suspected or identified during treatment or if oseltamivir route of 
administration challenges are encountered then, following discussion with the Sponsor’s 
Medical Monitormedical representative, an alternative NAI to oseltamivir may be used. 


 
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SECTION 4.6.1:  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 by authorized representatives may be obtained only if allowed by and 
in accordance with local regulations and Independent Review Board (IRB)/Independent 
Ethics Committee (IEC) policies and procedures.  Informed Consent Forms (ICF) for 
enrolled patients and for patients who are not subsequently enrolled will be maintained 
at the study site. 
SECTION 4.6.2:  Diagnostic Testing for Enrollment 
All hospitalized patients with severe influenza A must be assessed for disease 
confirmation prior to and enrollment into the study.  A Sponsor-approved influenza test is 
required as an aid in the diagnosis of influenza A infection.  This requires a 
nasopharyngeal swab be introduced into one nostril.  A lower respiratory tract sample 
may be used if appropriate for the Sponsor-approved local PCR test.  Note that the 
influenza antigen test or influenza PCR test result must be available within the 48-hour 
screening window.   
SECTION 4.6.5:  
 
 
 
 
 
 
 
 
SECTION 4.6.6:  
 
 
 
 
 
 
 
SECTION 4.6.7:  Physical Examinations 
Day 1 physical examination is optional if already completed on Day -1 or -2. 
SECTION 4.6.8:  Vital Signs 
Vital signs will include measurements of respiratory rate, heartpulse rate, temperature, 
and systolic and diastolic blood pressures after the patient has been in a seated or 
supine position for > 5 minutes.  Temperature should be measured using the same 
methodology throughout the study and should be measured prior to administration of 


 
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any antipyretic drugs.  Patients in intensive care may have vital signs assessed 
following local procedures, but those procedures should be captured in the eCRF in 
accordance with the eCRF instructions. 
SECTION 4.6.9:  Oxygen Saturation Measurements 
To ensure that the respiratory status is well recorded, the following daily measurements 
will be performed.  Unless clinically contraindicated, allAll patients will have their SpO2 
and corresponding respiratory assessments recorded daily in the morning between 
6:00 a.m. and 12:00 noon local time.  PatientsUnless clinically contraindicated*, 
patients on low flow O2 will have a daily trial of their SpO2 while on and off the 
supplementation, as outlined in Appendix 2, and both values will be recorded. Appendix 
2, and both values will be recorded.  If a patient is clinically able to be removed from 
oxygen outside the time window above (6:00 a.m. to 12:00 noon), the trial-off data 
should be recorded as an unscheduled visit. 
If the patient is on oxygen supplementation, SpO2 measured by pulse oximetry and the 
corresponding respiratory assessments (e.g., FiO2, flow rate) will be recorded.  If the 
patient is on PPV, partial pressure of arterial O2 (PaO2) and the corresponding 
respiratory assessments (e.g., FiO2, ventilator mode, ventilator respiratory rate, positive 
end expiratory pressure) will be recorded.  If clinically appropriate (i.e., the patient is on 
non-invasive PPV), the conversion table in Appendix 11 may be used for PaO2.  
*If a patient has an SpO2  < 95% while on oxygen supplementation, he/she shall be 
considered to be “clinically contraindicated” from requiring a trial off oxygen; however, 
corresponding respiratory assessments should be recorded. 
SECTION 4.6.10:  Laboratory, Biomarker, and Other Biological Samples 
 
    
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 


 
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SECTION 4.6.11:  Electrocardiograms 
Single ECG recordings will be obtained at specified timepoints, as outlined in the 
schedule of assessmentsactivities (see Appendix 1a and Appendix 1b), 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:  HR, 
RR interval, QRS interval, PR duration, uncorrected QT interval, and QTcF (or 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 QTcFcorrected 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 corrected using Fridericia’s formula (QTcF) has stabilized on two successive 
ECGs.  The Medical Monitor should be notified.  If QTcF is not available, QTcB may be 
recorded.  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 4.9.2.  The investigator should also evaluate the patient for 
potential concurrent risk factors (e.g., electrolyte abnormalities, medications known to 
prolong the QT interval, severe bradycardia). 
SECTION 4.9.4:  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 AEs in this or other studies indicates a potential health 
hazard to patients. 
• 
Patient enrollment is unsatisfactory. 
 


 
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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 (GCP) 
• 
No further study activity (i.e., all patients have completed the study, and all 
obligations have been fulfilled) 
 
SECTION 4.10:  Assay Methods 
 
 
 
 
 
 
 
SECTION 5.1.1:  Risks Associated with MHAA4549A 
There are no known risks associated with MHAA4549A based on completed Phase 1 
(GV28916 and GV29609) and Phase 2a (GV28985) studies. 
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 assays with appropriate sensitivity and therapeutic 
tolerance will be employed to assess ATAs before and after treatment with 
MHAA4549A. 
SECTION 5.3.1:  Adverse Event Reporting Period 
After initiation of study drug, all adverse events, regardless of relationship to study 
drug, will be reported until study completion at the Day 60 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 
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becomes aware of a congenital anomaly/birth defect in a subsequently conceived 
offspring of a female patient exposed to study drug (see Section 5.4.3.3).   
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, a paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form should be completed and faxed 
or scanned and emailed to the SponsorSafety Risk Management or its designee 
immediately (i.e., no more than 24 hours after learning of the event), using the contact 
information provided to investigators (see Section 5.4.2.1).  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 after the last 
dose of study drug. administration.  A paper Clinical Trial Pregnancy Report 
eCRFReporting Form should be completed by the investigatorand submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
pregnancy) and submitted via), either by faxing or by scanning and emailing the form 
using the EDC system.  A pregnancy report will automatically be generated and sent to 
Safety Risk Managementfax number or email address provided in Section 5.4.2.1.  
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 
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, a paper Clinical Trial Pregnancy 
Reporting Form should be completed, faxed, or scanned and emailed to Safety Risk 
Management or its designee immediately (i.e., no more than 24 hours after learning of 
the pregnancy), using the contact information provided to investigators (see 
Section 5.4.2.1).  Once the EDC system is available, all information will need to be 
entered and submitted via the EDC system. 
SECTION 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 after the dose of study drug. administration.  A paper Clinical Trial Pregnancy 


 
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Report eCRFReporting Form should be completed by and submitted to the 
investigatorSponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the pregnancy) and submitted via), either by faxing or by scanning and 
emailing the EDC system.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.  OnceAfter 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. 
In the event that the EDC system is unavailable, follow reporting instructions provided in 
Section 5.4.2.1. 
SECTION 5.5.1:  Investigator Follow-Up 
All pregnancies reported during the study should be followed until pregnancy outcome.  
If the EDC system is not available at the time of pregnancy outcome, follow reporting 
instructions provided in Section 5.4.3. 
SECTION 5.6:  POST-STUDY ADVERSE EVENTS 
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 
60 days (see Section 5.3.1) after the last dose of study drug), if the event is believed to 
be related to prior study drug treatment.    
TheThese events should be reported through the use of the Adverse Event eCRF and 
submit the report via the EDC system.  However, if the EDC system is not available, 
the investigator should report these events directly to Roche,the Sponsor or its designee, 
either by faxing or by scanning and emailing the a paper Clinical Trial Serious Adverse 
Event / Adverse Event of Special Interest Reporting Form using the fax number or email 
address provided to investigators (refer to site binder). 
SECTION 6.4:  EFFICACY ANALYSES 
Time to event data will be analyzedcomputed using Kaplan-Meier methodology and 
stratified Cox proportional hazards models 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 
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The ordinal outcomes will be analyzed using a proportional odds model.  To supplement 
the overall summary odds ratio, separate odds ratios will be estimated for each 
dichotomized definition of improvement that can be formulated from the components of 
the ordinal outcome.  A test for the proportionality assumption will also be made.  
Patients discharged from the hospital to a rehabilitation facility will be included in 
category 5.  Patients discharged from the hospital to a nursing home will also be 
included in category 5, unless the patient lived in a nursing home prior to admission to 
the hospital, in which case the patient will be characterized based on resumption of 
normal activities. 
Estimation of the treatment difference of proportions and the correspondingits 95% 
confidence intervals 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. 
SECTION 6.4.2:  Secondary Efficacy Endpoints 
• 
Clinical status at Days 1-7, 14, and 30 categorizing proportion of patients in each 
of the 6 pre-defined categories  
• 
Proportion of patients with clinical failure after 24 hours post-infusion of study drug 
• 
Median time to clinical resolution of vital signs 
• 
Hazard ratio for mortality at Day 14, Day 30, and Day 60 
• 
Mean and median AUC of viral load 
• 
Mean and median peak viral load 
• 
Median duration of viral shedding in nasopharyngeal samples 
• 
Proportion of patients with detectable infection 
• 
Median duration of hospitalization 
• 
Median duration of ICU stay 
• 
Proportion of patients requiring antibiotics for respiratory indications during study 
• 
Proportion of patients with influenza secondary complications 
• 
Median duration of ventilation 
• 
Proportion of patients who are readmitted by Day 30 and Day 60 
 
SECTION 6.6:  PharmacodynamicPharmacokinetic Analyses 
This heading was updated. 
SECTION 6.7:  IMMUNOGENICITY ANALYSES 
The immunogenicity analyses will include patients with at least one predose and one 
postdose ATA assessment, with patients grouped according to treatment received. 


 
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The numbers and proportions of ATA-positive patients and ATA-negative patients 
during the treatment and follow-up periods will be summarized by treatment group.  
Patients are considered to be ATA positive if they are ATA negative at baseline but 
develop an ATA response following study drug administration (treatment-induced 
ATA response), or if they are ATA positive at baseline and the titer of one or more post-
baseline samples is at least 4-fold greater (i.e., ≥ 0.60 titer units) than the titer of the 
baseline sample (treatment-enhanced ATA response).  Patients are considered to be 
ATA negative if they are ATA negative at baseline and all post-baseline samples are 
negative, or if they are ATA positive at baseline but do not have any post-baseline 
samples with a titer that is at least 4-fold greater than the titer of the baseline sample 
(treatment unaffected). 
The relationship between ATA status and safety, efficacy, PK, and biomarker endpoints 
will be analyzed and reported descriptively via subgroup analyses. 
SECTION 6.8:  Biomarker Analyses 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
SECTION 6.9:  Exploratory Pharmacokinetics Analyses 
 
 
 
SECTION 8.4:  CONFIDENTIALITY 
Given the exploratory nature of the biomarker 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). 


 
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FIGURE 1:  Phase 2b Study Design (GV29216) 
Figure 1 has been revised to clarify the timing of assessments and division of 
assessment periods. 
TABLE 3:  Laboratory Tests at Screening 
Table 3 has been revised for consistency with Section 4.6.10. 
TABLE 1:  Interim Efficacy Results from Phase 2a Challenge Study 
(GV28985) 
Table 1 has been deleted.  Subsequent tables have been renumbered accordingly. 
TABLE 1:  GV28985 Efficacy Results from Intent-to-Treat Infected 
Population 
Table 1 has been added.  Subsequent tables have been renumbered accordingly. 
APPENDIX 1a:  Schedule of Activities 
The schedule of assessments has been revised to reflect the changes to the protocol. 
APPENDIX 1b:  Schedule of Activities:  Follow-Up Period 
The schedule of assessments has been revised to reflect the changes to the protocol. 
APPENDIX 2:  Time to Normalization of Respiratory Function 
Appendix 2 has been revised for consistency with the other changes in the protocol. 
APPENDIX 12:  Clinical Status Assessment 
Appendix 12 has been added.  Subsequent appendices have been renumbered 
accordingly. 
SAMPLE INFORMED CONSENT FORM 
The sample Informed Consent Form has been revised to reflect the changes to the 
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TABLE OF CONTENTS 
PROTOCOL ACCEPTANCE FORM .................................................................. 48 
PROTOCOL SYNOPSIS .................................................................................... 49 
1. 
BACKGROUND .......................................................................................... 60 
1.1 
Background on Influenza....................................................... 60 
1.2 
Background on MHAA4549A................................................. 60 
1.2.1 
Nonclinical Background ......................................................... 60 
1.2.2 
Clinical Safety Background.................................................... 61 
1.2.2.1 
Phase 1 Entry-into-Human Study (GV28916)........................ 61 
1.2.2.2 
Phase 1 High-Dose Safety Study (GV29609)........................ 62 
1.2.2.3 
Phase 2a Influenza Nasal Challenge Study 
(GV28985)............................................................................. 62 
1.2.3 
Clinical Pharmacokinetics...................................................... 63 
1.2.4 
Clinical Efficacy Background ................................................. 64 
1.2.4.1 
Virologic Efficacy ................................................................... 64 
1.2.4.2 
Symptomatic Efficacy ............................................................ 65 
1.3 
Study Rationale and Benefit-Risk Assessment...................... 66 
1.3.1 
Study Rationale ..................................................................... 66 
1.3.2 
Benefit-Risk Assessment....................................................... 67 
1.3.2.1 
Patient Monitoring and Supervision ....................................... 67 
2. 
OBJECTIVES.............................................................................................. 68 
2.1 
Safety Objectives................................................................... 68 
2.2 
Primary Efficacy Objectives................................................... 68 
2.3 
Secondary Efficacy Objectives .............................................. 68 
2.4 
Pharmacokinetic Objectives .................................................. 69 
2.5 
Exploratory Objectives........................................................... 70 
3. 
STUDY DESIGN ......................................................................................... 70 
3.1 
Description of Study .............................................................. 70 
3.1.1 
Overview of Study Design ..................................................... 70 
3.1.2 
Internal Monitoring Committee and Scientific 
Oversight Committee............................................................. 72 


 
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3.1.3 
End of Study.......................................................................... 73 
3.2 
Rationale for Study Design.................................................... 73 
3.2.1 
Rationale for Study Design.................................................... 73 
3.2.2 
Rationale for Patient Population and Primary 
Endpoint ................................................................................ 73 
3.2.3 
Rationale for Control Group and Treatment 
Window.................................................................................. 74 
3.2.4 
Rationale for MHAA4549A Dosage ....................................... 76 
3.2.5 
Rationale for Biomarker Assessments................................... 77 
3.3 
Outcome Measures ............................................................... 78 
3.3.1 
Safety Outcome Measures .................................................... 78 
3.3.2 
Primary Efficacy Outcome Measures .................................... 78 
3.3.3 
Secondary Efficacy Outcome Measures................................ 78 
3.3.4 
Pharmacokinetic Outcome Measures.................................... 79 
3.3.5 
Exploratory Outcome Measures ............................................ 80 
4. 
MATERIALS AND METHODS .................................................................... 81 
4.1 
Patients.................................................................................. 81 
4.1.1 
Inclusion Criteria.................................................................... 81 
4.1.2 
Exclusion Criteria................................................................... 82 
4.2 
Method of Treatment Assignment and Blinding..................... 83 
4.3 
Study Treatment.................................................................... 85 
4.3.1 
Formulation, Packaging, and Handling.................................. 85 
4.3.1.1 
MHAA4549A and Placebo..................................................... 85 
4.3.1.2 
Oseltamivir (Tamiflu®)........................................................... 85 
4.3.2 
Dosage, Administration, and Compliance.............................. 85 
4.3.2.1 
MHAA4549A and Placebo..................................................... 85 
4.3.2.2 
Oseltamivir-Neuraminidase Inhibitor (NAI) ............................ 86 
4.3.3 
Investigational Medicinal Product Accountability ................... 86 
4.4 
Post-Trial Access to MHAA4549A......................................... 87 
4.5 
Concomitant Therapy and Food ............................................ 88 
4.5.1 
Permitted Therapy ................................................................. 88 
4.5.2 
Prohibited Therapy ................................................................ 88 
4.5.3 
Prohibited Food ..................................................................... 88 




 
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5.2 
Safety Parameters and Definitions ........................................ 98 
5.2.1 
Adverse Events ..................................................................... 99 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 99 
5.2.3 
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) ............................ 100 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters.............................................. 101 
5.3.1 
Adverse Event Reporting Period ......................................... 101 
5.3.2 
Eliciting Adverse Event Information ..................................... 102 
5.3.3 
Assessment of Severity of Adverse Events ......................... 102 
5.3.4 
Assessment of Causality of Adverse Events ....................... 102 
5.3.5 
Procedures for Recording Adverse Events.......................... 103 
5.3.5.1 
Diagnosis versus Signs and Symptoms............................... 103 
5.3.5.2 
Adverse Events That Are Secondary to Other 
Events.................................................................................. 104 
5.3.5.3 
Persistent or Recurrent Adverse Events.............................. 104 
5.3.5.4 
Abnormal Laboratory Values ............................................... 105 
5.3.5.5 
Abnormal Vital Sign Values ................................................. 106 
5.3.5.6 
Abnormal Liver Function Tests............................................ 106 
5.3.5.7 
Deaths ................................................................................. 106 
5.3.5.8 
Preexisting Medical Conditions............................................ 107 
5.3.5.9 
Lack of Efficacy or Worsening of Influenza A 
Infection............................................................................... 107 
5.3.5.10 
Hospitalization or Prolonged Hospitalization........................ 108 
5.3.5.11 
Adverse Events Associated with an Overdose .................... 108 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 109 
5.4.1 
Emergency Medical Contacts.............................................. 109 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest.................................................................... 110 
5.4.2.1 
Events That Occur prior to Study Drug Initiation.................. 110 
5.4.2.2 
Events That Occur after Study Drug Initiation...................... 110 
5.4.3 
Reporting Requirements for Pregnancies............................ 110 


 
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5.4.3.1 
Pregnancies in Female Patients.......................................... 110 
5.4.3.2 
Pregnancies in Female Partners of Male Patients............... 111 
5.4.3.3 
Congenital Anomalies/Birth Defects and 
Abortions ............................................................................. 111 
5.5 
Follow-Up of Patients after Adverse Events ........................ 111 
5.5.1 
Investigator Follow-Up......................................................... 111 
5.5.2 
Sponsor Follow-Up .............................................................. 112 
5.6 
Post-Study Adverse Events................................................. 112 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 112 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 113 
6.1 
Determination of Sample Size ............................................. 113 
6.2 
Summaries of Conduct of Study.......................................... 114 
6.3 
Summaries of Treatment Group Comparability ................... 114 
6.4 
Efficacy Analyses ................................................................ 115 
6.4.1 
Primary Efficacy Endpoint.................................................... 115 
6.4.2 
Secondary Efficacy Endpoints............................................. 115 
6.4.3 
Subgroup Analyses ............................................................. 116 
6.5 
Safety Analyses................................................................... 116 
6.6 
Pharmacokinetic Analyses................................................... 117 
6.7 
Immunogenicity Analyses.................................................... 117 
6.8 
Biomarker Analyses............................................................. 117 
6.9 
Exploratory Pharmacokinetics Analyses.............................. 118 
6.10 
Optional Interim Analyses.................................................... 118 
7. 
DATA COLLECTION AND MANAGEMENT ............................................. 118 
7.1 
Data Quality Assurance....................................................... 118 
7.2 
Electronic Case Report Forms............................................. 119 
7.3 
Source Data Documentation................................................ 119 
7.4 
Use of Computerized Systems ............................................ 120 
7.5 
Retention of Records........................................................... 120 
8. 
ETHICAL CONSIDERATIONS.................................................................. 120 
8.1 
Compliance with Laws and Regulations .............................. 120 


 
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8.2 
Informed Consent ................................................................ 120 
8.3 
Institutional Review Board or Ethics Committee.................. 121 
8.4 
Confidentiality...................................................................... 122 
8.5 
Financial Disclosure ............................................................ 122 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 123 
9.1 
Study Documentation .......................................................... 123 
9.2 
Protocol Deviations.............................................................. 123 
9.3 
Site Inspections ................................................................... 123 
9.4 
Administrative Structure....................................................... 123 
9.5 
Publication of Data and Protection of Trade 
Secrets ................................................................................ 124 
9.6 
Protocol Amendments ......................................................... 124 
10. REFERENCES ......................................................................................... 126 
 
 
LIST OF TABLES 
Table 1 
GV28985 Efficacy Results from Intent-to-Treat Infected 
Population................................................................................... 66 
Table 2 
Oseltamivir Dosing Regimen....................................................... 75 
Table 3 
Laboratory Tests at Screening.................................................... 91 
Table 4 
Laboratory Tests during the Study ..............................................92 
Table 5 
Adverse Event Grading (Severity) Scale................................... 102 
Table 6 
Causal Attribution Guidance ..................................................... 103 
Table 7 
Operating Characteristics for Proposed Study Design for 
Several Possible True Underlying Median Values .................... 114 
 
 
LIST OF FIGURES 
Figure 1 
Phase 2b Study Design (GV29216)............................................ 72 
Figure 2 
Semi-Quantitative Pharmacokinetic Model of Nasal 
Exposure..................................................................................... 77 
 




 
MHAA4549A—Genentech, Inc. 
48/Protocol GV29216, Version 7 (Global)   
PROTOCOL ACCEPTANCE FORM 
TITLE: 
A PHASE 2 RANDOMIZED, DOUBLE-BLIND 
PLACEBO CONTROLLED TRIAL OF MHAA4549A, 
A MONOCLONAL ANTIBODY, IN COMBINATION 
WITH OSELTAMIVIR VERSUS OSELTAMIVIR FOR 
TREATMENT OF SEVERE INFLUENZA A 
INFECTION 
PROTOCOL NUMBER: GV29216 
VERSION NUMBER: 
7 (Global) 
EUDRACT NUMBER: 
2014-000461-43 
IND NUMBER: 
117,318 
TEST PRODUCT: 
MHAA4549A 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
Genentech, Inc. 
 
I agree to conduct the study in accordance with the current protocol. 
  
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please return a copy of the signed form as instructed by the CRO.  Please retain the 
original for your study files. 
 


 
 
MHAA4549A—Genentech, Inc. 
49/Protocol GV29216, Version 7 (Global)   
PROTOCOL SYNOPSIS 
TITLE: 
A PHASE 2 RANDOMIZED, DOUBLE-BLIND PLACEBO 
CONTROLLED TRIAL OF MHAA4549A, A 
MONOCLONAL ANTIBODY IN COMBINATION WITH 
OSELTAMIVIR VERSUS OSELTAMIVIR FOR 
TREATMENT OF SEVERE INFLUENZA A INFECTION 
PROTOCOL NUMBER: 
GV29216 
VERSION NUMBER: 
7 (Global) 
EUDRACT NUMBER: 
2014-000461-43 
IND NUMBER: 
117,318 
TEST PRODUCT: 
MHAA4549A 
INDICATION: 
INFLUENZA A 
SPONSOR: 
Genentech, Inc. 
 
Objectives 
Safety Objectives 
The safety objectives for this study are as follows: 
• 
To evaluate the safety of MHAA4549A in combination with oseltamivir compared with 
placebo and oseltamivir in patients with severe influenza A, focusing on the nature, 
frequency, and severity of serious and non-serious adverse events (AEs), as well as effects 
on laboratory values, vital signs, electrocardiogram (ECG) parameters, anti-therapeutic 
antibodies (ATA), and other safety biomarkers 
Efficacy Objectives 
The primary efficacy objective for this study is as follows: 
• 
To determine the time to normalization of respiratory function of patients dosed with 
MHAA4549A in combination with oseltamivir compared to patients dosed with placebo and 
oseltamivir 
The secondary efficacy objectives for this study are as follows: 
• 
To compare the clinical status of patients at Days 1-7, 14, and 30 using an ordinal 
outcome with six clinical statuses.  Patients will be categorized into one of the following 
six mutually exclusive categories on Days 1-7, 14, and 30 
1. Death; 
2. In the ICU; 
3. Non-ICU hospitalization, requiring supplemental oxygen; 
4. Non-ICU hospitalization, not requiring supplemental oxygen; 
5. Not hospitalized, but unable to resume normal activities; or 
6. Not hospitalized with full resumption of normal activities 
• 
To measure clinical failure after 24 hours post-infusion of study drug  
• 
To determine the time to clinical resolution of abnormal vital signs 
• 
To measure mortality in patients 
• 
To determine changes in the extent and duration of viral burden in nasopharyngeal samples 
as a measure of pharmacodynamic response 




 
 
MHAA4549A—Genentech, Inc. 
51/Protocol GV29216, Version 7 (Global)   
or a single IV dose of 8400 mg MHAA4549A in hospitalized patients with severe influenza A in 
combination with oseltamivir versus a comparator arm of oseltamivir with placebo.  A Sponsor-
approved influenza test that includes influenza antigen test or influenza polymerase chain 
reaction (PCR) test must be used to diagnose influenza A infection for study eligibility.   
Initially, GV29216 enrolled and randomized patients into two treatment groups: a single IV dose 
of 3600 mg of MHAA4549A with oseltamivir or a single IV dose of placebo with oseltamivir.   
Patients will be randomized 1:1:1 into three treatment groups:  a single IV dose of 3600 mg of 
MHAA4549A with oseltamivir, a single IV dose of 8400 mg of MHAA4549A with oseltamivir, or a 
single IV dose of placebo with oseltamivir. 
All patients must begin study drug infusion within 48 hours of hospital admission; therefore, 
screening must be completed within this window.  All patients will receive oseltamivir for a 
minimum of 5 days (10 doses), starting on Day 1 beginning no later than 12 hours after 
completion of study drug administration.  All patients will be followed for 60 days from the time 
of study drug administration. 
Number of Patients 
The study has a planned enrollment of approximately 330 patients (adult men and women) 
globally.  Patients will receive 3600 mg MHAA4549A, 8400 mg, or placebo in 1:1:1 ratio.  The 
number of patients on PPV should not exceed 45% of the total enrolled patients. 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Men or women ≥ 18 years of age on day of signing informed consent or obtaining surrogate 
consent from an authorized representative 
• 
Diagnosis of influenza A where a Sponsor-approved influenza test is used as an aid in 
diagnosis.  A Sponsor-approved influenza test includes: 
– 
Influenza antigen test –OR– 
– 
Influenza polymerase chain reaction (PCR) test  
• 
One of the following markers of severity within 24 hours of hospital admission: 
– 
Requirement for PPV, OR 
– 
Requirement for O2 supplementation to maintain SpO2 > 92% (Source documentation 
should show that the patient’s SpO2 was less than 92% off oxygen.  Source 
documentation may consist of either a SpO2 off oxygen with a value below 92% or a 
documentation of the Investigator’s rationale in lieu of this SpO2 documentation.) 
• 
A negative urine or serum pregnancy test for women of childbearing potential 
• 
Patients of reproductive potential must agree to use reliable means of contraception as 
described below as a minimum (adherence to more stringent local requirements may be 
required): 
– 
For women who are not postmenopausal (postmenopausal defined as ≥ 12 months of 
non-therapy-induced amenorrhea) or surgically sterile (absence of ovaries and/or 
uterus):  agreement to remain abstinent or use two adequate methods of contraception, 
including at least one method with a failure rate of < 1% per year, during the treatment 
period and for at least 120 days after the dose of 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 post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
Barrier methods must always be supplemented with the use of a spermicide. 


 
 
MHAA4549A—Genentech, Inc. 
52/Protocol GV29216, Version 7 (Global)   
Examples of contraceptive methods with a failure rate of < 1% per year include tubal 
ligation, male sterilization, hormonal implants, proper use of combined oral or injected 
hormonal contraceptives, and certain intrauterine devices. 
– 
For men:  agreement to remain abstinent or use a condom during the treatment period 
and for at least 30 days after the dose of study drug and agreement to refrain from 
donating sperm during this same period 
Men with a pregnant partner must agree to remain abstinent or use a condom for the 
duration of the pregnancy. 
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. 
 
Non-reproductive potential is defined below (but could be superseded by local definitions, if they 
are more stringent): 
– 
Women who are postmenopausal (≥ 12 months of non-therapy-induced amenorrhea)  
– 
Women who are surgically sterile (i.e., hysterectomy, complete bilateral oophorectomy) 
– 
Men who are surgically sterile (castration) 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Pregnant or lactating, or intending to become pregnant during the study 
− 
Women who are not postmenopausal (postmenopausal defined as ≥ 12 months of 
non-therapy-induced amenorrhea) or who are not surgically sterile must have a negative 
pregnancy test result within 2 days prior to study treatment 
• 
Hypersensitivity to monoclonal antibodies or to any constituents (sodium succinate, 
sucrose, polysorbate 20) of MHAA4549A study drug 
• 
Hypersensitivity to the active substance or to any excipients of oseltamivir 
• 
Investigational therapy within the 30 days prior to study treatment  
• 
Received prior therapy with any anti-influenza monoclonal antibody therapy (including 
MHAA4549A) within 8 months prior to study treatment 
• 
Current treatment (within 7 days of dosing) with probenecid, amantadine, or rimantidine 
• 
Patients who have taken more than a total of 6 doses (3 doses for peramivir) of 
anti-influenza therapy (e.g., oseltamivir, zanamivir, laninamivir, peramivir) in the period 
from onset of symptoms and prior to study treatment 
• 
Admission > 48 hours prior to study treatment 
• 
Onset of influenza symptoms (including fever, chills, malaise, dry cough, loss of appetite, 
myalgias, coryza, or nausea) > 5 days prior to study treatment 
• 
Positive influenza B or influenza A + B infection within 2 weeks prior to study treatment 
• 
High probability of mortality in the next 48 hours as determined by the investigator  
• 
Patient requiring home or baseline oxygenation therapy 
• 
Patient with history of chronic lung disease with a documented SpO2 < 95% off oxygen 
• 
Patient on chronic dose of corticosteroids exceeding 10 mg/day of prednisone or equivalent 
steroid dose for a duration of greater than 14 days within 30 days of entry into study 
• 
Creatinine clearance ≤10 mL/min 
• 
Patients who received nasally administered influenza A vaccine within 7 days prior to 
screening 


 
 
MHAA4549A—Genentech, Inc. 
53/Protocol GV29216, Version 7 (Global)   
• 
Patients with the following significant immune suppression: 
– 
Bone marrow or solid organ transplant in the previous 12 months 
– 
Cancer chemotherapy in the previous 12 month 
– 
Human immunodeficiency virus (HIV) infection with most recent CD4 < 200 cells/mL 
– 
Other significant immune suppression as determined by the investigator in discussion 
with the Sponsor Medical Monitor 
• 
Patient on extracorporeal membrane oxygenation (ECMO) at time of randomization 
• 
Any disease or condition that would, in the opinion of the site investigator or Sponsor, place 
the subject at an unacceptable risk of injury or render the subject unable to meet the 
requirements of the protocol 
Length of Study 
This study will consist of the following study periods: 
• 
A screening period of 48 hours, beginning at time of hospital admission 
• 
A treatment period of 1 day, during which patients will receive a single dose of MHAA4549A 
or placebo and a minimum of 5 days of oseltamivir. 
• 
A follow-up period beginning at hospital discharge through 60 days post study drug 
(MHAA4549A/placebo) administration 
End of Study 
The end of the study is defined as the first day when all patients have had a study completion 
visit or early termination visit or have otherwise been discontinued from the study. 
Outcome Measures 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
AEs and clinical laboratory abnormalities 
• 
Vital signs, physical findings, ATAs, and clinical laboratory results during and following 
administration of MHAA4549A 
Efficacy Outcome Measures 
The primary outcome measure for this study is as follows: 
• 
Time to normalization of respiratory function defined as: 
– 
The time to cessation of O2 support resulting in a stable SpO2 ≥ 95%  
The secondary efficacy outcome measures for this study are as follows: 
• 
Clinical status of patient at Days 1-7, 14, and 30.  This is an ordinal outcome with six 
mutually exclusive categories: 
1. Death; 
2. In the ICU; 
3. Non-ICU hospitalization, requiring supplemental oxygen; 
4. Non-ICU hospitalization, not requiring supplemental oxygen; 
5. Not hospitalized, but unable to resume normal activities; or 
6. Not hospitalized with full resumption of normal activities 
• 
Clinical failure after 24 hours post-infusion of study drug defined as: 
– 
Progression to increased O2 requirement defined by an increase in oxygen 
supplementation from low flow oxygen (i.e., 2 − 6 L/min) to high flow oxygen (i.e., > 6 
L/min) or from oxygen supplementation alone to any PPV or ECMO 
– 
Progression to ICU 
– 
Prolonged ventilation or O2 support defined by > 2 weeks, or 
– 
Death 






 
 
MHAA4549A—Genentech, Inc. 
56/Protocol GV29216, Version 7 (Global)   
Time to event data will be computed using Kaplan-Meier methodology and stratified Cox 
proportional hazards models 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.  For continuous endpoints, 
Analysis of Covariance methods (after appropriate transformation of data) will be used to 
estimate treatment differences at 95% confidence intervals.  
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 I error penalty of 0.0001 will be taken.  In addition, as discussed below, the 
Sponsor will conduct interim safety analyses separate from and in conjunction with the above. 
Determination of Sample Size   
A total of 330 patients will be enrolled in this study.  It is assumed that the median time to 
normalization of respiratory function in the control arm is 5 days 
 


 
 
MHAA4549A—Genentech, Inc. 
57/Protocol GV29216, Version 7 (Global)   
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
 
 
AE 
Adverse event 
AESI 
Adverse events of special interest 
ALT 
Alanine aminotransferase 
APAC 
Asia-Pacific 
APACHE 
Acute Physiology and Chronic Health Evaluation 
APTT 
Activated partial thromboplastin time 
ARDS 
Acute respiratory distress syndrome 
AST 
Aspartate aminotransferase 
ATA 
Anti-therapeutic antibody 
AUC 
Area under serum concentration-time curve 
AUC0-infinity 
Area under the curve from zero to infinity 
AUEC 
Area under viral load-time curve 
BID 
Twice a day 
°C 
Celsius 
CDC 
Centers for Disease Control and Prevention 
CL 
clearance 
Cmax 
Maximum observed concentration 
Cmin 
Minimum observed concentration 
CPK 
Creatine phosphokinase 
CRO 
Contract research organization 
CRP 
C-reactive protein 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAIDS 
Division of Acquired Immunodeficiency Syndrome 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ECMO 
Extracorporeal membrane oxygenation 
EDC 
Electronic data capture 
EIH 
Entry-into-human 
ELISA 
Enzyme-linked immunosorbent assay 
EMEA 
Europe, Middle East, and Africa 
ESR 
Erythrocyte sedimentation rate  
EU 
European Union 
EVA 
Ethylene vinyl acetate 
FDA 
Food and Drug Administration 


 
 
MHAA4549A—Genentech, Inc. 
58/Protocol GV29216, Version 7 (Global)   
FiO2 
Fraction of inspired oxygen 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
HA 
Hemagglutinin 
HAI 
Hemagglutinin inhibition 
HAP 
Hospital Acquired Pneumonia 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
hMPV 
Human metapneumovirus 
HPLC 
High-performance liquid chromatography 
HR 
Heart rate 
HRP 
Horseradish peroxidase 
HRV 
Human rhinovirus 
 
 
IC50 
Concentration required for 50% inhibition 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
ICU 
Intensive care unit 
IDSA 
Infectious Diseases Society of America 
IEC 
Independent Ethics Committee 
IMC 
Internal Monitoring Committee 
IMP 
Investigational medicinal product 
IND 
Investigational New Drug (application) 
INR 
International normalization ratio 
IQR 
Interquartile range 
IRB 
Institutional Review Board 
IRR 
Infusion-related reactions 
ITT 
Intent-to-treat 
ITTI 
Intent-to-treat infected 
IV 
Intravenous 
IxRS 
Interactive voice and web response system 
LFTs 
Liver function tests 
LLN 
Lower limit of normal 
LPLV 
Last patient, last visit 
NA 
Neuraminidase 
NAI 
Neuraminidase inhibitor 


 
 
MHAA4549A—Genentech, Inc. 
59/Protocol GV29216, Version 7 (Global)   
NIMP 
Non-investigational medicinal product 
O2 
Oxygen 
PaO2 
Partial pressure of arterial oxygen 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamic 
PE 
Paired end 
PK 
Pharmacokinetic 
PIV 
Parainfluenza virus 
PPV 
Positive pressure ventilation 
PT 
Prothrombin time 
qPCR 
Quantitative polymerase chain reaction 
QTcB 
QT interval corrected using Bazett’s formula 
QTcF 
QT interval corrected using Fridericia’s formula 
RBC 
Red blood cell 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SOA 
Schedule of activities 
SOC 
Scientific Oversight Committee 
SOFA 
Sequential Organ Failure Assessment 
SpO2 
Oxygen saturation by pulse oximetry 
SUSAR 
Suspected unexpected serious adverse reactions 
TCID50 
50% tissue culture infectious dose 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
US 
United States 
UVTM 
Universal viral transport medium 
VAP 
Ventilation Acquired Pneumonia 
WBC 
White blood cell 


 
 
MHAA4549A—Genentech, Inc. 
60/Protocol GV29216, Version 7 (Global)   
1. 
BACKGROUND 
1.1 
BACKGROUND ON INFLUENZA  
Influenza A is a membrane-enveloped RNA virus that causes significant morbidity and 
mortality.  Currently, there is a great need in hospitalized influenza patients for a 
parenteral therapeutic option that is well tolerated, can rapidly resolve influenza-related 
signs and symptoms, decrease mortality, reduce hospital and intensive care unit (ICU) 
stays, as well as have a prolonged window for initiation of treatment beyond the current 
standard of care (i.e., within 48 hours of the onset of flu symptoms). 
Approximately 200,000 to 278,000 patients are hospitalized with severe influenza 
infections annually in the United States (US) (Thompson et al. 2004; Zhou et al. 2012), 
and assuming the same rate reported in the US, an estimated 319,000 to 
445,000 patients are hospitalized in the European Union (EU).  Hospitalization due to 
severe influenza is associated with high mortality (4%−8%), ICU admission (5%−17%; 
Lee and Ison 2012), mechanical ventilation support in an ICU setting (7%−11%; 
Doshi et al. 2011), and prolonged hospital stays (5−9 days; Lee and Ison 2012).  During 
a pandemic season, the outcomes may be more serious, with up to 34% of patients 
requiring ICU care and a mortality rate as high as 15% (Lee and Ison 2012). 
Influenza infection is an upper and lower respiratory disease with a broad spectrum of 
presentations that can result in fever, shortness-of-breath, pneumonia, respiratory 
failure, secondary respiratory infections, and even death.  The standard of care therapy 
for patients hospitalized with influenza consists of supportive measures and 
administration of available antiviral agents, primarily neuraminidase inhibitors (NAI) that 
include but are not limited to oseltamivir, zanamivir, laninamivir, and peramivir.  
However, a significant unmet medical need still exists in the severely ill patient 
population, as evidenced by the considerable degree of morbidity and mortality in this 
setting.  To address this need, the Sponsor is developing a highly-specific 
anti-influenza A (MHAA4549A) antibody therapy for treatment of hospitalized patients 
with severe influenza. 
1.2 
BACKGROUND ON MHAA4549A  
1.2.1 
Nonclinical Background 
MHAA4549A is a human monoclonal IgG1 antibody that binds to the influenza A virus 
and is 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 


 
 
MHAA4549A—Genentech, Inc. 
61/Protocol GV29216, Version 7 (Global)   
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. 
1.2.2 
Clinical Safety Background 
To date, MHAA4549A has been shown to be safe and well tolerated in three clinical 
studies, which altogether enrolled 84 healthy volunteers who were dosed with 
MHAA4549A.  
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 (n = 5) or MHAA4549A (n = 16) at 1.5, 5, 15, 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 four 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 (four 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 and those who received 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 1 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 results or ECG 
measurements.  For all clinical laboratory results, no relevant differences in mean 
values or deviations from baseline over time were observed in subjects receiving 
MHAA4549A doses as compared to placebo.  No drug-emergent anti-therapeutic 
antibodies (ATAs) were detected in this study. 


 
 
MHAA4549A—Genentech, Inc. 
62/Protocol GV29216, Version 7 (Global)   
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 (n = 6) or MHAA4549A (n = 8) at 8400 mg (Cohort A) or 10800 mg 
(Cohort B) and were followed for 120 days. 
A total of 34 TEAEs were reported by 12 of the 14 subjects (85.7%) who received one 
dose of the study medication or placebo (safety population). Of these 34 TEAEs, 
24 TEAEs were reported by 7 of the 8 subjects (87.5%) who had received MHAA4549A 
and 10 TEAEs were reported by 5 of the 6 subjects (83.3%) who had received placebo. 
TEAEs were reported by 3 of the 4 subjects receiving 8400 mg MHAA4549A and all 4 
subjects receiving 10800 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 (4 subjects who received 
MHAA4549A [3 subjects in Cohort A, 1 subject in Cohort B]) and nasopharyngitis 
(3 subjects who received MHAA4549A [1 subject in Cohort A, 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 1 subject who received 8400 mg 
MHAA4549A, and elevations of blood creatine phosphokinase [CK] observed twice in 
1 subject who received 10800 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 to 
36 hours after inoculation, 60 subjects received single IV doses of 400, 1200, 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).  Consistent 
with the Phase 1 studies (GV28916 and GV29609), there was no evidence of a dose-
related pattern of TEAEs in MHAA4549A-treated subjects.  Expected influenza-related 
symptoms and AEs were observed in inoculated subjects; these influenza-related AEs 
were similar in subjects who received MHAA4549A or placebo.  Of the 101 subjects 


 
 
MHAA4549A—Genentech, Inc. 
63/Protocol GV29216, Version 7 (Global)   
inoculated, 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%), which occurred in a similar pattern across all 
treatment groups.  Thirty-six of the 86 subjects (42%) experienced at least 
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 in 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 subject 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 
postoperative 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 were dose proportional with a mean half-life of approximately 23 days 
(range: 21.9−24.6 days).  The pharmacokinetic (PK) profile appeared consistent with 
that of a human IgG1 antibody that lacks known endogenous host targets 
(Bai et al. 2012; 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 pharmacokinetics.  The group mean 
maximum observed concentration (Cmax) increased in a dose-proportional manner, at 
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 


 
 
MHAA4549A—Genentech, Inc. 
64/Protocol GV29216, Version 7 (Global)   
1800 and 18100 day • µg/mL for the 400- and 3600-mg dose groups, respectively, and 
was approximately dose proportional.  PK data from the Phase 2a study (GV28985) are 
consistent with those observed in the Phase 1 EIH study (GV28916), with 
MHAA4549A demonstrating a mean half-life of approximately 23 days (range: 
22.5−23.7 days). 
In the Phase 1 high-dose study (GV29609), MHAA4549A showed linear 
pharmacokinetics, with a mean half-life of approximately 21.5 days 
(range: 21.4−21.6 days).  For the 8400- and 10800-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) is consistent with those observed in the Phase 1 
EIH study (GV28916) and Phase 2a study (GV28985). 
1.2.4 
Clinical Efficacy Background 
The virologic efficacy analysis for the Phase 2a influenza nasal 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 postchallenge virus inoculation 
Or 
• 
At least two positive detections by any quantitative polymerase chain reaction 
(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 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 the variability from the 
challenge model and intersubject differences. 


 
 
MHAA4549A—Genentech, Inc. 
65/Protocol GV29216, Version 7 (Global)   
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.  
The 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. 
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). 


 
 
MHAA4549A—Genentech, Inc. 
66/Protocol GV29216, Version 7 (Global)   
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; qPCR = quantitative polymerase chain reaction; TCID50 = 50% tissue culture 
infectious dose; vc = viral copies. 
Note:  Comparison of 400, 1200, and 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 
1.3.1 
Study Rationale 
Two Phase 1 (GV28916, GV29609) studies have demonstrated that MHAA4549A is safe 
and well tolerated to date in healthy volunteers at doses up to 10800 mg.  Data from a 
Phase 2a study (GV28985) demonstrated that the3600 mg MHAA4549A dose is safe, 
well tolerated, and effective in reducing viral titers as compared to placebo in healthy 
volunteers inoculated with influenza virus.  No MHAA4549A-specific TEAEs have been 
identified in any of our clinical studies. When combined with nonclinical studies 


 
 
MHAA4549A—Genentech, Inc. 
67/Protocol GV29216, Version 7 (Global)   
demonstrating that MHAA4549A has a well-tolerated safety profile and in vitro and in 
vivo efficacy against influenza virus, these findings support further development of 
MHAA4549A. 
Initially, this GV29216 Phase 2b study enrolled patients in a two-arm treatment study 
comparing 3600 mg MHAA4549A with oseltamivir versus placebo with oseltamivir.  
This current Phase 2b study has added an additional arm to evaluate the improvement 
in outcome of a combination therapy of 3600 mg MHAA4549A with oseltamivir or of 
8400 mg MHAA4549A with oseltamivir versus placebo with oseltamivir for additional 
dose-response information.  All patients will receive oseltamivir, which is part of the 
recommended standard of care for hospitalized influenza patients.  Therefore, at a 
minimum, all patients will be treated with standard of care for influenza.  There are 
three primary goals for this Phase 2b study:  
• 
Demonstrate the safety and efficacy of MHAA4549A in combination with oseltamivir 
in hospitalized influenza A patients  
• 
 
  
• 
Demonstrate and evaluate the optimal endpoints for study in hospitalized patients 
with influenza A, given the lack of precedence for approval in patients hospitalized 
with influenza infection, an area of high unmet medical need 
 
1.3.2 
Benefit-Risk Assessment 
Although there has been no benefit demonstrated for MHAA4549A in the setting of 
hospitalized influenza, there is a possibility that patients may have improved clinical 
outcomes from this therapy.  Potential risks of MHAA4549A include immunogenicity 
and infusion-related reactions.  Theoretically, any biologic 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 nonclinical 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.   
1.3.2.1 
Patient Monitoring and Supervision 
MHAA4549A will be administered to enrolled patients in a hospital environment under 
close medical supervision by a physician or medically qualified designee.  Medical staff 
will be available for prompt evaluation and treatment of any AEs.  Emergency 
resuscitation equipment and emergency facilities will be readily available.  Patients will 
undergo screening assessments to confirm eligibility, will be closely monitored during the 
administration of MHAA4549A, and will be resident for at least 24 hours following the 
administration of MHAA4549A.  Furthermore, safety laboratory tests relating to the blood 
chemistries, including liver function tests will be conducted. 


 
 
MHAA4549A—Genentech, Inc. 
68/Protocol GV29216, Version 7 (Global)   
An internal monitoring committee (IMC) in combination with a scientific oversight 
committee (SOC) will provide safety monitoring for the study in addition to the ongoing 
review of safety by the Medical Monitor and Safety Scientist.  See Section 3.1.2 for more 
information.  
In addition to the regularly scheduled safety reviews of the patient data by the IMC and 
SOC, an additional sentinel safety cohort of the first 30 patients or patients after the first 
influenza season, whichever occurs first, will be assessed by the IMC and SOC. 
The 120-day follow-up period in the Phase 1 and 2a studies allowed for monitoring of 
subjects for approximately 5 half-lives of MHAA4549A.  No treatment-induced ATAs 
were detected in both Phase 1 studies.  One subject who received placebo in the 
Phase 2a study tested positive for ATAs at baseline and post-baseline timepoints as 
described in Section 1.2.2.  The Phase 2b study will also include a safety follow-up 
period of 60 days and an unlimited collection of all SAEs believed related to 
MHAA4549A. 
Based on the above data and design of this study, the Sponsor concludes that the 
benefit-risk profile of MHAA4549A in the population with severe influenza is favorable.  
2. 
OBJECTIVES 
2.1 
SAFETY OBJECTIVES 
The safety objectives for this study are as follows: 
• 
To evaluate the safety of MHAA4549A in combination with oseltamivir compared 
with placebo and oseltamivir in patients with severe influenza A, focusing on the 
nature, frequency, and severity of serious and non-serious AEs as well as effects on 
laboratory values, vital signs, electrocardiogram (ECG) parameters, ATAs, and 
other safety biomarkers 
 
2.2 
PRIMARY EFFICACY OBJECTIVES 
The primary efficacy objective for this study is as follows: 
• 
To determine the time to normalization of respiratory function of patients dosed with 
MHAA4549A in combination with oseltamivir compared to patients dosed with 
placebo and oseltamivir. 
 
2.3 
SECONDARY EFFICACY OBJECTIVES 
The secondary efficacy objectives for this study are as follows: 
• 
To compare the clinical status of patients at Days 1−7, 14, and 30 using an ordinal 
outcome with six clinical statuses. Patients will be categorized into one of the 
following six mutually exclusive categories on Days 1−7, 14, and 30 
1. Death; 
2. In the ICU; 


 
 
MHAA4549A—Genentech, Inc. 
69/Protocol GV29216, Version 7 (Global)   
3. Non-ICU hospitalization, requiring supplemental oxygen; 
4. Non-ICU hospitalization, not requiring supplemental oxygen; 
5. Not hospitalized, but unable to resume normal activities; or 
6. Not hospitalized with full resumption of normal activities 
• 
To measure clinical failure, as defined in Section 3.3.3, after 24 hours post infusion 
of study drug  
• 
To determine the time to clinical resolution of abnormal vital signs  
• 
To measure mortality in patients  
• 
To determine changes in the extent and duration of viral burden in nasopharyngeal 
samples as a measure of the pharmacodynamic response 
• 
To measure the duration of hospital and/or ICU stay 
• 
To measure antibiotic usage for respiratory infections 
• 
To measure the frequency and severity of the following secondary complications of 
influenza:  
– 
Pneumonia (hospital acquired pneumonia [HAP]/ ventilator acquired 
pneumonia [VAP]) 
– 
Exacerbations of chronic lung disease 
– 
Myocarditis 
– 
Acute respiratory distress syndrome (ARDS) 
– 
Otitis media 
– 
Other related complications 
– 
Readmission rates at 30 and 60 days after study treatment 
• 
To measure duration of PPV 
• 
To measure readmission rates 
 
2.4 
PHARMACOKINETIC OBJECTIVES 
The PK objectives for this study are as follows: 
• 
To characterize the PK profile of MHAA4549A in serum 
 
The exploratory PK objectives for this study are as follows: 
 
 
 
 
 
 
 


 
 
MHAA4549A—Genentech, Inc. 
70/Protocol GV29216, Version 7 (Global)   
2.5 
EXPLORATORY OBJECTIVES 
The exploratory objectives for this study are as follows: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
3.1.1 
Overview of Study Design 
This is a Phase 2b (GV29216), randomized, double-blind, placebo-controlled study 
designed to assess the safety and clinical activity of a single IV dose of 3600 mg 
MHAA4549A or a single IV dose of 8400 mg MHAA4549A in hospitalized patients with 
severe influenza A in combination with oseltamivir versus a comparator arm of placebo 
with oseltamivir.  A Sponsor-approved influenza test that includes influenza antigen 
test or influenza polymerase chain reaction (PCR) test must be used to diagnose 
influenza A infection for study eligibility.  This study is planned to take place in 
approximately 170 study centers globally. 
Initially, GV29216 targeted enrollment into two treatment groups: a single IV dose of 
3600 mg of MHAA4549A with oseltamivir or a single IV dose of placebo with oseltamivir.  
In this version of the protocol, patients will be randomized 1:1:1 into three treatment 
groups:  a single IV dose of 3600 mg of MHAA4549A with oseltamivir, a single IV dose 
of 8400 mg of MHAA4549A with oseltamivir, or a single IV dose of placebo with 
oseltamivir.  Patients will be stratified by country, PPV versus supplemental O2 at 
randomization, and suspected or confirmed bacterial pneumonia versus no bacterial 


 
 
MHAA4549A—Genentech, Inc. 
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pneumonia based on the status at randomization.  All patients must begin study drug 
infusion within 48 hours of hospital admission.  In addition, all patients will receive 
oseltamivir as standard therapy for a minimum of 5 days (10 doses) starting no later 
than 12 hours after completion of study drug administration.  Oseltamivir treatment for 
longer than 5 days is permitted based on local investigator discretion. 
Hospitalized patients with an O2 or PPV requirement will be evaluated for influenza A 
infection.  Enrollment in this study requires ongoing treatment within 24 hours of hospital 
admission with one of the following:  
• 
any PPV or  
• 
any supplemental O2 to maintain oxygen saturation (SpO2) > 92% (Section 3.3.2)  
 
Patients on PPV should not exceed approximately 45% of the total patients enrolled in 
the study. 
 
  
 
 
 
 
 
 
 
 
 
 
 
Safety evaluations will also be provided by an IMC and SOC, as defined in the IMC and 
SOC agreement (see Section 3.1.2).  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. 
An additional safety cohort of the first 30 patients, or patients from the first influenza 
season (whichever occurs first), will be assessed by the IMC and SOC.  A review of 
chemistry laboratory test results, AEs, SAEs, vital signs, and deaths will be assessed.  
A schedule of activities is provided in Appendix 1a and Appendix 1b.  A diagram of the 
study design is presented in Figure 1.  


 
 
MHAA4549A—Genentech, Inc. 
72/Protocol GV29216, Version 7 (Global)   
Figure 1 Phase 2b Study Design (GV29216) 
 
  
3.1.2 
Internal Monitoring Committee and Scientific Oversight 
Committee 
A combined approach with both an IMC and a SOC is proposed to enhance 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 patient treatment and assignment.  The Clinical Science 
representative on the IMC (IMC Chair) will be a person other than the Study Medical 
Monitor and will not be involved in the conduct of the study or have any contact with 
study investigators or site staff.  The Study Medical Monitor will remain blinded to 
individual treatment assignments, unless, in exceptional cases, specific circumstances 
require Study Medical Monitor unblinding after IMC Chair approval.  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.  The Biostatistician and Statistical Programmer are 
the only IMC members involved in the conduct of the study; however, they do not have 
any contact with study investigators, and all discussion within the IMC are kept 


 
 
MHAA4549A—Genentech, Inc. 
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confidential.  All other Sponsor and Contract Research Organization personnel involved 
in the conduct of the study will remain blinded to individual treatment assignments. 
The two SOC members are external experts in the field and will be unblinded to 
treatment allocation.  The SOC may be further expanded by the IMC during the course 
of the study to include additional external experts if the need arises.  
A detailed description of the procedures, data flow, and meeting schedule of the IMC 
and SOC will be provided in a separate IMC and SOC agreement. 
3.1.3 
End of Study 
The end of study is defined as the first day when all patients have had a study 
completion visit or early termination visit or have otherwise been discontinued from the 
study. 
3.2 
RATIONALE FOR STUDY DESIGN 
3.2.1 
Rationale for Study Design 
Hospitalized influenza A infection represents a high unmet need, which, when left 
untreated, may progress to a more serious disease that may result in significant 
morbidity and mortality in otherwise healthy adults as well as in vulnerable populations.   
This study is designed to estimate the improvement in outcome of a combination 
regimen of MHAA4549A with oseltamivir compared to a standard of care arm of placebo 
with oseltamivir.  The study population will include hospitalized patients with influenza A 
requiring ongoing O2 support and/or PPV support within 24 hours of hospital admission.  
Study GV29216 will be a Phase 2b study involving approximately 330 patients.  The 
sample size was determined based on an expected clinically meaningful difference of 
1 − 2 days improvement in time to normalization of respiratory function between the 
control and treatment arms, assuming a 5 day median time to the time to normalization 
of respiratory function in the standard of care arm (Blackwood et al. 2011; Premier Inc, 
Charlotte, NC).   
This design ensures that all patients in the trial will receive the current NAI treatment, 
oseltamivir, as standard of care at a minimum, and will evaluate the clinical benefit of 
combining MHAA4549A with this standard of care regimen.  Therefore, this study aims 
to identify a regimen that could deliver maximum benefit in this high unmet need 
disease, while still treating all enrolled patients with the currently accepted standard of 
care. 
3.2.2 
Rationale for Patient Population and Primary Endpoint 
Severe influenza, for the purpose of this study, is defined as requiring one of the 
following treatments: any supplemental O2 to maintain an SpO2 > 92% or PPV.  PPV is 


 
 
MHAA4549A—Genentech, Inc. 
74/Protocol GV29216, Version 7 (Global)   
defined as any mechanical positive pressure device to maintain oxygenation; this can 
include positive pressure mask and intubation.   
This patient population was chosen based on the rationale that respiratory failure is a 
hallmark of influenza and a major driver of morbidity and mortality, as well as 
hospitalization.  The recovery from ventilator support has been shown to be directly 
proportional to time spent in the ICU (Blackwood et al. 2011; Premier Inc, Charlotte, 
NC).  Based upon an analysis of morbidity and mortality, the patient population that 
requires supplemental O2 or ventilation on their first day of admission was determined to 
have a high unmet medical need as they have an estimated mortality of 9%-32%, and 
27% require admission to the ICU, according to analysis of a database of over 70,000 
hospitalized patients in the U.S. from 2005-2012 (Premier Inc, Charlotte, NC).   
The proposed primary efficacy outcome measure in this study is “Time to normalization 
of respiratory function,” defined as oxygen saturation ≥ 95% without oxygen 
supplementation.  Support for use of a respiratory endpoint in this population comes 
from recently published data demonstrating that a composite endpoint that captured 
respiratory rate, fever, heart rate, and blood pressure resolution was primarily driven by 
the respiratory component of the endpoint (Marty et al. 2014).  Given that influenza 
infections generally do not cause systemic infections and influenza disease is restricted 
to the respiratory tract, the Sponsor believes that the primary endpoint represents a 
clinically meaningful outcome in this patient population (as shown by analysis of 
PREMIER database) and measures an important physiologically relevant 
pharmacodynamic response parameter of MHAA4549A.  This endpoint is a measure of 
patient function, measures a symptom that represents a serious consequence of 
influenza, and is consistent with clinically relevant endpoints discussed in the US Food 
and Drug Administration (FDA) Guidance, “Influenza: Developing Drugs for Treatment 
and/or Prophylaxis” (FDA 2011).  
3.2.3 
Rationale for Control Group and Treatment Window  
In this study, the standard of care regimen for the control or comparator group 
(hospitalized influenza A patients) is oseltamivir, an NAI.  In the treatment groups, 
MHAA4549A will be dosed in addition to oseltamivir.  Oseltamivir for a minimum of 
5 days is permitted following treatment with MHAA4549A.  Treatment for longer than 
5 days is permitted based on local investigator discretion (WHO 2005; Fiore et al. 2011; 
CDC 2016).  The oseltamivir dosing regimen is listed in Table 2.  This control treatment 
was based on consideration of safety, ethics, and efficacy for treatment of severe 
influenza and is consistent with guidelines for antiviral treatment of hospitalized patients 
with influenza (Harper et al. 2009; Fiore et al. 2011). 


 
 
MHAA4549A—Genentech, Inc. 
75/Protocol GV29216, Version 7 (Global)   
Table 2 
Oseltamivir Dosing Regimen  
Neuraminidase Inhibitor 
Dosing Regimen 
Duration of Therapy 
Oseltamivir 
75 mg or 150 mg oral twice 
daily a 
5 days b 
a 75 mg or 150 mg dose at the discretion of the investigator, and dose must be documented.  
Capsules can be opened and the granules administered via nasogastric tube, if required.  For 
renal dose adjustments, follow local standard of care practice/local package insert and 
document in the eCRF.  
b Longer treatment times are at the discretion of the investigator (WHO 2005; Fiore et al. 2011; 
CDC 2016). 
  
If oseltamivir resistance is highly suspected or identified or oseltamivir route of 
administration challenges are encountered, then following discussion with the Sponsor 
Medical Monitor, an alternative NAI to oseltamivir may be used.  For renal 
dose adjustments, local standard-of-care practice/local package insert should be followed 
and documented in the eCRF.  Capsules other than 75 mg (for 75 mg twice a day [BID] 
or 150 mg BID regimens) cannot be provided through the study Interactive Voice and 
Web Response System (IxRS). In these instances, the study site may supply the 
appropriate dose and be reimbursed by the Sponsor.  
From a safety standpoint there are no expected drug interactions between MHAA4549A, 
a monoclonal antibody, and any NAI, which are small molecule drugs that bind to a 
different viral protein than MHAA4549A.  In the Phase 2a challenge study, all subjects 
that were dosed with MHAA4549A also received a 5-day course of oseltamivir starting 
on Day 7.  There were no safety effects attributable to the combination when the drugs 
were present concurrently.  In the Phase 2a challenge study, MHAA4549A treatment 
did not appear to impact the exposure of oseltamivir and its active metabolite oseltamivir 
carboxylate. There was no suggestion of PK drug-drug interaction between MHAA4549A 
and oseltamivir. 
For this Phase 2b study, a combination of MHAA4549A and oseltamivir was determined 
to be the most clinically feasible treatment regimen, both from an ethical as well as a 
practical perspective.  The treatment of all patients with oseltamivir ensures that all 
patients will receive the standard of care.  Given the high morbidity and mortality of 
hospitalized patients with influenza A along with guidelines from Centers for Disease 
Control and Prevention (CDC) and Infectious Diseases Society of America (IDSA) it is 
recommended that NAIs are the standard of care for hospitalized patients with influenza 
A (Harper et al. 2009; CDC 2016).  Furthermore, pre-clinical efficacy data from a study 
using MHAA4549A and oseltamivir in combination showed a potential synergistic effect 
of both compounds which may be due to the different and potentially complementary 
mechanisms of action, i.e. targeting viral HA and neuraminidase (NA). 
Dosing of MHAA4549A is confined to a treatment window designed for best expected 
treatment success and to ensure that any observed effects can be attributed to the study 


 
 
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drug with high confidence.  MHAA4549A shall only be dosed within 5 days of onset of 
symptoms (including fever, chills, malaise, dry cough, loss of appetite, myalgias, coryza, 
or nausea), no later than 48 hours after admission to the hospital, and if a subject has 
taken less than a total of 6 doses (3 doses for peramivir) of approved anti-influenza 
therapy from onset of symptoms.  This proposed window is supported by data 
demonstrating that hospitalized influenza patients benefit from NAI treatment even at 
5 days from onset of symptoms (Louie et al. 2012).  The patient must start 
standard-of-care oseltamivir no later than 12 hours after completion of MHAA4549A 
administration. 
3.2.4 
Rationale for MHAA4549A Dosage 
Single IV doses of 3600 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, 
and the relationship between the pharmacokinetics, pharmacodynamics, and efficacy 
observed in the Phase 2a challenge study 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).  An exploratory exposure-response analysis of this group 
demonstrated that subjects with nasal viral loads greater than the median viral load 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 viral loads less than the 
median viral load 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 
previous clinical Phase 1 Phase 2a studies. 




 
 
MHAA4549A—Genentech, Inc. 
78/Protocol GV29216, Version 7 (Global)   
 
 
 
  
 
  
 
 
 
 
3.3 
OUTCOME MEASURES 
3.3.1 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
AEs and clinical laboratory abnormalities  
• 
Vital signs, physical findings, ATAs, and clinical laboratory results during and 
following administration of MHAA4549A 
 
3.3.2 
Primary Efficacy Outcome Measures 
The primary efficacy outcome measure for this study is as follows: 
• 
Time to normalization of respiratory function defined as: 
– 
The time to cessation of O2 support resulting in a stable SpO2 ≥ 95% (see 
Appendix 2 for details) 
 
3.3.3 
Secondary Efficacy Outcome Measures 
The secondary efficacy outcome measures for this study are as follows: 
• 
Clinical status of patient at Days 1−7, 14, and 30.  This is an ordinal outcome with 
six mutually exclusive categories: 
1. Death; 
2. In the ICU; 
3. Non-ICU hospitalization, requiring supplemental oxygen; 
4. Non-ICU hospitalization, not requiring supplemental oxygen; 
5. Not hospitalized, but unable to resume normal activities; or 
6. Not hospitalized with full resumption of normal activities 
• 
Clinical failure after 24 hours post-infusion of study drug; defined as: 
– 
Progression to increased O2 requirement defined by an increase in oxygen 
supplementation from low flow oxygen (i.e., 2−6 L/min) to high flow oxygen 


 
 
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(i.e., > 6 L/min) or from oxygen supplementation alone to any PPV or 
extracorporeal membrane oxygenation (ECMO) 
– 
Progression to ICU 
– 
Prolonged ventilation or O2 support defined by > 2 weeks, or 
– 
Death 
• 
Time to clinical resolution of abnormal vital signs (3/5 criteria must be met): 
– 
SpO2 ≥ 95% without supplemental O2  
– 
Respiratory rate < 24 breaths per minute without supplemental O2  
– 
Core temperature < 37.2°C immediately prior to receipt of any antipyretic drug, 
and at least 6-8 hours from the last dose of antipyretic or core 
temperature > 36°C in patients who are initially hypothermic 
– 
Heart rate (HR) < 100 beats/minute 
– 
Systolic blood pressure (SBP) > 90 mmHg 
• 
All-cause mortality at Day 14, Day 30, and Day 60 
• 
Influenza A viral load in nasopharyngeal samples   
– 
AUEC (qPCR) 
– 
Peak viral load (qPCR) 
– 
Duration of viral shedding (qPCR) 
• 
Duration of hospitalization 
• 
Duration of ICU stay 
• 
Antibiotic usage for respiratory infections 
• 
Complications of influenza: 
– 
Pneumonia (HAP/VAP) 
– 
Exacerbations of chronic lung disease 
– 
Myocarditis 
– 
ARDS 
– 
Otitis media 
– 
Other related complications 
• 
All-cause readmission at Day 30 and Day 60 
• 
Duration of ventilation 
 
3.3.4 
Pharmacokinetic Outcome Measures 
The primary PK outcome measures for this study are as follows: 
• 
PK parameters for MHAA4549A in serum including total exposure (i.e., AUC), 
maximum observed concentration (Cmax), clearance, half-life, and volume of 
distribution, when appropriate, as data allow   


 
 
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The exploratory PK outcome measures for this study are as follows: 
 
 
 
 
 
 
 
3.3.5 
Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
This study aims to enroll approximately 330 men and women and is designed to assess 
the safety and clinical activity of a single IV administration of 3600 mg MHAA4549A or a 
single IV administration of 8400 mg MHAA4549A in adult patients hospitalized with 
severe influenza A.   
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Hospitalized men or women ≥ 18 years of age on the day of signing the informed 
consent or obtaining surrogate consent from an authorized representative 
• 
Diagnosis of influenza A where a Sponsor-approved influenza test is used as an aid 
in diagnosis.  A Sponsor-approved influenza test includes: 
− 
Influenza antigen test –OR– 
− 
Influenza PCR test 
• 
One of the following markers of severity within 24 hours of hospital admission: 
– 
Requirement for PPV −OR− 
– 
Requirement for O2 supplementation to maintain SpO2 > 92% (Source 
documentation should show that the patient’s SpO2 was less than 92% off 
oxygen.  Source documentation may consist of either a SpO2 off oxygen with a 
value below 92% or a documentation of the Investigator’s rationale in lieu of 
this SpO2 documentation.) 
• 
A negative urine or serum pregnancy test for women of child-bearing potential 
• 
Patients of reproductive potential must agree to use reliable means of contraception 
as described below as a minimum (adherence to more stringent local requirements 
may be required): 
– 
For women who are not postmenopausal (postmenopausal defined as 
≥ 12 months of non-therapy-induced amenorrhea) or surgically sterile (absence 
of ovaries and/or uterus):  agreement to remain abstinent or use two adequate 
methods of contraception, including at least one method with a failure rate of 
< 1% per year, during the treatment period and for at least 120 days after the 
dose of 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. 
Barrier methods must always be supplemented with the use of a spermicide. 


 
 
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Examples of contraceptive methods with a failure rate of < 1% per year include 
tubal ligation, male sterilization, hormonal implants, proper use of combined 
oral or injected hormonal contraceptives, and certain intrauterine devices. 
Male partners who have had a vasectomy should have the appropriate 
post-vasectomy documentation available of the absence of sperm in the 
ejaculate.  The vasectomized male partner should be the sole partner for that 
patient. 
– For men:  agreement to remain abstinent or use a condom during the treatment 
period and for at least 30 days after the dose of study drug and agreement to 
refrain from donating sperm during this same period 
Men with a pregnant partner must agree to remain abstinent or use a condom 
for the duration of the pregnancy. 
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. 
– 
Non-reproductive potential is defined below (but could be superseded by local 
definitions, if they are more stringent): 
Women who are postmenopausal (≥ 12 months of non-therapy-induced 
amenorrhea) 
Women who are surgically sterile (i.e., hysterectomy, complete bilateral 
oophorectomy) 
Men who are surgically sterile (i.e., castration) 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Pregnant or lactating, or intending to become pregnant during the study 
– 
Women who are not postmenopausal (postmenopausal defined as ≥ 12 months 
of non-therapy-induced amenorrhea) or surgically sterile must have a negative 
pregnancy test result within 2 days prior to initiation of study drug. 
• 
Hypersensitivity to monoclonal antibodies or to any constituents (sodium succinate, 
sucrose, polysorbate 20) of MHAA4549A study drug 
• 
Hypersensitivity to the active substance or to any excipients of oseltamivir 
• 
Investigational therapy within the 30 days prior to study treatment  
• 
Received prior therapy with any anti-influenza monoclonal antibody therapy 
(including MHAA4549A) within 8 months prior to study treatment 
• 
Current treatment (within 7 days of dosing) with probenecid, amantadine, or 
rimantidine 


 
 
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• 
Patients who have taken more than a total of 6 doses (3 doses of peramivir) of 
anti-influenza therapy (e.g., oseltamivir, zanamivir, laninamivir, peramivir) in the 
period from onset of symptoms and prior to study treatment 
• 
Admission > 48 hours prior to study treatment 
• 
Onset of influenza symptoms (including fever, chills, malaise, dry cough, loss of 
appetite, myalgias, coryza, or nausea) > 5 days prior to study treatment  
• 
Positive influenza B or influenza A + B infection within 2 weeks prior to study 
treatment 
• 
High probability of mortality in the next 48 hours as determined by the investigator  
• 
Patient requiring home or baseline oxygenation therapy 
• 
Patient with history of chronic lung disease with a documented SpO2 < 95% off 
oxygen 
• 
Patient on a chronic dose of corticosteroids exceeding 10 mg/day of prednisone or 
equivalent steroid dose for a duration of greater than 14 days within 30 days of entry 
into study 
• 
Creatinine clearance ≤ 10 mL/min 
• 
Patients who received nasally administered influenza A vaccine within 7 days prior 
to screening 
• 
Patients with the following significant immune suppression:  
– 
Bone marrow or solid organ transplant in the previous 12 months 
– 
Cancer chemotherapy in the previous 12 months 
– 
HIV infection with most recent CD4 < 200 cells/mL 
– 
Other significant immune suppression as determined by the investigator in 
discussion with the Sponsor Medical Monitor 
• 
Patient on ECMO at time of randomization 
• 
Any disease or condition that would, in the opinion of the site investigator or 
Sponsor, place the subject at an unacceptable risk of injury or render the subject 
unable to meet the requirements of the protocol 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
The randomization of patients will be managed by a central Interactive Voice and Web 
Response System (IxRS) through use of a dynamic hierarchical algorithm which 
includes a random component.  The treatment assignments will be unblinded to selected 
Sponsor personnel to facilitate ongoing monitoring of safety and tolerability, including 
members of the IMC and SOC.  
All patients will be randomly assigned to receive 3600 mg MHAA4549A, 8400 mg 
MHAA4549A, or placebo at a 1:1:1 ratio stratified by country, whether patient is on PPV 
versus supplemental O2 at randomization, and whether the patient has suspected or 


 
 
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confirmed bacterial pneumonia vs no bacterial pneumonia at randomization.  Initially 
GV29216 randomly assigned patients to receive either 3600 mg MHAA4549A, or 
placebo at a 1:1 ratio.  The updated randomization scheme takes into account the 
numbers already allocated to these two arms and strata prior to allocating to the three 
arm design so that by the end of the study there will be an approximate 1:1:1 allocation 
between the three arms.  
All patients will receive oseltamivir (as described in Table 2) for a minimum of 5 days.  
Treatment for longer than 5 days is permitted based on local investigator discretion. 
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, 
as described in Section 4.3.3.  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. 
Bioanalytical laboratory 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 (e.g., to evaluate a possible error in study drug administration). 
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.   
If unblinding is necessary for patient management (e.g., in the case of an SAE for which 
patient management might be affected by knowledge of treatment assignment), the 
investigator will be able to break the treatment code in IxRS.  Treatment codes should 
not be broken except in emergency situations.  If the investigator wishes to know the 
identity of the study drug for any other reason, they should contact the Medical Monitor 
directly.  The investigator should document and provide an explanation for any 
premature unblinding (e.g., accidental unblinding, unblinding due to an SAE). 
For regulatory reporting purposes, and if required by local health authorities, the 
Sponsor will break the treatment code for all suspected unexpected serious adverse 
reactions (SUSAR) (see Section 5.4) that are considered by the investigator or Sponsor 
to be related to study drug. 


 
 
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4.3 
STUDY TREATMENT  
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. 
4.3.1.2 
Oseltamivir (Tamiflu®) 
Oseltamivir (Tamiflu®) is an influenza NAI indicated for treatment of acute, 
uncomplicated influenza.  The Sponsor will provide 75-mg capsules of oseltamivir for up 
to a 10-day treatment course (for 75- or 150-mg BID regimens).  For renal dose 
adjustments, follow local standard-of-care practice/local package insert and document 
in the eCRF. Capsules other than 75 mg (for 75- or 150-mg BID regimens) cannot be 
provided through the study IxRS.  In these instances, the study site may supply the 
appropriate dose and be reimbursed by the Sponsor. 
For information on the formulation, packaging, and handling of oseltamivir; see the local 
prescribing information for oseltamivir. 
Storage: Capsules should be stored at 25°C (77.7°F); excursions are permitted to 15°C 
to 30°C (59°F to 86°F). 
4.3.2 
Dosage, Administration, and Compliance 
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. 
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- to 0.22-μm in-line filter.  Compatibility testing has shown that 
MHAA4549A is stable when diluted in 0.9% normal saline in a polyvinylchloride bag, 
polyolefin bag, or ethylene vinyl acetate bag (EVA), at concentrations 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 for preparation of study drug can be found 
in the Pharmacy Manual.   


 
 
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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 will be halted until the safety of the drug is assessed. 
There are no recommended dosage modifications for MHAA4549A since it is a single 
infusion.  Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  AEs 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 AEs associated 
with overdose.  Patients experiencing such AEs 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.  
4.3.2.2 
Oseltamivir-Neuraminidase Inhibitor (NAI)  
The Sponsor will supply 75-mg oseltamivir (Tamiflu®) capsules for this study for up to a 
10-day course (for 75- or 150-mg BID regimens).  Oseltamivir will be administered 
twice daily as described in Section 3.1.1.  Capsules can be opened and the granules 
administered via nasogastric tube, if required.  Doses should be captured in the eCRF.  
For renal dose adjustments, follow local standard-of-care practice/local package insert 
and document in the eCRF.  Capsules other than 75 mg (for 75- or 150-mg BID 
regimens) cannot be provided through the study IxRS.  In these instances, the study 
site may supply the appropriate dose and be reimbursed by the Sponsor. 
Any overdose or incorrect administration of oseltamivir should be noted on the 
oseltamivir Administration eCRF.  AEs associated with an overdose or incorrect 
administration of oseltamivir should be recorded on the Adverse Event eCRF. 
Patients who are discharged from the hospital with oseltamivir will be required to 
complete a medication diary and return the medication diary, empty (used) oseltamivir 
packets and unused oseltamivir capsules to the study site at the next follow up visit.  
Patients will record the date and time when each oseltamivir capsule is administered. 
4.3.3 
Investigational Medicinal Product Accountability 
Investigational medicinal products (IMPs) required for completion of this study 
(i.e., MHAA4549A and 75-mg oseltamivir capsules) will be provided by the Sponsor.  The 


 
 
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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 to 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 to 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. 
The total duration from the preparation of dose solutions to the end of infusion should 
not exceed 24 hours.  Vials are intended for single use only; therefore, any remaining 
solution should be discarded (see the Pharmacy Manual).  
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 or their delegate 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. 
4.4 
POST-TRIAL ACCESS TO MHAA4549A 
As this is single dose administration, Genentech 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 


 
 
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4.5 
CONCOMITANT THERAPY AND FOOD 
Concomitant medication 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/early discontinuation 
visit.  All concomitant medications should be reported to the investigator and recorded 
on the Concomitant Medications eCRF.  For any NAIs (e.g., oseltamivir, peramivir, 
zanamivir, laninamivir) that have been taken prior to study drug therapy, the number of 
doses and duration of therapy must be recorded. 
4.5.1 
Permitted Therapy 
Patients who use oral contraceptives, hormone-replacement therapy, or other 
maintenance therapy should continue their use. 
All therapies required for management of the patient’s acute illness are permitted except 
for those listed below in Section 4.5.2. 
4.5.2 
Prohibited Therapy 
Use of the following therapies is prohibited during the study and for at least 7 days prior 
to study treatment, unless otherwise specified below:  probenecid, amantadine, or 
rimantidine. 
Use of other NAIs, including but not limited to oseltamivir, zanamivir, laninamivir, and 
peramivir, are prohibited during the study, but allowed up to a total of 6 doses (3 doses 
for peramivir) in the period from onset of symptoms and prior to study treatment as 
outlined in the exclusion criteria.  Patients must start standard-of-care oseltamivir no 
later than 12 hours after completion of MHAA4549A administration.  If oseltamivir 
resistance is highly suspected or identified or if oseltamivir route of administration 
challenges are encountered then, following discussion with the Sponsor’s Medical 
Monitor, an alternative NAI to oseltamivir may be used. 
 
4.5.3 
Prohibited Food 
There are no prohibited foods for this study.  
4.6 
STUDY ASSESSMENTS  
Please see Appendix 1a and Appendix 1b for the schedule of activities performed during 
the study. 
4.6.1 
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 by authorized 
representatives may be obtained only if allowed by and in accordance with local 
regulations and Independent Review Board (IRB)/Independent Ethics Committee (IEC) 


 
 
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policies and procedures.  Informed Consent Forms (ICF) 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. 
4.6.2 
Diagnostic Testing for Enrollment 
All hospitalized patients with severe influenza A must be assessed for disease 
confirmation prior to and enrollment into the study.  A Sponsor-approved influenza test is 
required as an aid in the diagnosis of influenza A infection.  This requires a 
nasopharyngeal swab be introduced into one nostril.  A lower respiratory tract sample 
may be used if appropriate for the Sponsor-approved local PCR test.  Note that the 
influenza antigen test or influenza PCR test result must be available within the 48-hour 
screening window.   
4.6.3 
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.  A careful assessment of the patient’s baseline SpO2 will be made 
especially if the patient has a history of severe chronic lung disease. 
Demographic data will include age, sex, and self-reported race/ethnicity. 
4.6.4 
Priority of Assessments 
When events warrant, or in the opinion of the investigator, safety issues become 
paramount, safety assessments will always have priority over all other measurements 
and procedures.  Under routine circumstances, however, PK, nasal virological, and 
biomarker serum/plasma samples have priority over other measurements.  The timing 
and number of safety measurements may be modified based on clinical evaluations. 
Assessments on Day 1 must be concluded prior to dosing as specified in Appendix 1a.  
Any screening assessments completed prior to consent as standard of care do not need 
to be repeated if done within the screening period. 
4.6.5 
 
 
 
 


 
 
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4.6.6 
 
 
 
 
 
4.6.7 
Physical Examinations 
A complete physical examination 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 protocol designated visits (or as clinically indicated), limited, symptom-directed 
physical examinations should be performed which include, 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, if appropriate, on the 
adverse event eCRF.   
Day 1 physical examination is optional if already completed on Day -1 or -2. 
4.6.8 
Vital Signs 
Vital signs will include measurements of respiratory rate, heart rate, temperature, and 
systolic and diastolic blood pressures after the patient has been in a seated or supine 
position for > 5 minutes.  Temperature should be measured using the same methodology 
throughout the study and should be measured prior to administration of any antipyretic 
drugs.  Patients in intensive care may have vital signs assessed following local 
procedures, but those procedures should be captured in the eCRF in accordance with 
the eCRF instructions. 
4.6.9 
Oxygen Saturation Measurements 
To ensure that the respiratory status is well recorded, the following daily measurements 
will be performed.  All patients will have their SpO2 and corresponding respiratory 


 
 
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assessments recorded daily in the morning between 6:00 a.m. and 12:00 noon local 
time.  Unless clinically contraindicated*, patients on low flow O2 will have a daily trial of 
their SpO2 while on and off the supplementation, as outlined in Appendix 2, and both 
values will be recorded.  If a patient is clinically able to be removed from oxygen 
outside the time window above (6:00 a.m. to 12:00 noon), the trial-off data should be 
recorded as an unscheduled visit. 
If the patient is on oxygen supplementation, SpO2 measured by pulse oximetry and the 
corresponding respiratory assessments (e.g., FiO2, flow rate) will be recorded.  If the 
patient is on PPV, partial pressure of arterial O2 (PaO2) and the corresponding 
respiratory assessments (e.g., FiO2, ventilator mode, ventilator respiratory rate, positive 
end expiratory pressure) will be recorded.  If clinically appropriate (i.e., the patient is on 
non-invasive PPV), the conversion table in Appendix 11 may be used for PaO2.  
*If a patient has an SpO2  < 95% while on oxygen supplementation, he/she shall be 
considered to be “clinically contraindicated” from requiring a trial off oxygen; however, 
corresponding respiratory assessments should be recorded. 
4.6.10 
Laboratory, Biomarker, and Other Biological Samples 
Samples for the laboratory tests listed in Table 3 and Table 4 will be sent to the study 
site's local laboratory for analysis at screening and during the study, respectively. 
Table 3 
Laboratory Tests at Screening 
Hematology: 
Clinical Chemistry: 
Hemoglobin 
Thyroid stimulating hormone (optional) 
Hematocrit 
 
Erythrocyte count (RBC) 
Serology: 
Leukocytes (WBC) 
HIV Serology 
Neutrophils (segmented and bands if 
clinically indicated) 
 
Lymphocytes 
Misc: 
Monocytes 
Eosinophils 
Pregnancy Test (urine or serum; women of 
child-bearing potential) 
Basophils 
 
Platelets 
 
Note:  Investigators must document their review of each laboratory report by signing (or 
initialing) and dating each report. 
  


 
 
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Table 4 
Laboratory Tests during the Study 
Hematology: 
Clinical Chemistry (Blood):  
Hemoglobin 
Sodium 
Hematocrit 
Potassium 
Erythrocyte count (RBC) 
Bicarbonate 
Leukocytes (WBC) 
Chloride 
Neutrophils (segmented and bands if clinically 
indicated)  
Calcium 
Lymphocytes 
Phosphorus 
Monocytes 
Magnesium 
Eosinophils 
Glucose  
Basophils 
Urea nitrogen (BUN) or urea 
Platelets 
Creatinine 
 
Total cholesterol 
 
Total protein 
Coagulation:  
Albumin 
Activated partial thromboplastin time (APTT) 
Total bilirubin 
Prothrombin time (PT) 
Alkaline phosphatase 
International Normalized Ratio (INR) 
Aspartate aminotransferase (AST) 
 
Alanine aminotransferase (ALT) 
Urinalysis: 
Amylase 
pH 
Specific gravity 
Gamma-glutamyl transpeptidase (GGT) 
 (if clinically indicated) 
Glucose 
C-reactive protein (CRP) (optional) 
Protein 
Ketones 
Erythrocyte Sedimentation Rate (ESR) 
(optional) 
Blood 
 
Bilirubin 
Misc:  
Nitrite 
Pregnancy Test (urine or serum; if clinically 
indicated) 
Leukocyte esterase 
 
Microscopic examination (if clinically indicated) 
Note:  Investigators must document their review of each laboratory report by signing (or initialing) 
and dating each report. 
  


 
 
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The following samples will be sent to the Sponsor or a designee for PK or ATA analysis: 
 
 
 
• 
Serum samples for ATA testing (see Appendix 1a and Appendix 1b)  
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.   
4.6.11 
Electrocardiograms 
Single ECG recordings will be obtained at specified timepoints, as outlined in the 
schedule of activities (see Appendix 1a and Appendix 1b), 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:  HR, 
RR interval, QRS interval, PR duration, uncorrected QT interval, and QTcF (or QTcB if 


 
 
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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 discontinuation should be made, as described in Section 4.9.2.  
The investigator should also evaluate the patient for potential concurrent risk factors 
(e.g., electrolyte abnormalities, medications known to prolong the QT interval, severe 
bradycardia). 
4.6.12 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  


 
 
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4.7 
APACHE AND SOFA SCORES 
Acute Physiology and Chronic Health Evaluation (APACHE) and Sequential Organ 
Failure Assessment (SOFA) scores are for patients that are admitted into the ICU.  
These assessments are not required for study conduct or entry but should be collected if 
available.  The initial scores for APACHE and SOFA should be taken within 24 hours of 
entry into the ICU and at the time points specified in Appendix 1a. 
For the calculation of the initial APACHE and SOFA scores, the worst values in the first 
24 hours of ICU admission should be used.  SOFA scores are only for patients admitted 
into the ICU that have available data for calculation (i.e., partial pressure of arterial 
oxygen/fraction of inspired oxygen [PaO2/FiO2] in mmHg).  See Appendix 7 for SOFA 
score calculation. 
4.8 
OSELTAMIVIR MEDICATION DIARY 
Patients who are discharged from the hospital with oseltamivir will be required to 
complete a medication diary and return the medication diary, empty (used) oseltamivir 
packets, and unused oseltamivir capsules to the study site at the next follow up visit.  
Patients will record the date and time when each oseltamivir capsule is administered.  
4.9 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
4.9.1 
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 or 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 from the study will not be replaced. 
4.9.2 
Study Treatment Discontinuation 
Patients must discontinue MHAA4549A infusion and therefore treatment if they 
experience any of the following: 
• 
Life threatening infusion-related reactions  
 


 
 
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Patients must discontinue oseltamivir treatment if they experience any of the following: 
• 
Pregnancy 
• 
Serious skin/hypersensitivity reactions 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.   
The IMC and SOC may recommend to permanently discontinue dosing for all patients 
within one or both study arms in the event of a general safety concern. 
4.9.3 
Study Completion/Early Discontinuation Visit 
Patients who complete all study visits through Day 60 are considered to have completed 
study.  All patients who discontinue from the study early will be asked to complete all 
assessments for the early discontinuation visit.  Please see Schedule of Activities 
provided in Appendix 1a for assessments performed at the Study Completion/Early 
Discontinuation visit. 
4.9.4 
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 AEs 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 (GCP) 
• 
No further study activity (i.e., all patients have completed the study, and all 
obligations have been fulfilled) 
 
4.10 
ASSAY METHODS 
 
 
 
 
 


 
 
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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 and is designed to 
ensure patient safety.  It will include specific eligibility criteria and monitoring 
assessments as detailed below and in Section 4.1. 
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. 
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 and SOC agreement.  
5.1.1 
Risks Associated with MHAA4549A 
There are no known risks associated with MHAA4549A based on completed Phase 1 
(GV28916 and GV29609) and Phase 2a (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.  Subjects will be closely 
monitored for any potential immune response to MHAA4549A.  Screening, 
confirmatory, and characterization assays with appropriate sensitivity and therapeutic 
tolerance will be employed to assess ATAs before and after treatment with 
MHAA4549A. 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and non-serious adverse events of special interest; 
measurement of protocol specified safety laboratory assessments; measurement of 
protocol-specified vital signs; and other protocol-specified tests that are deemed critical 
to the safety evaluation of the study. 


 
 
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Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for GCP, an adverse event is any untoward medical 
occurrence in a clinical investigation patient 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 5.3.5.9. 
• 
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 60 
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: 
• 
Fatal (i.e., the adverse event actually causes or leads to death) 
• 
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 5.3.5.10) 
• 
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) 
• 
Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 


 
 
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• 
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 
listed above) 
 
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 Division of 
AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events [DAIDS]; see 
Section 5.3.3, Appendix 8, and Appendix 9); 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 
Non-Serious Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) 
Non-serious adverse events of special interest (AESI) 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 5.3.5.6) 
• 
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 AEs 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 
– 
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– 
Nausea, vomiting, and/or diarrhea 
– 
Various types of skin rashes 
– 
Anaphylaxis 
 
Anaphylaxis due to IV drugs most often presents with the following signs and symptoms:   
• 
Cutaneous symptoms: flushing, itching, urticaria, 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: such as 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 Section 5.4− 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, regardless of relationship to study 
drug, will be reported until study completion at the Day 60 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 
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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 5). 
Table 5 
Adverse Event Grading (Severity) Scale 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE-
THREATENING 
ESTIMATING SEVERITY GRADE 
Clinical AE 
NOT identified 
elsewhere in 
this DAIDS AE 
Grading Table  
Symptoms 
causing no or 
minimal 
interference with 
usual social and 
functional 
activities 
Symptoms 
causing greater 
than minimal 
interference with 
usual social & 
functional 
activities 
Symptoms 
causing 
inability to 
perform usual 
social & 
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 
AE = adverse event; 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 6): 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, considering especially 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 


 
 
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• 
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 6 
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., chronic obstructive pulmonary disease [COPD] 
diagnosed 2 days after first dose of study drug). 
  
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
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 
Diagnosis versus Signs and Symptoms 
Infusion-Related Reactions  
Adverse events that occur during or within 24 hours after study drug infusion should be 
captured as individual signs and symptoms 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). 
Other Adverse Events 
For adverse events other than infusion-related reactions, 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 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 


 
 
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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. 
5.3.5.2 
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. 
5.3.5.3 
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.  If a persistent adverse event 
becomes more severe, it should be recorded 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 event became more severe.  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; see Section 5.4.2 for reporting 
instructions).  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 event became 
serious. 
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. 


 
 
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5.3.5.4 
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 meets any of the following criteria: 
• 
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 
• 
Clinically significant in the investigator’s judgment (laboratory abnormalities should 
be repeated at the first opportunity and only considered clinically significant if they 
persist on repeat assessment) 
 
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 × upper limit of normal [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 not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 


 
 
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5.3.5.5 
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 meets any of the following criteria: 
• 
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 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 5.3.5.3 for 
details on recording persistent adverse events). 
5.3.5.6 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × baseline value) 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.  
Therefore, investigators must report as an adverse event the occurrence of either of the 
following: 
• 
Treatment-emergent ALT or AST > 3 × baseline value in combination with total 
bilirubin > 2 × ULN (of which  ≥ 35% is direct bilirubin) 
• 
Treatment-emergent ALT or AST > 3 × baseline value 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 5.3.5.4) 
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 a non-serious adverse event of special 
interest (see Section 5.4.2). 
5.3.5.7 
Deaths 
For this protocol, mortality is an efficacy endpoint.  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 severe influenza or any related co-morbidities 
should be recorded on the Study Completion/Early Discontinuation eCRF.  All other on 


 
 
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study deaths, regardless of relationship to study drug, must be recorded on the Adverse 
Event eCRF, and immediately reported to the Sponsor as an SAE (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 
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. 
5.3.5.8 
Preexisting 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.  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"). 
5.3.5.9 
Lack of Efficacy or Worsening of Influenza A Infection 
Medical occurrences or symptoms of deterioration that are anticipated as part of 
influenza A should only 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 "). 


 
 
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5.3.5.10 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization following initial discharge (i.e., in-patient 
admission to a hospital) or prolonged hospitalization (after the current study 
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 
• 
Hospitalization for a pre-existing condition, provided that all of the following criteria 
are met: 
o 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 
o 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 that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
5.3.5.11 
Adverse Events Associated with an Overdose 
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 serious 
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 clinical 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. 


 
 
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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) 
• 
Non-serious 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 IRB/EC. 
5.4.1 
Emergency Medical Contacts 
 24-Hour Safety Hotline 
• 
North America: 
 
• 
EMEA/APAC: 
 
• 
Latin America: 
 
 
Genentech Medical Monitor contact information for all sites if above contact cannot be 
reached: 
Medical Monitor:  
 
Telephone Nos.:  
US Office 
 
 
 
 
 
US Mobile 
 
Email Address: 
 
 
 




 
 
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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 or 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, non-serious 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 
POST-STUDY ADVERSE EVENTS 
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 
60 days after the dose of study drug), 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 and submit the report via the EDC system.  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 a paper Clinical Trial Serious 
Adverse Event / Adverse Event of Special Interest Reporting Form using the fax number 
or email address provided to investigators (refer to site binder).  
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events including suspected 
unexpected serious adverse reactions (SUSARs) and non-serious adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, IECs, 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 documents: 
• 
MHAA4549A Investigator's Brochure 
• 
Local prescribing information for oseltamivir 
 
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 
All 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: 
• 
Randomized patients who have confirmed influenza A infection as confirmed by a 
central PCR test from Day 1 samples 
 
Safety analyses will include all patients who were included in the randomization and who 
received at least one dose of study medication, with patients allocated to the treatment 
arm associated with the regimen actually received.  
No formal hypothesis testing will be done in this study.  As a result, no adjustment for a 
type 1 error will be made to account for the multiplicity of analyses. 
Results will be presented both for the MHAA4549A 3600 mg and 8400 mg treatment 
groups separately and combined for the purpose of comparison to standard of care. 
Final efficacy and safety analyses of the total study population will be conducted at the 
end of the study after all patients have completed all study assessments and the 
database has been cleaned and closed.  Further details of the analyses, including 
analysis of the exploratory endpoints, will be contained in the statistical analysis plan 
(SAP) which will be prepared and finalized before the first optional interim analysis (see 
Section 6.10) or the final efficacy and safety analysis, if no interim analysis takes place.   
6.1 
DETERMINATION OF SAMPLE SIZE 
The purpose of this study is estimation of the effect size and hypothesis generation 
regarding the effect of MHAA4549A on the time to normalization of respiratory function 
relative to the standard of care rather than hypothesis testing.  Point and interval 
estimates will be obtained.  Approximately 330 patients will be enrolled.  It is assumed 
that the median time to normalization of respiratory function in the control arm is 5 days.  
This sample size (approximately 110 patients per arm) provides 71% power to detect a 


 
 
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treatment difference of 1 day for the primary endpoint in both MHAA4549A arms 
assuming a 2-sided alpha of 0.2 and no difference in efficacy between the two active 
arms.  If the 3600-mg dose shows a treatment difference of 1 day and the 8400-mg dose 
shows a treatment difference of 1.5 days or more then this sample size provides > 86% 
power assuming a 2-sided alpha of 0.2. 
Operating characteristics (power) under other possible assumptions for 2-sided alpha of 
0.2 and true differences of 0.5 to 2 days are provided in Table 7.   
Table 7 
Operating Characteristics for Proposed Study Design for Several 
Possible True Underlying Median Values 
True Underlying Median for MHAA4549A 
3600 
mg 
8400 
mg 
3600 
mg 
8400 
mg 
3600 
mg 
8400 
mg 
3600 
mg 
8400 
mg 
 
4 days 
4 days 
4 days 
3.5 
days 
4 days 
3 days 
4.5 
days 
4 days 
Hazard Ratio 
0.8 
0.8 
0.8 
0.7 
0.8 
0.6 
0.9 
0.8 
Power of log-rank 
test a 
71.4% 
86.6% 
98.8% 
56.2% 
Note:  Operating characteristics are based on the following assumptions:  330 evaluable 
patients, event times are exponentially distributed, median time to normalization of respiratory 
function in the control arm is 5 days, and patients are followed for 60 days. 
a Two-sided α = 0.20. 
  
It should be noted that the study is underpowered for detection of minimally clinically 
meaningful differences at a 2-sided alpha of 0.05 such as a true hazard ratio of 0.80 in 
both MHAA4549A arms.   
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. 


 
 
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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 
EFFICACY ANALYSES 
The primary and secondary 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. 
Time to event data will be analyzed using Kaplan-Meier methodology and stratified Cox 
proportional hazards models 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.  
The ordinal outcomes will be analyzed using a proportional odds model.  To supplement 
the overall summary odds ratio, separate odds ratios will be estimated for each 
dichotomized definition of improvement that can be formulated from the components of 
the ordinal outcome.  A test for the proportionality assumption will also be made.  
Patients discharged from the hospital to a rehabilitation facility will be included in 
category 5.  Patients discharged from the hospital to a nursing home will also be 
included in category 5, unless the patient lived in a nursing home prior to admission to 
the hospital, in which case the patient will be characterized based on resumption of 
normal activities. 
Estimation of the treatment difference of proportions and the corresponding 95% 
confidence intervals 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. 
6.4.1 
Primary Efficacy Endpoint 
• 
Median time to normalization of respiratory function. 
 
6.4.2 
Secondary Efficacy Endpoints 
• 
Clinical status at Days 1-7, 14, and 30 categorizing proportion of patients in each 
of the 6 pre-defined categories  
• 
Proportion of patients with clinical failure after 24 hours post-infusion of study drug 
• 
Median time to clinical resolution of vital signs 
• 
Hazard ratio for mortality at Day 14, Day 30, and Day 60 
• 
Mean and median AUC of viral load 


 
 
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• 
Mean and median peak viral load 
• 
Median duration of viral shedding in nasopharyngeal samples 
• 
Proportion of patients with detectable infection 
• 
Median duration of hospitalization 
• 
Median duration of ICU stay 
• 
Proportion of patients requiring antibiotics for respiratory indications during study 
• 
Proportion of patients with influenza secondary complications 
• 
Median duration of ventilation 
• 
Proportion of patients who are readmitted by Day 30 and Day 60 
 
6.4.3 
Subgroup Analyses 
Subgroup analyses will be performed to examine the consistency of the treatment 
estimates with use of the primary and selected secondary endpoints.  Subgroups will 
include the stratification factors as well as patients who are identified at baseline as 
influenza A positive by the upper, lower, or both airways and by patients with bacterial 
co-infections at admission as well as by the influenza season during which the patient 
was randomized.  Additional subgroups may be added following assessment of baseline 
characteristics as exploratory analyses. 
6.5 
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 AEs (including deaths, SAEs, discontinuations due to AEs, and the 
incidence and severity of AEs), clinical laboratory tests, vital signs (including SpO2 
measurements), and ECGs. 
All collected AE event data will be listed by study site and patient number.  All AEs 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 SAEs, including deaths, will be listed 
separately and summarized.  SAEs 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. 
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 


 
 
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6.6 
PHARMACOKINETIC ANALYSES 
Individual and mean serum MHAA4549A concentration versus time data will be 
tabulated and plotted.  The serum pharmacokinetics of MHAA4549A will be summarized 
by estimating total serum drug exposure (i.e., AUC), Cmax, Cmin, 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).  
Interpatient variability will be evaluated.  MHAA4549A serum concentration–time data 
may be compared with available data from other MHAA4549A clinical studies. 
 
 
  
 
 
 
 
 
6.7 
IMMUNOGENICITY ANALYSES 
The immunogenicity analyses will include patients with at least one predose and one 
postdose ATA assessment, with patients grouped according to treatment received. 
The numbers and proportions of ATA-positive patients and ATA-negative patients 
during the treatment and follow-up periods will be summarized by treatment group.  
Patients are considered to be ATA positive if they are ATA negative at baseline but 
develop an ATA response following study drug administration (treatment-induced 
ATA response), or if they are ATA positive at baseline and the titer of one or more post-
baseline samples is at least 4-fold greater (i.e., ≥ 0.60 titer units) than the titer of the 
baseline sample (treatment-enhanced ATA response).  Patients are considered to be 
ATA negative if they are ATA negative at baseline and all post-baseline samples are 
negative, or if they are ATA positive at baseline but do not have any post-baseline 
samples with a titer that is at least 4-fold greater than the titer of the baseline sample 
(treatment unaffected). 
The relationship between ATA status and safety, efficacy, PK, and biomarker endpoints 
will be analyzed and reported descriptively via subgroup analyses. 
6.8 
BIOMARKER ANALYSES 
 
 
 


 
 
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6.9 
EXPLORATORY PHARMACOKINETICS ANALYSES 
 
 
 
6.10 
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 I 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 


 
 
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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. 
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 
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.  
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 7.5. 


 
 
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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/IEC review.  The study site must also allow 
inspection by applicable health authorities. 
7.4 
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. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, 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. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for GCP 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 US Investigational New Drug (IND) 
application will comply with US FDA regulations and applicable local, state, and federal 
laws.  Studies conducted in the European Union or European Economic Area will comply 
with the EU Clinical Trial Directive (2001/20/EC). 
8.2 
INFORMED CONSENT 
The Sponsor’s sample ICFs (and ancillary sample ICFs) will be provided to each site.  If 
applicable, it will be provided in a certified translation of the local language.  The 


 
 
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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/IEC submission.  The final 
IRB/IEC-approved Consent Forms must be provided to the Sponsor for health authority 
submission purposes according to local requirements. 
The Consent Forms must be signed and dated by the patient or the patient’s authorized 
representative as applicable and in accordance with local regulations, and IRB/IEC 
policies, 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/IEC-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/IEC policy) during their participation in the study.  For any updated or revised 
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 
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. 
For sites in the United States, 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/IEC by the Principal 
Investigator and reviewed and approved by the IRB/IEC before the study is initiated.  In 
addition, any patient recruitment materials must be approved by the IRB/IEC.  


 
 
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The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/IEC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/IEC.  Investigators are 
also responsible for promptly informing the IRB/IEC of any protocol amendments (see 
Section 9.1).  
In addition to the requirements for reporting all AEs to the Sponsor, investigators must 
comply with requirements for reporting SAEs to the local health authority and IRB/IEC.  
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/IEC, 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 ICF (or separate authorization for use and 
disclosure of personal health information) signed by the patient, unless permitted or 
required by law. 
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 exploratory nature of the biomarker 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/IEC 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 


 
 
MHAA4549A—Genentech, Inc. 
123/Protocol GV29216, Version 7 (Global)   
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/IEC 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/IEC in accordance with established IRB/IEC 
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/IECs to inspect facilities and records relevant to this study. 
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, clinical monitoring and site management, data quality 
support, medical monitoring, and some safety reporting and regulatory activities as 
specified in 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 dynamic hierarchical 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.   


 
 
MHAA4549A—Genentech, Inc. 
124/Protocol GV29216, Version 7 (Global)   
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 from 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 website:  
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. 
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/IEC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/IEC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 


 
 
MHAA4549A—Genentech, Inc. 
125/Protocol GV29216, Version 7 (Global)   
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. 
126/Protocol GV29216, Version 7 (Global)   
10. 
REFERENCES 
Bai S, Jorga K, Xin Y, et al. A guide to rational dosing of monoclonal antibodies. Clin 
Pharmacokinet 2012;51(2):119 − 135. 
Blackwood B, Alderdice F, Burns K, et al. Use of weaning protocols for reducing duration 
of mechanical ventilation in critically ill adult patients: Cochrane systematic review 
and meta-analysis. BMJ 2011;342(c7237). 
Centers for Disease Control and Prevention (CDC). 2015-2016 Influenza antiviral 
medications [resource on the Internet]. 2016 [Updated 2016, Feb 22; cited 2016 Apr]. 
Available from: http://www.cdc.gov/flu/professionals/antivirals/summary-
clinicians.htm. 
Dejnirattisai W, Jumnainsong A, Onsirisakul N, et al. Cross reacting antibodies 
enhance dengue virus infection in humans. Science 2010;328(5979):745-8. 
Doshi S, Kamimoto L, Finellie L, et al. Description of antiviral treatment among adults 
hospitalized with influenza before and during the 2009 pandemic: United States, 
2005−2009. J Inf Dis 2011;204:1848 − 1856. 
Fiore AE, Fry A, Shay D, et al. (2011). Antiviral agents for the treatment and 
chemoprophylaxis of influenza---recommendations of the Advisory Committee on 
Immunization Practices (ACIP). MMWR. Recommendations and reports: Morbidity 
and mortality weekly report. Recommendations and reports/Centers for Disease 
Control. 2011; 60(1):1 − 24. 
Harper SA, Bradley JS, Englund JA, et al. Expert Panel of the Infectious Diseases 
Society of America. Seasonal influenza in adults and children--diagnosis, treatment, 
chemoprophylaxis, and institutional outbreak management: clinical practice 
guidelines of the Infectious Diseases Society of America. Clin Infect Dis 2009 Apr 
15;48(8):1003 − 1032. 
INSIGHT FLU005 IVIG Pilot Study Group. INSIGHT FLU005: An anti-influenza 
virus hyperimmune intravenous immunoglobulin pilot study. J Infect Dis 2016; 
213(4): 574-8. 
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. 


 
 
MHAA4549A—Genentech, Inc. 
127/Protocol GV29216, Version 7 (Global)   
Lawton MP, Brody EM. Assessment of older people: self-maintaining and instrumental 
activities of daily living. Gerontologist 1969;9:179 − 186. 
Lee N, Ison MG. Diagnosis, management and outcomes of adults hospitalized with 
influenza. Antiviral Therapy 2012:17(1 Pt B):143 − 157. 
Louie JK, Yang S, Acosta M, et al. Treatment with neuraminidase inhibitors for critically 
ill patients with influenza A (H1N1). CID 2012;55:1198 − 1204. 
Marty FM, Man CY, van der Horst C, et al. Safety and pharmacokinetics of intravenous 
zanamivir treatment in hospitalized adults with influenza: an open-label, multicenter, 
single-arm, Phase II study. J Infect Dis 2014;209(4):542 − 550. 
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. 
Polakos NK, Cornejo JC, Murray DA, et al. Kupffer cell-dependent hepatitis occurs 
during influenza infection. Am J Pathol 2006;168(4):1169 − 1178. 
Premier Perspective Hospital Database (Premier Inc, Charlotte, NC)  
Roozenbeek B, Lingsma HF, Perel P, et al. The added value of ordinal analysis in 
clinical trials: an example of traumatic brain injury. Crit Care 2011; 15: R127.  
Thompson WW, Shay DK, Weintraub E, et al. Influenza-associated hospitalizations in 
the United States. JAMA 2004;292(11):1333 − 1340. 
Writing Committee of the World Health Organization (WHO) consultation on human 
influenza A/H5. Avian influenza A (H5N1) infection in humans. N Engl J Med 2005; 
353: 1374 − 1385. 
Yingying C. Abnormal liver chemistry in patients with influenza A H1N1. Liver Int 2011; 
31(6):902. 
Zhou H, Thompson WW, Vioud CG, et al. Hospitalizations associated with influenza and 
respiratory syncytial virus in the United States 1993−2008. Clin Inf Dis 
2012;54(10):1427 − 36. 


 
 
MHAA4549A—Genentech, Inc. 
128/Protocol GV29216, Version 7 (Global)   
Appendix 1a 
 
Schedule of Activities 
Notes: Unless otherwise indicated, all assessments on Day 1 should be performed prior to study drug administration; x’s within 
parentheses, i.e., (x), indicate optional assessments.  Please refer to Follow-up Period table for visits to be completed after patient is 
discharged from hospital prior to Day 60.  Any screening assessments completed prior to consent as standard of care do not need to 
be repeated if done within the screening period.  If a patient is unable to be present at the site for a follow-up visit, a telephone visit is 
encouraged. 
Hospitalized Days (only to be completed while patients are hospitalized 
 
D -2,-1 
D1 
(Randomization) 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 
D11-13 
D14 
D15-19 
D20 
D21-24 
D25 
D26-29 
D30 
Hospital Discharge
a 
D60 Study Completion or Early 
Discontinuation while hospitalized 
Unscheduled 
Informed 
consent
 b 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsor-
approved 
influenza test
 c 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusi
on criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
and 
demographic 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Appendix 1a 
 
Schedule of Activities (cont.) 
 
MHAA4549A—Genentech, Inc. 
129/Protocol GV29216, Version 7 (Global)   
Hospitalized Days (only to be completed while patients are hospitalized 
 
D -2,-1 
D1 
(Randomization) 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 
D11-13 
D14 
D15-19 
D20 
D21-24 
D25 
D26-29 
D30 
Hospital Discharge
a 
D60 Study Completion or Early 
Discontinuation while hospitalized 
Unscheduled 
data 
Pregnancy test 
d 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(x) 
Confirm O2 
requirement 
e 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Respiratory 
Assessment 
f 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
(x) 
Concomitant 
medications 
g 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
(x) 
Vital signs
 h 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
(x) 
APACHE score 
i 
 
(x 
j) 
 
 
 
 
 
 
 
 
 
 
(x) 
 
 
 
 
 
(x
) 
(x
) 
(x) 
(x) 
SOFA score
  k 
 
(x 
j) 
 
 
 
 
 
(x) 
 
 
 
 
(x) 
 
 
 
 
 
(x
) 
(x
) 
(x) 
(x) 
Electrocardiogra
 
x 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
x 
x 
(x) 


Appendix 1a 
 
Schedule of Activities (cont.) 
 
MHAA4549A—Genentech, Inc. 
130/Protocol GV29216, Version 7 (Global)   
Hospitalized Days (only to be completed while patients are hospitalized 
 
D -2,-1 
D1 
(Randomization) 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 
D11-13 
D14 
D15-19 
D20 
D21-24 
D25 
D26-29 
D30 
Hospital Discharge
a 
D60 Study Completion or Early 
Discontinuation while hospitalized 
Unscheduled 
m (12-lead)
 l 
Randomization 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MHAA4549A 
administration 
m 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Oseltamivir 
administration
 n 
 
x 
x 
x 
x 
x 
(x) 
(x) 
(x) 
(x) 
(x) 
 
 
 
 
 
 
 
 
 
 
 
Complete 
physical 
examination
 o 
x 
(x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(x) 
Limited, 
symptom-
directed physical 
examination
 p 
 
 
x 
x 
x 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
x 
x 
(x) 
Weight & height 
q
 
x
 
x 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
x 
x 
(x) 


Appendix 1a 
 
Schedule of Activities (cont.) 
 
MHAA4549A—Genentech, Inc. 
131/Protocol GV29216, Version 7 (Global)   
Hospitalized Days (only to be completed while patients are hospitalized 
 
D -2,-1 
D1 
(Randomization) 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 
D11-13 
D14 
D15-19 
D20 
D21-24 
D25 
D26-29 
D30 
Hospital Discharge
a 
D60 Study Completion or Early 
Discontinuation while hospitalized 
Unscheduled 
Adverse events 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
(x) 
Hematology
 r 
x 
 
x 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
x 
x 
(x) 
Chemistry panel
 
r 
(x) 
s 
x 
x 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
x 
x 
(x) 
Coagulation 
panel
 r 
 
x 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
x 
x 
(x) 
Erythrocyte 
sedimentation 
rate 
 
(x) 
(x) 
 
 
(x) 
 
 
 
 
 
 
(x) 
 
 
 
 
 
(x)
(x)
(x) 
(x) 
C-reactive 
protein 
 
(x) 
(x) 
 
 
(x) 
 
 
 
 
 
 
(x) 
 
 
 
 
 
(x)
(x)
(x) 
(x) 
Urinalysis
  r, t 
 
x 
x 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
x 
x 
(x) 
Serology (HIV)
 r, 
u 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Appendix 1a 
 
Schedule of Activities (cont.) 
 
MHAA4549A—Genentech, Inc. 
132/Protocol GV29216, Version 7 (Global)   
Hospitalized Days (only to be completed while patients are hospitalized 
 
D -2,-1 
D1 
(Randomization) 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 
D11-13 
D14 
D15-19 
D20 
D21-24 
D25 
D26-29 
D30 
Hospital Discharge
a 
D60 Study Completion or Early 
Discontinuation while hospitalized 
Unscheduled 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
(x) 
 
  
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
(x) 
Flu antibodies 
(HAI) 
x 
 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
x 
x 
(x) 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
(x) 
Serum for 
MHAA4549A PK 
measurements
 y 
 
x 
x 
x 
 
x 
 
x 
 
 
 
 
x 
 
 
 
 
 
x 
x 
x 
(x) 
 
 
 
x 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
(x
)
 
 
(x) 


Appendix 1a 
 
Schedule of Activities (cont.) 
 
MHAA4549A—Genentech, Inc. 
133/Protocol GV29216, Version 7 (Global)   
Hospitalized Days (only to be completed while patients are hospitalized 
 
D -2,-1 
D1 
(Randomization) 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 
D11-13 
D14 
D15-19 
D20 
D21-24 
D25 
D26-29 
D30 
Hospital Discharge
a 
D60 Study Completion or Early 
Discontinuation while hospitalized 
Unscheduled 
 
aa 
 
 
 
 
 
x 
x 
x 
 
x 
 
x 
 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
(x) 
 
 
  
 
x 
x 
x 
 
x 
 
x 
 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
(x) 
  
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
(x) 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
(x) 
 
  
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
(x) 
  
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
(x) 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 


Appendix 1a 
 
Schedule of Activities (cont.) 
 
MHAA4549A—Genentech, Inc. 
134/Protocol GV29216, Version 7 (Global)   
Hospitalized Days (only to be completed while patients are hospitalized 
 
D -2,-1 
D1 
(Randomization) 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 
D11-13 
D14 
D15-19 
D20 
D21-24 
D25 
D26-29 
D30 
Hospital Discharge
a 
D60 Study Completion or Early 
Discontinuation while hospitalized 
Unscheduled 
Oseltamivir 
medication diary 
dd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
Clinical status 
assessment
ee 
 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 


Appendix 1a 
 
Schedule of Activities (cont.) 
 
MHAA4549A—Genentech, Inc. 
135/Protocol GV29216, Version 7 (Global)   
; AE = adverse event; APACHE = Acute Physiology and Chronic Health Evaluation; 
ATA = Anti-therapeutic antibodies; D = day; Dx = diagnostics; eCRF = electronic Case Report Form; ECG = electrocardiogram; HAI = hemagglutinin 
inhibition; 
; ICU = Intensive Care Unit; IRB/IEC = Independent Review Board/Independent Ethics 
Committee; NAI = neuraminidase inhibitor; O2 = oxygen; PaO2/FiO2 = partial pressure of oxygen/fraction of inspired oxygen; PCR = polymerase chain 
reaction; PD = pharmacodynamics; PK = pharmacokinetic; PPV = positive pressure ventilation; qPCR = quantitative Polymerase Chain Reaction; 
RBCs = red blood cells; SOFA = Sequential Organ Failure Assessment; SpO2 = oxygen saturation measured by pulse oximetry; WBCs = white blood 
cells. 
a Assessments to be performed irrespective of day of discharge.  Assessments on discharge day will supersede assessments for matching day 
except for the study completion/early discontinuation visit (e.g., If a patient is discharged from the hospital on Day X, use assessments under 
“hospital discharge” column instead of the Day X column and record under the hospital discharge folder in the eCRF.  If a patient discontinues 
from the study early on Day X, complete all assessments under the “early discontinuation” column and record under the early discontinuation 
folder in the eCRF.  
b Informed consent must be obtained from all patients.  For patients who are unable to consent, an authorized representative may be used if 
allowed by local regulations and IRB/IEC policy.   
c Sponsor-approved influenza test using a nasopharyngeal swab in one nostril or lower respiratory tract sample (if appropriate for the sponsor-
approved local PCR test).  A Sponsor-approved influenza test includes influenza antigen test or influenza polymerase chain reaction (PCR) test.  
Result must be available within the 48-hour screening window. 
d A urine or serum pregnancy test should be collected only for women considered by the investigator to be of childbearing potential, see exclusion 
criteria.  This result must be available within 2 days prior to study treatment.  If urine testing is not available at the site, blood already collected 
from an existing sample may be tested for pregnancy. 
e Confirm patient requires supplemental O2 or PPV within 24 hours of hospital admission. 
f Unless clinically contraindicated, all patients will have their on-study SpO2 and corresponding respiratory assessments recorded daily in the 
morning between 6:00 a.m. and 12:00 noon local time; screening SpO2 may be taken outside this window.  From Day 1 onward post-study drug 
administration, patients on low flow O2 should have a daily trial of their SpO2 while on and off the supplementation and both values will be 
recorded.  If the patient is on oxygen supplementation, SpO2 measured by pulse oximetry and the corresponding respiratory assessments (e.g., 
FiO2, flow rate) will be recorded.  If the patient is on PPV, PaO2 and the corresponding respiratory assessments (e.g., FiO2, ventilator mode, 
ventilator respiratory rate, positive end-expiratory pressure) will be recorded.  If clinically appropriate (i.e., the patient is on non-invasive PPV), 
the conversion table in Appendix 11 may be used. 
g Concomitant medications should be recorded for 30 days prior to screening, through the study completion/early discontinuation visit.  See 
exclusion criteria in Section 4.5.2 for prohibited therapies. 


Appendix 1a 
 
Schedule of Activities (cont.) 
 
MHAA4549A—Genentech, Inc. 
136/Protocol GV29216, Version 7 (Global)   
h Vital signs will be collected within 1 hour before MHAA4549A infusion and within 1 hour after completion of MHAA4549A infusion and include 
temperature, 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.  In patients who have multiple 
vital signs taken during any day, the most abnormal value should be recorded from that 24-hour period.  Temperature, blood pressure, 
respiratory rate, and heart rate will be completed after the patient has been in a seated or supine position for > 5 minutes.  The worst/most 
abnormal value from the last 24-hour period should be recorded for patients who are in the ICU.  
i APACHE scores are optional and only for patients that are in the ICU.  For calculation of the screening APACHE score, the worst values in the 
first 24 hours should be used.  APACHE scores are not required for study conduct or entry but should be collected if available.  
j Assessment to be conducted based on entry into ICU; may vary from patient to patient. 
k SOFA scores are optional and only for patients in the ICU that have available data such as PaO2/FiO2 (mmHg).  See Appendix 7 for SOFA score 
calculation. 
l Patient should rest in a supine position for 10 minutes prior. 
m  Patient will be a resident for at least 24 hours following administration of MHAA4549A. 
n Oseltamivir must be given for a minimum of 5 days.  Treatment longer than 5 days is permitted based on the discretion of the investigator 
[indicated by (x)].   
o Complete physical examination includes evaluations of general appearance of head, eyes, ears, 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.  Day 1 physical examination is optional if 
already completed on Day -1 or -2. 
p 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, if appropriate. 
q Height will be obtained at screening only.  Weight will be obtained at all indicated visits.  Height and weight will be recorded in centimeters and 
kilograms, respectively.  
r Local laboratory measurements should be utilized. 
s For optional thyroid stimulating hormone test. 
t 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. 
u HIV serology result not needed for randomization and a positive result does not require patient discontinuation. 


Appendix 1a 
 
Schedule of Activities (cont.) 
 
MHAA4549A—Genentech, Inc. 
137/Protocol GV29216, Version 7 (Global)   
 
 
 
 
 
 
 
 
 
 
   
 
 
y Day 1 serum PK samples are to be drawn 30 (± 5) minutes pre-dose of MHAA4549A, 60 (± 15) minutes after the end of infusion.  Serum PK 
samples on Day 2 and after are to be drawn immediately before oseltamivir dosing. 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.  
 
 
 
aa   If patient is discharged on or before Day 5, the oseltamivir PK samples are to be taken on the discharge day. 
 
 
 
 
 
 
dd Patients who are discharged from the hospital with oseltamivir will be required to complete a medication diary and return the medication diary, 
empty (used) oseltamivir packets and unused oseltamivir capsules to the study site at the next follow up visit.  Patients will record the date and 
time when each oseltamivir capsule is administered.  


Appendix 1a 
 
Schedule of Activities (cont.) 
 
MHAA4549A—Genentech, Inc. 
138/Protocol GV29216, Version 7 (Global)   
ee Indicate which clinical status the patient is categorized under: death; in the ICU; non-ICU hospitalization, requiring supplemental oxygen; 
non-ICU hospitalization, not requiring supplemental oxygen; not hospitalized, but unable to resume normal activities; or not hospitalized 
with full resumption of normal activities 


 
 
MHAA4549A—Genentech, Inc. 
139/Protocol GV29216, Version 7 (Global)   
Appendix 1b 
 
Schedule of Activities:  Follow-Up Period  
• 
If a patient is discharged prior to Day 14, he/she will need to complete the following assessments for Day 14, Day 30, and Day 60 below. 
• 
If a patient is discharged after Day 14 but prior to Day 30, he/she will need to complete the following assessments for Day 30 and Day 60 
below. 
• 
If a patient is discharged after Day 30, but prior to Day 60, he/she will need to complete the following assessments for Day 60 below. 
• 
If patient is hospitalized for Day 14, Day 30, and/or Day 60, please refer to Appendix 1a.  
Day (D) 
D14 ± 1 
(If discharged  
BEFORE Day 14) 
D30 ± 4  
(If discharged  
BEFORE Day 30)  
Day 60 ± 7 (Study 
Completion)  
or Early Discontinuation  
Concomitant medications a 
x 
x 
x 
Vital signs b 
x 
x 
x 
Electrocardiogram (12-lead) c 
x 
x 
x 
Weight, BMI d 
x 
x 
x 
Adverse events 
x 
x 
x 
Hematology e
 
x 
x 
x 
Chemistry panel e 
x 
x 
x 
Coagulation panel e 
x 
x 
x 
Urinalysis e 
x 
x 
x 
Flu antibodies (HAI) 
x 
x 
x 
 
 
x 
x 
Serum for MHAA4549A PK measurements f 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
x 
  
 
x 
x 
 
 
x 
x 
 
 
x 
x 


Appendix 1b 
 
Schedule of Activities:  Follow-Up Period (cont.) 
 
MHAA4549A—Genentech, Inc. 
140/Protocol GV29216, Version 7 (Global)   
Day (D) 
D14 ± 1 
(If discharged  
BEFORE Day 14) 
D30 ± 4  
(If discharged  
BEFORE Day 30)  
Day 60 ± 7 (Study 
Completion)  
or Early Discontinuation  
  
 
x 
x 
Clinical status assessmenth 
x 
x 
 
  
; ATA = Anti-therapeutic antibodies; BMI = body mass index; D = day; 
Dx = diagnostics; eCRF = electronic Case Report Form; ECG = electrocardiogram; HAI = hemagglutinin inhibition; 
 
 
 PD = pharmacodynamics; PK = pharmacokinetic. 
a Concomitant medications should be recorded for 30 days prior to screening, through the study completion/early discontinuation visit.  See 
exclusion criteria in Section 4.1.2 for prohibited therapies. 
b Vital signs include temperature, 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 study drug administration of any antipyretic drugs.  
In patients who have multiple vital signs taken during any day, the most abnormal value should be recorded from that 24-hour period.  
Temperature, blood pressure, respiratory rate, and heart rate will be completed after the patient has been in a seated or supine position for 
> 5 minutes.  
c ECG should be recorded after the patient has rested in a supine position for 10 minutes. 
d Weight will be recorded in kg.  
e Local laboratory measurements should be used. 
f PK samples  must be labeled with the exact time of draw.  
 
 
 
 
h  Indicate which clinical status the patient is categorized under: death; in the ICU; non-ICU hospitalization, requiring supplemental oxygen; 
non-ICU hospitalization, not requiring supplemental oxygen; not hospitalized, but unable to resume normal activities; or not hospitalized 
with full resumption of normal activities 
 
 


 
 
MHAA4549A—Genentech, Inc. 
141/Protocol GV29216, Version 7 (Global)   
Appendix 2 
 
Time to Normalization of Respiratory Function 
For the purposes of this study, the time to normalization of respiratory function will be 
defined as the time to removal of the patient from O2 supplementation in order to 
maintain an SpO2 ≥95%.   
Unless clinically contraindicated*, patients who are on low flow O2 (i.e., 2-6 L/min) 
should receive a daily trial off O2 in the morning between 6:00 a.m. and 12:00 noon as 
described below.  
1. 
Patient should be resting or sitting. 
2. 
Patient should be fitted with pulse oximeter, and their SpO2 should be checked once 
while on O2 and then again 3 − 5 minutes after turning off O2 supplementation. 
Clinical judgment should be used to determine when the SpO2 result is stable to 
record.   
3. 
If the SpO2 ≥95%, then the time and reading should be recorded.  Notify the study 
doctor so that he/she can make a clinical judgment to determine whether the O2 can 
be removed. 
4. 
The recorded time for the endpoint corresponds with the initial discontinuation of O2 
and reading. 
 
If a patient is clinically able to be removed from oxygen outside the time window above 
(6:00 a.m. and 12:00 noon), the trial off data should be recorded as an unscheduled 
visit.  
* If a patient has an SpO2 <95% while on oxygen supplementation, he/she shall be 
considered to be “clinically contraindicated” from requiring a trial off oxygen; however, 
corresponding respiratory assessments should be recorded. 
 




 
 
MHAA4549A—Genentech, Inc. 
143/Protocol GV29216, Version 7 (Global)   
Appendix 4 
 
  
 
 
 
 
 
 
 


 
MHAA4549A—Genentech, Inc. 
144/Protocol GV29216, Version 7 (Global)   
Appendix 5 
 
  
 
 
 
 
  
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
MHAA4549A—Genentech, Inc. 
145/Protocol GV29216, Version 7 (Global)   
Appendix 6 
 
 
 
  
 
  
 


 
 
MHAA4549A—Genentech, Inc. 
146/Protocol GV29216, Version 7 (Global)   
Appendix 7 
 
SOFA Score Calculation  
SOFA Score 
Variables 
0 
1 
2 
3 
4 
Respiratory  
(PaO2/FiO2, mmHg) 
> 400 
≤ 400 
≤ 300 
≤ 200a 
≤ 100a 
Coagulation  
(Platelets x 103/μL) b 
> 150 
≤ 150 
≤ 100 
≤ 50 
≤ 20 
Liver  
(Bilirubin, mg/dL) b 
< 1.2 
1.2 − 1.9 
2.0 − 5.9 
6.0 − 11.9 
> 12.0 
Cardiovascular 
(Hypotension) 
No 
hypotension
MAP < 70 
mmHg 
Dop ≤ 5 or dob 
(any dose) c 
Dop > 5, 
epi ≤ 0.1, or 
norepi ≤ 0.1c 
Dop > 15, 
epi > 0.1, or 
norepi > 0.1c 
Central Nervous System 
(Glasgow Coma Score 
Scale) 
15 
13 − 14 
10 − 12 
6 − 9 
< 6 
Renal  
(Creatinine, mg/dL or 
urine output, mL/day) d 
< 1.2 
1.2 − 1.9 
2.0 − 3.4 
3.5 − 4.9 or 
< 500 
> 5.0 or < 200
Norepi = norepinephrine; Dob = dobutamine; Dop = dopamine; Epi = epinephrine; FiO2 = fraction of 
inspired oxygen; MAP = mean arterial pressure; PaO2 = partial pressure of arterial oxygen. 
a Values are with respiratory support. 
b To convert bilirubin from mg/dL to μmol/L, multiply by 17.1. 
c Adrenergic agents administered for at least 1 hour (doses given are in μg/kg per minute). 
d To convert creatinine from mg/dL to μmol/L, multiply by 88.4. 
  
References for Appendix 7: 
Ferreira FL, Bota DP, Bross A et al. Serial evaluation of the SOFA score to predict 
outcome in critically ill patients. JAMA 2001; 286(14):1754−1758 
Vincent JL, de Mendonca A, Cantraine F et al. Use of the SOFA score to assess the 
incidence of organ dysfunction/failure in intensive care units: results of a multicenter, 
prospective study.  Working group on “sepsis-related problems” of the European Society 
of Intensive Care Medicine.  Crit Care Med 1998;26(11): 1793−1800. 


 
 
MHAA4549A—Genentech, Inc. 
147/Protocol GV29216, Version 7 (Global)   
Appendix 8 
 
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 8 (cont’d)  
DAIDS Toxicity Grading Tables for Clinical Abnormalities 
MHAA4549A—Genentech, Inc. 
148/Protocol GV29216, Version 7 (Global)   
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 
 
 
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. 
149/Protocol GV29216, Version 7 (Global)   
Appendix 9 
 
DAIDS Toxicity Grading Tables for Laboratory Abnormalities 
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 
Abbreviations used in the table: 
 
; CPK = creatine phosphokinase; Dec = Decreased; 
IV = Intravenous; LLN = Lower limit of normal; Mod = Moderate; Req = Required; 
Rx = Therapy; SGOT = serum glutamic oxaloacetic transaminase; SGPT = serum glutamic 
pyruvic transaminase; ULN = Upper limit of normal. 
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 gm/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 x 
ULN 
1.26 – 1.50 x 
ULN 
1.51 – 3.0 x 
ULN 
>3 x ULN 
Activated Partial 
Thromboplastin 
Time (APTT) 
1.01 – 1.66 x 
ULN 
1.67 – 2.33 x 
ULN 
2.34 – 3 x ULN 
>3 x ULN 
Methemoglobin 
5.0 – 9.9% 
10.0 – 14.9% 
15.0 – 19.9% 
>20.0% 
From the FDA Guidance document ‘Toxicity Grading Scale from Healthy Adult and Adolescent 
Volunteers Enrolled in Preventative Vaccine Clinical Trials’ 
 


Appendix 9 (cont’d)  
DAIDS Toxicity Grading Tables for Laboratory Abnormalities 
MHAA4549A—Genentech, Inc. 
150/Protocol GV29216, Version 7 (Global)   
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  
Hyperbilirubinemia 
(when accompanied by 
any increase in other 
liver function test) 
1.1 – <1.25 x 
ULN 
1.25 – <1.5 x 
ULN 
1.5 – 1.75 x  
ULN 
>1.75 x ULN 
Hyperbilirubinemia 
(when other liver 
function are in the 
normal range) 
1.1 – <1.5 x 
ULN 
1.5 – <2.0 x 
ULN 
2.0 – 3.0 x  
ULN 
>3.0 x ULN 


Appendix 9 (cont’d)  
DAIDS Toxicity Grading Tables for Laboratory Abnormalities 
MHAA4549A—Genentech, Inc. 
151/Protocol GV29216, Version 7 (Global)   
From the FDA Guidance document ‘Toxicity Grading Scale from Healthy Adult and 
Adolescent Volunteers Enrolled in Preventative Vaccine Clinical Trials’ 
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 
* From the FDA Guidance document ‘Toxicity Grading Scale from Healthy Adult and Adolescent 
Volunteers Enrolled in Preventative Vaccine Clinical Trials’ 
  
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 
From the FDA Guidance document ‘Toxicity Grading Scale from Healthy Adult and Adolescent 
Volunteers Enrolled in Preventative Vaccine Clinical Trials’ 
 


 
 
MHAA4549A—Genentech, Inc. 
152/Protocol GV29216, Version 7 (Global)   
Appendix 10 
 
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. 
153/Protocol GV29216, Version 7 (Global)   
Appendix 11 
 
Respiratory Conversion Table for PaO2 
Estimating PaO2 from a given oxygen saturation 
Oxygen Saturation (%) 
PaO2 (mmHg) 
80 
44 
81 
45 
82 
46 
83 
47 
84 
49 
85 
50 
86 
52 
87 
53 
88 
55 
89 
57 
90 
60 
91 
62 
92 
65 
93 
69 
94 
73 
95 
79 
96 
86 
97 
96 
98 
112 
99 
145 
From The Extended Study of Prevalence of Infection in Intensive Care: 
http://www.intensive.org/epic2/Documents/Estimation%20of%20PO2%20and%20FiO2.pdf 
 


 
MHAA4549A—Genentech, Inc. 
154/Protocol GV29216, Version 7 (Global)   
Appendix 12 
 
Clinical Status Assessment 
Clinical status will be assessed on Days 1-7, 14, and 30.  Assessment should be 
collected at a consistent time throughout the study. Indicate the patient’s clinical 
status for the day: 
1. 
Death; 
2. 
In the ICU; 
3. 
Non-ICU hospitalization, requiring supplemental oxygen; 
4. 
Non-ICU hospitalization, not requiring supplemental oxygen; 
5. 
Not hospitalized, but unable to resume normal activities; or 
6. 
Not hospitalized with full resumption of normal activities