Evaluation of a Screen and Treat Protocol for Influenza in Socially Vulnerable Communities.
Conditions: Influenza
Sponsor: Tricore, Inc

CONFIDENTIAL 
This is a TriCore document that contains confidential information.  It is intended 
solely for the recipient clinical investigator(s) and must not be disclosed to any other 
party.  This material may be used only for evaluating or conducting clinical 
investigations; any other proposed use requires written consent from TriCore. 
Xofluza ⎯TriCore 
Protocol ML44485, Version {Number} 
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PROTOCOL 
TITLE: 
EVALUATION OF A SCREEN AND TREAT 
PROTOCL FOR INFLUENZA IN SOCIALLY 
VULNERABLE COMMUNITIES 
STUDY NUMBER: 
ML44485  
VERSION NUMBER: 
2.2 
TEST PRODUCTS: 
XOFLUZA® (baloxavir marboxil) (RO7191686) 
INDICATION: 
 
INVESTIGATOR: 
Michael Crossey, MD. PhD. 
1001 Woodward Pl NE 
Albuquerque, NM 87102 
Telephone: 505-938-8174 
E-mail:  Michael.crossey@tricore.org 
SUB-INVESTIGATORS: 
Karissa Culbreath, PhD, D (ABMM) 
 
STUDY COORDINATOR: Liliana Talamantes 
SUPPORT PROVIDED 
BY: 
Genentech, Inc. 
 
PROTOCOL DATE: 
09 Oct 2023 
 
 

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TABLE OF CONTENTS 
1. 
BACKGROUND ............................................................................. 8 
1.1 
Background on influenza .......................................................... 8 
1.2 
Background on Xofluza ............................................................. 9 
1.2.1 
Overview of Xofluza Clinical Development .............................. 10 
1.2.1.1 
Efficacy ................................................................................... 10 
1.2.1.2 
Safety ..................................................................................... 11 
1.2.2 
Post-Marketing Safety Data .................................................... 13 
1.3 
Study Rationale and Benefit-Risk Assessment ....................... 13 
2. 
OBJECTIVES AND ENDPOINTS ................................................. 15 
2.1 
Primary Objective(s) ............................................................... 15 
2.2 
Secondary Objective(s) ........................................................... 15 
3. 
STUDY DESIGN .......................................................................... 15 
3.1 
Description of the Study .......................................................... 15 
3.2 
End of Study and Length of Study........................................... 18 
3.3 
Rationale for Study Design ..................................................... 18 
3.3.1 
Rationale for Xofluza Dose ..................................................... 18 
3.3.2 
Rationale for Patient Population .............................................. 18 
4. 
MATERIALS AND METHODS...................................................... 18 
4.1 
Patients................................................................................... 18 
4.1.1 
Inclusion Criteria ..................................................................... 19 
4.1.2 
Exclusion Criteria .................................................................... 20 
4.2 
Method of Treatment Assignment ........................................... 21 
4.3 
Study Treatment ..................................................................... 21 
4.3.1 
Study Treatment Formulation, Packaging, and Handling ........ 21 
4.3.1.1 
Xofluza.................................................................................... 21 
4.3.2 
Study Treatment Dosage, Administration, and Compliance .... 21 
4.3.2.1 
Xofluza.................................................................................... 21 
4.4 
Concomitant Therapy.............................................................. 21 
4.4.1 
Permitted Therapy .................................................................. 21 
4.4.2 
Cautionary Therapy ................................................................ 22 

TABLE OF CONTENTS (CONT.) 
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Protocol ML44485, Version {Number} 
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4.4.3 
Prohibited Therapy ................................................................. 22 
4.5 
Study Assessments ................................................................ 22 
4.5.1 
Informed Consent Forms and Screening Log .......................... 22 
4.5.2 
Medical History, Concomitant Medication, and 
Demographic Data .................................................................. 23 
4.5.3 
Physical Examinations ............................................................ 23 
4.5.4 
Vital Signs ............................................................................... 23 
4.5.5 
Rapid Influenza Diagnostic Test ............................................. 23 
4.5.6 
Laboratory, Biomarker, and Other Biological Samples ............ 23 
4.6 
Treatment, Patient, and Study Discontinuation ....................... 24 
4.6.1 
Patient Discontinuation from Study ......................................... 24 
4.6.2 
Study Discontinuation ............................................................. 25 
5. 
ASSESSMENT OF SAFETY ........................................................ 25 
5.1 
Safety Plan ............................................................................. 25 
5.1.1 
Potential Risks Associated with Xofluza .................................. 25 
5.1.1.1 
Hypersensitivity ....................................................................... 26 
5.1.1.2 
Increased Incidence of Treatment-Emergent Resistance in 
Patients Less Than 5 Years of Age ......................................... 26 
5.1.1.3 
Risk of Bacterial Infections ...................................................... 26 
5.1.2 
Management of Patients Who Experience Adverse Events .... 26 
5.1.2.1 
Dose Modifications ................................................................. 26 
5.1.2.2 
Treatment Interruption ............................................................ 26 
5.2 
Safety reporting of adverse events.......................................... 26 
5.2.1 
Specification of Safety Variables ............................................. 26 
5.2.2 
Adverse Events ....................................................................... 27 
5.2.3 
Serious Adverse Events .......................................................... 27 
5.3 
METHODS AND TIMING FOR ASSESSING AND 
RECORDING SAFETY VARIABLES ......................................... 27 
5.3.1 
Adverse Event Reporting Period ............................................. 28 
5.3.2 
Assessment of Adverse Events .............................................. 28 
5.4 
Procedures for Eliciting, Recording, and Reporting 
Adverse Events ....................................................................... 29 
5.4.1 
Eliciting Adverse Events ......................................................... 29 

TABLE OF CONTENTS (CONT.) 
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5.4.2 
Specific Instructions for Recording Adverse Events ................ 29 
5.4.2.1 
Diagnosis vs. Signs and Symptoms ........................................ 29 
5.4.2.2 
Deaths .................................................................................... 29 
5.4.2.3 
Preexisting Medical Conditions ............................................... 29 
5.4.2.4 
Hospitalizations for Medical or Surgical Procedures ............... 29 
5.4.2.5 
Assessment of Severity of Adverse Events ............................. 30 
5.4.2.6 
Pregnancy .............................................................................. 30 
5.4.2.7 
Adverse Events of Special Interest ......................................... 31 
5.4.2.8 
Other Special Situations Reports ............................................ 31 
5.4.2.9 
Product Complaints ................................................................ 32 
5.4.2.10 
Post-Study Adverse Events .................................................... 32 
5.4.2.11 
Exchange of Single Case Reports with Genentech ................. 32 
5.4.2.12 
Case Transmission Verification of Single Case Reports ......... 33 
5.5 
Reporting Requirements For Adverse Events Originating From 
Patient-Reported Outcomes ...................................................... 33 
5.6 
MedWatch 3500A Reporting Guidelines ................................. 33 
5.6.1 
Follow-Up Information ............................................................. 33 
5.7 
Reporting to Regulatory Authorities, Ethics Committees 
and Investigators .................................................................... 34 
5.8 
Aggregate Reports .................................................................. 34 
5.9 
Study Close-Out ..................................................................... 35 
5.10 
Queries ................................................................................... 35 
5.11 
Signal Management and Risk Management ............................ 35 
5.12 
Compliance with Pharmacovigilance Agreement / Audit ......... 36 
6. 
STATISTICAL CONSIDERATIONS ............................................. 36 
6.1 
Determination of Sample Size ................................................. 36 
6.2 
Planned Efficacy Evaluations .................................................. 37 
6.3 
Secondary Efficacy Variables ................................................. 37 
6.4 
Safety Analyses ...................................................................... 37 
6.5 
Method of Analysis ................................................................. 37 
7. 
INVESTIGATOR REQUIREMENTS ............................................. 38 
7.1 
Retention of Records .............................................................. 38 

TABLE OF CONTENTS (CONT.) 
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7.2 
Study Medical Monitoring Requirements ................................. 38 
7.3 
Data Collection ....................................................................... 38 
8. 
ETHICAL CONSIDERATIONS ..................................................... 39 
8.1 
Compliance with Laws and Regulations .................................. 39 
8.2 
Informed Consent ................................................................... 39 
8.3 
Institutional Review Board or Ethics Committee ...................... 39 
8.4 
Confidentiality ......................................................................... 40 
9. 
REFERENCES ............................................................................ 41 
 
 
LIST OF TABLES 
Table 1 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE .. Error! Bookmark not defined. 
Table 2 
Causal Attribution Guidance.......... Error! Bookmark not defined. 
 
 
LIST OF APPENDICES 
Appendix 1 
Study Flowchart......................................................... 43 
Appendix 2 
Safety Reporting Fax Cover Sheet ............................ 46 
Appendix 3 
FDA MedWatch 3500 Form ....................................... 47 
Appendix 4 
Management Criteria for Abnormal 
Liver Function Tests .................................................. 48 
Appendix 5 
New Mexico Board of Pharmacy 
Protocol for Pharmacist Prescribing of 
Dangerous Drugs in Conjunction with 
Point of Care Testing (POCT).......................Attachment 
 

 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
ADA 
anti-drug antibody 
AE 
adverse event 
AERO 
adverse event reporting online 
AESI 
adverse event of special interest 
AUC 
area under the curve 
CIOMS 
Council for International Organizations of Medical Sciences 
ClinRO 
clinician‑reported outcome 
Cmax 
maximum concentration observed 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSUR 
Development Safety Update Report 
EC 
Ethics Committee 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EMA 
European Medicines Agency 
FDA 
U.S. Food and Drug Administration 
HA 
hemagglutinin complex  
HAHA 
human anti-human antibody 
HBV 
hepatitis B virus 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonisation 
ICU 
intensive care unit 
iDMC 
independent Data Monitoring Committee 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (Application) 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
IRF 
Independent Review Facility 
IxRS 
interactive voice or web-based response system 
LPLV 
last patient, last visit 
M2 
matrix-2 
mITTI 
modified intent-to-treat (influenza) infected (population) 
MN 
mobile nursing 
NA 
neuraminidase 

 
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Abbreviation 
Definition 
NAI 
neuraminidase inhibitor 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NGS 
next-generation sequencing 
ObsRO 
observer-reported outcome 
OS 
overall survival 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PRO 
patient-reported outcome 
PRO-CTCAE 
Patient-Reported Outcomes version of the Common Terminology Criteria 
for Adverse Events 
RIDT 
Rapid Influenza Diagnostic Test 
RT-PCR 
reverse transcriptase-polymerase chain reaction 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SOC 
standard of care 
SUSAR 
suspected unexpected serious adverse reaction 
TCID50 
50% tissue culture infectious dose 
tmax 
time to maximum concentration 
TQT 
Thorough QT 
TTAS 
time to alleviation of symptoms 
TTCI 
time to clinical improvement 
TTIIS 
time to improvement of influenza symptoms 
ULN 
upper limit of normal 
USPI 
U.S. Package Insert 
Vc/F 
apparent volume of distribution for the central compartment 
WES 
whole exome sequencing 
WGS 
whole genome sequencing 
 

 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON INFLUENZA 
Influenza is an acute respiratory infectious disease caused by a virus of the 
orthomyxovirus family.  Two forms are known to infect humans, influenza A and 
B.  These viruses cause an acute febrile infection of the respiratory tract after an 
incubation period of 1 to 4 days, characterized by the sudden onset of fever, 
cough, fatigue, headache, and myalgia.  Annual influenza epidemics are thought 
to result in between 3 and 5 million cases of severe illness, and between 250,000 
and 500,000 deaths every year around the world (WHO 2017). 
Although the condition is usually self-limiting in healthy adults, it can be 
associated with substantial morbidity and occasional mortality in children, the 
elderly, and the immunocompromised (Paules and Subbarao 2017). 
Hospitalization due to severe influenza is associated with high mortality 
(4%−8%), intensive care unit (ICU) admission (5%−17%), and prolonged hospital 
stays of between 5 and 9 days.  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). 
The influenza viruses have a segmented, negative-sense, single-stranded, 
lipid-encapsulated RNA genome; they range between 80 and 100 nm in size. 
Subtypes are defined according to glycoproteins present in the viral lipid coat. 
The hemagglutinin complex (HA) is the major surface protein of the virus. The 
neuraminidase (NA) proteins are the second major surface proteins in the virion 
and play a role in enhancing virus penetration of the mucus layer around the 
target cell and in release of virus from the cell surface. The matrix-2 (M2) protein 
triggers the disintegration of the virion during virus entry into the cell and may 
also be involved in protecting the HA prior to assembly of new virus particles. 
In addition to Xofluza, the following anti-influenza virus drugs are currently 
available for treatment of acute, uncomplicated influenza in different countries:  
the M2 ion channel inhibitors amantadine and rimantadine, the RNA polymerase 
inhibitor favipiravir, and the NA inhibitors (i.e., oseltamivir, zanamivir, and 
peramivir). Many cases of seasonal influenza infection are resistant to 
amantadine and rimantadine, hence their use in clinical practice is limited. NA 
inhibitor (NAI) oral formulations need to be administered for 5 days, potentially 
resulting in poor patient compliance and convenience, while inhalation 
formulations can only be used in patients who are able to inhale the drug. These 
factors contribute to an unmet medical need for new antiviral influenza drugs that 
can be easily and less frequently administered, particularly in patients who are 
severely ill and possibly intubated. 

 
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In February 2019, intravenous zanamivir (Dectova) received a positive opinion 
for use under exceptional circumstances from the European Medicines Agency 
for the treatment of complicated and potentially life-threatening influenza A or B 
virus infections in adult and pediatric patients (aged  6 months). Zanamivir is 
only indicated when the influenza virus is resistant to other antiviral drugs, or 
when other antiviral drugs are not suitable, and, therefore, have limited scope in 
treating influenza in hospitalized patients. Currently, there are no other licensed 
drugs specifically approved for the treatment of influenza in hospitalized patients. 
Despite this, NAIs are widely used as the mainstay of treatment for hospitalized 
patients, and evidence shows a potential reduction in mortality in hospitalized 
patients treated with NAIs, especially if initiated as early as possible (Muthuri et 
al. 2014).  
Influenza viruses are known to mutate during the course of replication and can 
mutate into a strain resistant to existing antiviral influenza drugs or a strain to 
which most people are not immune.  Certain strains of avian influenza have been 
found to be highly pathogenic with high rates of NAI-resistance (Hu et al. 2013). 
New antiviral influenza treatments with novel mechanisms of action may provide 
alternative therapy options, particularly when used in combination with NAIs, to 
overcome such highly pathogenic organisms. 
1.2 
BACKGROUND ON XOFLUZA 
Xofluza (also referred to as baloxavir marboxil) is a compound that exerts 
antiviral effects against influenza. Xofluza is a pro-drug, which is converted to an 
active form baloxavir through a metabolic process called hydrolysis, in the blood, 
liver, and small intestine. 
Xofluza acts on cap-dependent endonuclease, an enzyme specific to influenza 
viruses, and inhibits viral cap-snatching, thereby suppressing the replication of 
influenza viruses. 
To date, one Phase II study in otherwise healthy adults and two Phase III studies 
in adults and adolescents (i.e., one in otherwise healthy patients and one in 
patients with high risk of influenza-related complications) have been completed 
and are summarized below.  Xofluza is now indicated for treatment of acute 
uncomplicated influenza in patients who have been symptomatic for no more 
than 48 hours and who are otherwise healthy adults and pediatric patients 5 
years of age and older.  Also, Xofluza has been approved for post-exposure 
prophylaxis of influenza in patients 5 years of age and older following contact 
with an individual who has influenza.    
Xofluza is approved for use in Japan (since February 2018) for the treatment of 
influenza A or B virus infection in all age groups (10 kg) and in the United States 
(since October 2018), Hong Kong (since February 2019), and Thailand (since 

 
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March 2019).  In the US It is approved for the treatment of influenza in otherwise 
healthy patients aged 12 years and above who have been symptomatic for no 
more than 48 hours as well as pediatric patients 5 years of age and older. In 
addition, Xofluza is approved in Thailand for the treatment of influenza in patients 
aged 12 years and above who have been symptomatic for no more than 
48 hours and are at high risk of developing influenza-related complications as 
well as post-exposure prophylaxis.  Regulatory filings in other global regions are 
either completed, ongoing, or planned to gain market authorization for the use of 
Xofluza for the treatment of influenza. 
Detailed profiles of Xofluza are provided in the Xofluza Investigator’s Brochure. 
1.2.1 
Overview of Xofluza Clinical Development 
The efficacy and safety of Xofluza have been established in randomized 
placebo-controlled Phase 2 and 3 studies.  In clinical studies in adult and 
adolescent patients who were otherwise healthy (Phase 3 study T0831 and 
Phase 2 study T0821) or at high risk of developing influenza complications 
(Phase 3 study T0832), Xofluza was shown to be efficacious and well tolerated.  
Clinical efficacy was demonstrated against both influenza A virus subtypes 
(A/H1N1 and A/H3N2) and against type B virus.  The potent antiviral effect of 
Xofluza was also seen in terms of the median time to cessation of viral shedding 
by virus titer, with at least a 2-day reduction over placebo and, in the Phase 3 
studies in which oseltamivir was included as an active control group (T0832 and 
T0831), a 2-day reduction over oseltamivir.  Xofluza is unique in achieving this 
degree of anti-viral effect with a single oral dose administration. 
1.2.1.1 
Efficacy 
In the Phase 3 double-blind randomized study in otherwise healthy patients 
(Study 1601T0831/CAPSTONE-1; Hayden et al. 2018), efficacy and safety of a 
single dose of Xofluza in adult and adolescent patients with influenza were 
investigated.  Doses studied were 40 mg for patients who weigh < 80 kg and 80 
mg for patients who weigh ≥ 80 kg.  The median time to alleviation of symptoms 
was 53.7 hours in the Xofluza group compared with 80.2 hours in the placebo 
group.  The difference in the median time was −26.5 hours between the Xofluza 
group and the placebo group.  The Xofluza group showed a significantly greater 
reduction in the time to alleviation of symptoms compared with the placebo group 
(two-sided P value < 0.0001).  In the adult stratum of patients, the median time to 
alleviation of symptoms was 53.5 hours in the Xofluza group compared with 53.8 
hours in the oseltamivir group, and no significant difference was found.  
A phase 3 open-label study in otherwise healthy pediatric patients (Study 
1618T0822) investigated the efficacy of a single dose of Xofluza in patients aged 
6 months to 11 years.  Dosages studied were 5, 10, 20 and 40 mg for patients 
weighing 5 to < 10 kg, 10 to < 20 kg, 20 to < 40 kg and ≥ 40 kg, respectively.  The 

 
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median time to alleviation of influenza illness, i.e., alleviation of cough, nasal 
discharge/nasal congestion and fever, (primary endpoint) was 44.6 hours.  The 
median time to resolution of fever (a secondary endpoint) was 21.4 hours.  
A phase 3 double-blind randomized study in people aged 12 years or older who 
were at a high risk of complications from the flu (N=2184; Study 
1601T0832/CAPSTONE-2) compared the efficacy of a single oral dose of 
Xofluza (40 mg or 80 mg according to body weight) with placebo or 75 mg of 
oseltamivir twice a day for 5 days.  The time to improvement of influenza 
symptoms (TTIIS) was significantly shorter with Xofluza than placebo (median 
73.2 vs 102.3 hours, p< 0.0001) and numerically shorter than oseltamivir (81.0 
hours, p=0.8347).  TTIIS in patients with A/H3N2 virus was shorter with Xofluza 
than with placebo (median: 75.4 vs 100.4 hours; p=0.0141).  TTIIS in patients 
with influenza B was also significantly shorter with Xofluza (74.6 hours) than 
either placebo (100.6 hours; p=0.0138) or oseltamivir (101.6 hours; p=0.0251). 
The safety and effectiveness of Xofluza in otherwise healthy pediatric subjects 5 
to less than 12 years of age is supported by one randomized, double-blind, 
controlled trial, Trial CP40563 with a primary endpoint of safety.  In this trial, 118 
otherwise healthy pediatric subjects were randomized and treated in a 2:1 ratio 
and received either Xofluza (N=79) or oseltamivir (N=39).  Efficacy was 
extrapolated from adults and adolescents based on comparable pharmacokinetic 
(PK) exposures in adults, adolescents and pediatric subjects 5 to less than 
12 years of age.  The median time to alleviation of signs and symptoms in 
influenza-infected subjects was comparable in the Xofluza and oseltamivir arms.  
Adverse events (AEs) reported with Xofluza in pediatric subjects were similar to 
those observed in adults and adolescents except for vomiting and diarrhea, 
which were both more commonly reported in pediatric subjects. 
The safety and effectiveness of Xofluza for post-exposure prophylaxis in pediatric 
and adolescent subjects 5 to less than 18 years of age is supported by one 
randomized, double-blind, controlled trial conducted in Japan Trial T0834.  
Subjects in this trial were randomized in a 1:1 ratio to receive Xofluza or placebo.  
A total of 69 subjects from 5 to < 18 years of age in Trial T0834 received Xofluza.  
The incidence of reverse transcriptase-polymerase chain reaction (RT-PCR)-
confirmed symptomatic influenza in pediatric subjects 5 to < 18 years of age was 
similar to that observed in adult subjects.  Efficacy was extrapolated from adults 
based on comparable PK exposures in adults, adolescents and pediatric subjects 
5 to < 18 years of age.  Adverse events reported in pediatric and adolescent 
subjects were similar to those reported in adults in the same trial.  
1.2.1.2 
Safety 
In the phase 3 double-blind randomized study in otherwise healthy patients 
(Study 1601T0831/CAPSTONE-1), patients in the 20 to 64 years of age stratum 

 
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received a single dose of 40 or 80 mg (depending on the patient’s weight) of 
Xofluza, repeated dose of 75 mg oseltamivir twice daily for 5 days, or placebo, 
and patients in the 12 to 19 years of age stratum received a single dose of 40 or 
80 mg (depending on the patient’s weight) of Xofluza or placebo.  A total of 1,432 
patients received the study drug: 610 in the Xofluza group, 309 in the placebo 
group, and 513 in the oseltamivir group.  No deaths were reported in all the 3 
groups.  Two serious adverse events (SAEs) (1 event each of meningitis viral 
and incarcerated inguinal hernia) were reported in 2 of 610 patients (0.3%) in the 
Xofluza group.  The events resolved and were considered not related to the 
study drug.  A total of 9 AEs leading to withdrawal of study drug were reported: 3 
events in 2 of 610 patients (0.3%) in the Xofluza group, 4 events in 1 of 
309 patients (0.3%) in the placebo group, and 2 events in 2 of 513 patients 
(0.4%) in the oseltamivir group.  All of the AEs leading to withdrawal of study 
drug in the Xofluza group were considered not related to the study drug.  
In the phase 3 double-blind randomized study in people 12 years or older who 
were at a high risk of complications from the flu (N=2184; Study 
1602T0832/CAPSTONE-2), the incidence of any adverse event (25.1–29.7%) or 
any serious adverse events (0.7–1.2%) did not differ significantly between the 
groups treated with a single oral dose of Xofluza (40 mg or 80 mg according to 
body weight), placebo, or 75 mg of oseltamivir twice a day for 5 days. 
In the phase 3 open-label study in otherwise healthy pediatric patients (Study 
1618T0822), 2, 31, 66, and 8 patients (a total of 107) received a single 5, 10, 20, 
and 40 mg dose of Xofluza, respectively.  No deaths, serious AEs or 
discontinuations due to AEs were reported in the study.  
In the phase 3 open-label study in otherwise healthy pediatric patients (weighing 
≤ 20 kg and aged ≤ 12 years) with influenza (Study 1705T0833), a total of 33 
patients received a single dose of Xofluza.  The dosage was 10 mg of Xofluza in 
patients weighing ≥ 10 kg and 1 mg/kg of Xofluza in patients weighing < 10 kg.  
No deaths, serious AEs or discontinuations due to AEs were reported in the 
study.  Most common AEs reported were vomiting, diarrhea and pharyngitis.  
Treatment-related AEs (assessed by the investigator) were reported in 1 of 33 
patients (3.0%, 1 event of platelet count increased).  All AEs were classified as 
Grade 1 or 2.  All AEs resolved or were resolving. 
In a placebo-controlled clinical trial (post-exposure prophylaxis of influenza), Trial 
T0834, conducted in adults, and pediatric subjects  5 years of age, a total of 
360 subjects received Xofluza, of which 291 (81%) were adults  18 years; 12 
(3%) subjects were adolescents  12 to 17 years and 57 (16%) were pediatric 
subjects 5 to < 12 years of age.  The safety profile was similar in pediatric 
patients ages 5 to < 12 years old as that reported in adults and adolescents 12 
years of age and older. 

 
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Refer to the Xofluza Investigator’s Brochure for details on nonclinical and clinical 
studies. 
1.2.2 
Post-Marketing Safety Data 
Hypersensitivity reactions have been observed in the post-marketing setting which 
include reports of anaphylaxis/anaphylactic reactions and less severe forms of 
hypersensitivity reactions including angioedema, and urticaria. 
Refer to Section 6 of the Xofluza Investigator’s Brochure for current details 
relating to post-marketing safety information. 
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
Seasonal influenza is a major burden to global health.  There are an estimated 
3-5 million cases of severe disease worldwide and approximately 290–650 
thousand people die from influenza annually (WHO 2017a, WHO 2018, Baxter 
2016). Influenza also places significant demands on healthcare services each 
season, and impacts society through lost workforce productivity (WHO 2018).  
Annual vaccination programs are the cornerstone of attempts to prevent 
influenza infections, but the effectiveness of these programs is variable due to 
both suboptimal uptake of vaccinations and mismatches between the vaccine 
and circulating influenza strains (CDC 2017).  Consequently, the need for 
antiviral agents remains high. 
Influenza A and B viruses are highly contagious (Vanderlinden and Naesens 
2014).  Most individuals with influenza infection are advised to stay at home until 
they have been afebrile for at least 24 hours, which puts other household 
members at risk of infection (CDC 2018a).  Once one household member is 
infected with influenza, the risk of transmission to a household contact can be up 
to 38%, with a delay between onset in the index patient and infection of the 
household contact of around 3 days (Tsang et al. 2016).   
Successful methods to mitigate the spread of respiratory viruses, including 
COVID-19 and influenza, through testing include identifying and deploying testing 
capacity to communities where viral transmission is highest and communities 
where insufficient testing is being conducted. We have developed a data-
analytics driven algorithm based on laboratory data and the social vulnerability 
index (SVI) that identifies testing deserts and hot spots to identify vulnerable 
communities with active spread of respiratory infection (hot spots) and locations 
without enough testing penetration to effectively determine viral activity (testing 
deserts). 
 
It has been well described that socially vulnerable communities lack access to 
testing because testing locations may not be able to be reached by public 
transportation, long wait times because of centralized testing locations and lack 
of testing hours outside of the traditional work-day (5-10). Mobilization of a 

 
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COVID-19 and influenza testing unit to communities where individuals already 
gather for other social events provides increased access to testing addresses 
many of these challenges that are experienced in underserved and socially 
vulnerable communities. However, identification and testing of individuals who 
may reside in hot spots for respiratory viruses is not sufficient to completely 
mitigate the spread of disease or reduce the effects of infection. Rapid access to 
effective therapeutics within the narrow antiviral therapeutic window (48 hours 
from symptom onset) is necessary to reduce the spread of infection and reduce 
disease severity.  
 
In this study will use our Respiratory Infection Hot Spot Algorithm that identifies 
and supports deployment of mobile testing units to community centers, parks and 
senior centers in socially and economically disadvantaged communities to deploy 
a mobile test-to-treat model for Influenza A&B, along with testing for SARS-COV-
2 in socially vulnerable communities.  Use of a point care test (POCT) for 
Influenza A&B and SARS-CoV-2 and a mobile pharmacist model enables the 
test-to-treat model that will target vulnerable communities that may lack access 
to testing and/or providers for treatment for influenza.  
 
Xofluza is a first-in-class influenza antiviral that blocks RNA replication by 
inhibiting cap-dependent endonuclease activity (Omoto et al. 2018).  Xofluza is 
administered by a convenient and unique one-dose, one-time regimen.  In the 
Phase III CAPSTONE-1 double-blind randomized study in otherwise healthy 
patients (Hayden et al. 2018), a single treatment of Xofluza (40 mg for patients < 
80 kg and 80 mg for patients ≥ 80 kg) significantly reduced the time to alleviation 
of symptoms compared with placebo and also effectively reduce viral load, as 
shown by a significant reduction compared with placebo in: 
• 
The proportion of patients with positive influenza titer between Days 2 and 5 
• 
The proportion with positive influenza virus RNA determined by PCR on Day 
5 
• 
The median time to cessation of viral shedding 
 
Study ML44485 was therefore designed to use our Respiratory Infection Hot 
Spot Algorithm that identifies and supports deployment of mobile testing units to 
community centers, parks and senior centers in socially and economically 
disadvantaged communities to deploy a mobile test-to-treat model for Influenza 
A&B, along with testing for SARS-COV-2 in socially vulnerable communities.  
This study will target communities with high rates of respiratory infection or 
insufficient testing for a screen and treat program for influenza. Matched 
communities based on the census track-based SVI will be compared to assess 
impact of the screen and treat program on influenza rates at a population level.  
 
This study seeks to demonstrate that the laboratory can mitigate respiratory virus 
transmission in underserved populations through (1) use of analytics to identify 

 
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communities that are at risk for uncontrolled viral spread and (2) patient 
perception of a mobile screen and treat model for influenza. 
 
In summary, there is a strong rationale and a positive benefit risk assessment for 
studying Xofluza in a screen and treat model for socially vulnerable communities 
and results from the Hayden et al study suggests that Xofluza has an acceptable 
clinical safety profile and could benefit patients who test positive for influenza.  
The benefit-risk ratio for Xofluza is expected to be acceptable in this setting. 
2. 
OBJECTIVES AND ENDPOINTS 
2.1 
PRIMARY OBJECTIVE(S) 
This study seeks to demonstrate that the laboratory can mitigate respiratory virus 
transmission in underserved populations by using laboratory data to identify 
communities at risk for increase vial activity (hot spots) and intervening with a 
test-to-treat model provides increased access to influenza diagnostics and 
treatment in vulnerable and underserved communities. 
 
1. The hot-spot frequency and hot spot score trend will be measured for 
each census tract to determine if the screen and treat intervention has an 
impact on reducing hot spot identification or hot spot score. 
 
a. Following each mobile intervention, we will evaluate the hot spot 
score for the census tracts receiving a mobile screen and treat 
intervention and SVI-matched census tract not receiving an 
intervention for 14-days following the screen and treat 
intervention.  
 
b. Patients will receive a follow-up phone call 14-days following their 
initial screening visit to assess patient and household symptoms 
and the socioeconomic impact of their test result and treatment 
access. 
 
2.2 
SECONDARY OBJECTIVE(S)  
1. Secondarily, this study seeks to understand patient perception of a mobile screen 
and treat model for influenza, and patients will be provided a survey to better 
understand their experiences in access to testing for COVID and influenza and 
access to therapeutics for influenza at a mobile screen and treat unit.  
2. All patients will be provided a survey to better understand their experiences in 
access to testing and therapeutics for COVID and influenza at a mobile screen 
and treat unit. 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
We have developed an analytic algorithm that uses measures from the CDC 
COVID-19 Hot Spot Criteria and Brown University School of Public Health to 
determine COVID-19 and Influenza Hot Spots and Testing Deserts, respectively. 

 
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The Hot Spot designation was based on the CDC county-specific Hot Spot 
criteria that has been used to deploy resources for interventions (i.e., laboratory 
testing, community mitigation, health communications and health care) specific 
needs for the communities of interest. The CDC hot spot criteria is based on 
COVID-19 rates at the county level. We have adapted these criteria in several 
ways: (1) we have narrowed the scope of the population of interest to the census 
tract (2) we have included influenza transmission data (3) we have based our 
calculations on the proportion of the respiratory virus testing performed by 
TriCore Laboratories relative to the total testing in the State of New Mexico 
(approximately 40%) and (4) we have incorporated social determinants of health 
data to aid in identifying the most vulnerable community. The adaptations to the 
criteria allows interventions to focus on a concentrated community and deliver 
the interventions in places that the community is already engaging, such as 
community centers, senior centers and parks. The identification of communities 
with insufficient testing to assess the respiratory virus transmission rate, or 
testing deserts, in our algorithm is based on the Brown University School of 
Public Health testing targets which has identified a goal of 532/100,000 or 
1582/100,0000 COVID-19 or influenza tests for as the minimum target or 
suppression target, respectively. The algorithm also incorporates the social 
vulnerability index in the testing desert tool. 
 
Using a longitudinal patient database with an active system to prospectively geocode 
addresses entered into our system, we are able to determine, at the census tract level, 
neighborhoods that are at high risk for viral transmission because they are a hot spot or 
testing desert. We are then able to incorporate the social vulnerability index as an 
additional weighted measure to the hot spot or desert score in order to calculate an 
identified hot spot or desert risk for a census tract. Through collaboration with local 
community centers, we are able to deploy a mobile testing unit to a community center, 
park or senior center that is in close proximity to the identified neighborhood for rapid 
onsite testing for Influenza A&B and SARS-CoV2 using the cobas Liat system.  
 
New Mexico has adopted “New Mexico Board of Pharmacy Protocol for 
Pharmacists Prescribing of Dangerous Drugs in Conjunction with Point of Care 
Testing” (NMBOP POCT Protocol, Appendix 5) that allows pharmacists the 
prescriptive authority to prescribe Influenza antiviral therapy in conjunction with a 
positive point of care test (POCT).  TriCore employs two (2) on-site clinical 
pharmacists who will follow all of the pharmacist mandates included in the 
regulation to prescribe and distribute Xofluza according to the approved protocol 
in the test-to-treat model presented in this study. The NMBOP PCOT Protocol 
documents the eligibility and requirements of the certified prescribing 
pharmacists (pharmacist) following this protocol. 
 
The pharmacist will perform a screening physical assessment, health 
assessment and medical history for the patient. If the subject meets the inclusion 
criteria, they will have a point of care test performed. If the subject meets the 
exclusion criteria, they will be excluded from the study. Testing will be performed 
using the cobas® SARS-CoV-2 & Influenza A/B assay on the cobas® Liat® 
system from a self-collected nasal swab. Subjects who test positive for influenza 
A or B will be prescribed Xofluza with no additional refills. The pharmacist will 
follow-up with the patient 24-48 hours following administration for evaluation of 

 
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signs/symptoms and will refer the patient to their primary care provider, provider, 
or clinic for recommended laboratory testing and follow-up if appropriate.  
All subjects eligible for Xofluza will receive patient education and counseling on 
drug information, adherence, side effects, and other patient educational 
materials, as appropriate. All subjects eligible for influenza antiviral therapy, but 
having contraindications to the therapy, or do not wish to use the therapy will be 
referred to their primary care provider, provider, or clinic for further evaluation.  
 
Subjects testing positive for SARS-CoV-2 will be preferred by the pharmacist to 
the subjects’ primary care provider, provider, or clinic for further medical 
assessment and follow-up, if appropriate. Subjects testing negative for all targets 
(SARS-CoV-2 and Influenza A&B) with a high index of suspicion for influenza, 
will be referred by the pharmacist to the subjects’ primary care provider, provider, 
or clinic for further medical assessment and follow-up, if appropriate. All subjects 
will receive a follow-up call 14-days following the study visit to assess their 
symptom resolution and the impact of their illness on their well-being (Appendix 
1). 
 
The mobile testing unit will be deployed a minimum of 2 times per week following 
the determination of the influenza season by the New Mexico Department of 
Health. We expect to screen 50-100 patients per week for the duration of the 
influenza season (approximately 12 weeks) for a total of 600-1,2000 patients. 
With an anticipated 10% positivity rate for influenza, we expect at least 5-10 
patients per week to be eligible for treatment for a total of 60-120 subjects eligible 
over the course of the study. All subjects will be provided a survey to evaluated 
their ability to access respiratory virus testing and their acceptance of and trust in 
using a mobile unit for access to treatment and therapeutics. Patients positive for 
SARS-CoV-2 will be counseled on options for treatment and follow up for 
COVID-19 infection. All subjects enrolled in the study will receive a follow-up 
phone call 14-days following the initial screening visit. 
 
Description of Xofluza treatment schedule: 
Xofluza will be administered as a single oral dose as soon as possible and within 48-
hours of influenza symptom onset. Dosing will be delivered based on the package 
insert.: 
 
Patient Body Weight 
(kg) 
Recommended Single Oral Dose in 
Patients 5 years of Age and Older 
(Tablets) 
20 kg to less than 80 kg 
One 40 mg tablet (blister card contains 
one 40 mg tablet) 
At least 80 kg 
One 80 mg tablet (blister card contains 
one 80 mg tablet) 
 
 

 
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3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of this study is defined as the date when 12 weeks of mobile testing and 
treating deployment has concluded or the end of “influenza season” as defined 
by the New Mexico Department of Health, whichever is last. As this is a single 
dose observational study, there are no follow-up visits scheduled as part of the 
study. All subjects receiving the therapeutic will receive a follow-up phone call 
24-48 hours following administration of Xofluza. All enrolled subjects will receive 
a follow-up phone call 14-days following the initial screening visit to assess 
symptom resolution and socioeconomic impact of their test result. The end of the 
study is expected to occur 12 months after the last patient is enrolled to allow for 
complete data analysis and evaluation.  In addition, the Investigator may decide 
to terminate the study at any time. 
The total length of the study, from screening of the first patient to the end of the 
study, is expected to be approximately 15 months. 
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Xofluza Dose 
The dose of Xofluza for this study was selected based on the Xofluza package 
insert. 
3.3.2 
Rationale for Patient Population 
As described above, treatment with Xofluza has been shown to reduce viral load 
and symptoms in patients with influenza A or B. Therefore, this study was 
designed to see if a test and treat model would have significant impact on 
community transmission in socially vulnerable communities.  
The inclusion criteria limit index patients to those with symptom onset within 48 
hours. This is because it is believed that Xofluza will be most effective at 
preventing viral transmission if given early in the course of infection. (This 48-
hour period is also consistent with the labels approved to date for Xofluza in 
countries including the US, Hong Kong, and Japan). 
The study eligibility criteria allow for the inclusion of index patients who are 
minors. This is also consistent with the labels approved to date for baloxavir 
marboxil, which is approved for use in individuals aged ≥5 years of age.  
4. 
MATERIALS AND METHODS 
4.1 
PATIENTS 
Approximately 600-1,200 patients will be enrolled in the study to be screened for 
influenza A&B and SARS-CoV2. We expect approximately 10% positivity rate for 
60-120 patients to be eligible for treatment. 

 
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There are approximately 140 census tracts in the Albuquerque Metropolitan Area 
that will be tracked during this study. 
Zip Code 
Race/Ethnicity (% population) 
  
Hispanic 
Non-
Hispanic/White 
Black 
Native 
Indian 
Asian 
Hawaiian 
Other 
2 or 
More 
87108 
51.5 
33.7 
3.7 
4.7 
1.4 
0.0 
0.2 
2.6 
87123 
44.3 
40.7 
3.5 
3.5 
4.6 
0 
0.1 
3.7 
87121 
82.5 
9.7 
2.3 
3.8 
0.4 
0.2 
0.1 
1 
87102 
61.4 
26.6 
3.1 
5.6 
10.7 
0 
0.31 
1.5 
87105 
79.6 
14.1 
0.6 
4.4 
0.3 
0.1 
0.1 
0.6 
87106 
38.1 
48.2 
3.3 
3.1 
3.9 
0 
0.5 
2.9 
 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Adult patients:  Signed informed consent by any patient capable of giving 
consent, or, where the patient is not capable of giving consent, by his or her 
legal/authorized representative. 
• 
Adolescent patients not able to legally consent:  written informed consent for 
study participation is obtained from patient’s parents or legal guardian, with 
assent as appropriate by the patient, depending on the patient’s level of 
understanding and capability to provide assent 
• 
Age  5 years at the time of signing the Informed Consent Form/Assent Form 
• 
Ability to comply with the study protocol, in the investigator’s judgment. 
• 
Presence of (a) fever (≥38.0 °C per tympanic or rectal thermometer; ≥37.5 °C 
per axillary, oral or forehead/temporal thermometer) or (b) any influenza 
symptoms (cough, sore throat, nasal congestion, headache, feverishness or 
chills, muscle or joint pain, fatigue). 
• 
The time interval between the onset of fever or influenza symptoms and the 
pre-dose examinations is 48 hours or less. 
• 
For women of childbearing potential:  Agreement to remain abstinent (refrain 
from heterosexual intercourse): 
Women must remain abstinent or use contraceptive methods with a 
failure rate of  1% per year during the treatment period and for 28 days 
after the last dose of study treatment.  Hormonal contraceptive methods 
must be supplemented by a barrier method. 

 
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A woman is considered to be of childbearing potential if she is 
postmenarcheal, has not reached a postmenopausal state 
( 12 continuous months of amenorrhea with no identified cause other 
than menopause), and has not undergone surgical sterilization (removal 
of ovaries and/or uterus). 
Examples of contraceptive methods with a failure rate of  1% per year 
include bilateral tubal ligation, male sterilization, hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine 
devices, and copper intrauterine devices. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
or postovulation methods) and withdrawal are not acceptable methods 
of contraception. 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Patients who have received more than 48 hours of antiviral treatment for the 
current influenza infection prior to screening 
• 
Patients who have received Xofluza for the current influenza infection 
• 
Known contraindication to neuraminidase inhibitors 
• 
Patients weighing  20 kg 
• 
Patients unable to swallow tablets 
• 
Patients with known severe renal impairment (estimated glomerular filtration 
rate  30 mL/min/1.73 m2) or receiving continuous renal replacement therapy, 
hemodialysis, peritoneal dialysis 
• 
Patients with any of the following laboratory abnormalities detected within 
24 hours prior to or during screening (according to local laboratory reference 
ranges:  
– 
ALT or AST level  5 times the upper limit of normal (ULN)  
OR 
– 
ALT or AST  3 times the ULN and total bilirubin level  2 times the ULN  
• 
Pregnant or breastfeeding, or positive pregnancy test in a predose examination, or 
intending to become pregnant during the study or within 28 days after the last dose 
of study treatment 
• 
Exposure to an investigational drug within 5 half-lives or 30 days (whichever is 
longer) of randomization  
• 
Any serious medical condition or abnormality in clinical laboratory tests that, in the 
investigator’s judgment, precludes the patient’s safe participation in and completion 
of the study 
• 
Known hypersensitivity to Xofluza (baloxavir marboxil) or the drug product excipients 

 
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4.2 
METHOD OF TREATMENT ASSIGNMENT  
This is an observational study; all patients will be assigned to the treatment group. 
4.3 
STUDY TREATMENT 
The investigational medicinal product (IMP) for this study is Xofluza. 
4.3.1 
Study Treatment Formulation, Packaging, and Handling 
4.3.1.1 
Xofluza  
Xofluza will be supplied by the Sponsor as tablets.  
For information on the formulation and handling of Xofluza, see the 
Xofluza Investigator's Brochure. 
4.3.2 
Study Treatment Dosage, Administration, and Compliance 
The treatment regimens are summarized in Section 3.1. 
The study treatment will be administered by a certified prescribing provider at 
mobile testing sites. 
Any overdose or incorrect administration of Xofluza should be noted in the 
patient’s medical records and reported according to Section 5.5 (Special 
Situations Reports).  Adverse events associated with an overdose or incorrect 
administration of any of the study treatments should be recorded in the patient’s 
medical records. 
4.3.2.1 
Xofluza 
The treatment regimens are summarized in Section 3.1. 
Xofluza will be administered orally according to body weight (40 mg for patients 
weighing 20 to  80 kg; 80 mg for patients weighing  80 kg) either in tablet form 
(20 mg or 40 mg tablets). 
4.4 
CONCOMITANT THERAPY 
Concomitant therapy consists of any medication (e.g., prescription drugs, over-
the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated treatment from 
7 days prior to the study visit.  All such medications should be reported to the 
investigator and recorded in the patient’s medical records.  
4.4.1 
Permitted Therapy 
All therapies required for the management of the patient’s acute illness are 
permitted except for those listed below in Section 4.4.3 (Prohibited Therapy). 

 
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4.4.2 
Cautionary Therapy 
Polyvalent cation−containing products may decrease plasma concentrations of 
Xofluza.  Thus, dairy products, calcium-fortified beverages, polyvalent 
cation−containing oral laxatives or oral antacids, and oral supplements containing 
iron, zinc, selenium, calcium, or magnesium should not be taken with Xofluza, 
where possible.  Live attenuated influenza vaccines may be affected by 
antivirals. 
4.4.3 
Prohibited Therapy 
Use of the following concomitant therapies is prohibited as described below: 
• 
Investigational therapy (other than the protocol-mandated study treatment) is 
prohibited within 5 half-lives or 30 days (whichever is longer) prior to 
initiation of study treatment and during the study 
• 
Influenza antiviral drugs (peramivir, laninamivir, oseltamivir, zanamivir, 
rimantadine, umifenovir or amantadine) 
• 
Immunosuppressants (including biologics) 
• 
Investigational therapy (other than protocol-mandated study treatment)  
• 
Concomitant use of herbal therapies is prohibited as their pharmacokinetics, 
safety profiles, and potential drug-drug interactions are generally unknown 
 
4.5 
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in 
Appendix 1.  All activities must be performed and documented for each patient.  
Patients will be closely monitored for safety and tolerability throughout the study.  
Patients should be assessed for toxicity prior to each dose; dosing will occur only 
if the clinical assessment and local laboratory test values are acceptable. 
At applicable sites, certain study assessments may be performed by certified 
prescribing pharmacist (CPP) professional at the mobile testing location. The 
Investigator will ensure that all CPPs are licensed, qualified, and in good 
standing, as per applicable regulations, and that appropriate background checks 
have been performed.  
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  
Informed Consent Forms for enrolled patients and for patients who are not 
subsequently enrolled will be maintained at the study site. 
All screening evaluations must be completed and reviewed to confirm that 
patients meet all eligibility criteria before enrollment.  The investigator will 

 
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maintain a screening log to record details of all patients screened and to confirm 
eligibility or record reasons for screening failure, as applicable. 
4.5.2 
Medical History, Concomitant Medication, and Demographic 
Data 
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies, current cancer stage, and procedures), 
menstrual history, fertility history, and puberty history, will be recorded.  In 
addition, all medications (e.g., prescription drugs, over-the-counter drugs, 
vaccines, herbal or homeopathic remedies, nutritional supplements) used by the 
patient in addition to protocol-mandated treatment within 7 days prior to initiation 
of study treatment will be recorded.  At the time of each follow-up physical 
examination, an interval medical history should be obtained and any changes in 
medications and allergies should be recorded. 
Demographic data will include age, sex, and self-reported race/ethnicity. 
4.5.3 
Physical Examinations 
A limited, symptom-directed physical examinations will be performed to assess 
symptoms of influenza-like-illness (cough, sore throat, nasal congestion, 
headache, feverishness or chills, muscle or joint pain, fatigue). 
4.5.4 
Vital Signs 
Vital signs will include measurements of weight, respiratory rate, pulse rate, and 
systolic and diastolic blood pressure, oxygen saturation rate and temperature. 
Vital signs should be measured within 60 minutes prior to each Xofluza treatment. 
4.5.5 
Rapid Influenza Diagnostic Test 
For patients to be eligible for this study, RT-PCR is required to be performed to 
inform a diagnosis of influenza.   
4.5.6 
Laboratory, Biomarker, and Other Biological Samples 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Unless the patient gives specific consent for his or her leftover samples to be 
stored for optional exploratory research (see Section 4.5.), biological samples will 
be destroyed when the final Clinical Study Report has been completed, with the 
following exception: 
• 
Self-collected nasal swab samples collected for influenza testing may be 
required to be accessible to the New Mexico Department of Health 
(NMDOH) for serotyping or other analysis performed for routine influenza 

 
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surveillance. If not required for the NMDOH will be destroyed no later than 1 
year after the closure of the study or earlier depending on local regulations. 
 
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  
However, if samples have been tested prior to withdrawal, results from those 
tests will remain as part of the overall research data. 
Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4. 
4.6 
TREATMENT, PATIENT, AND STUDY DISCONTINUATION 
Patients must permanently discontinue study treatment (Xofluza) if they 
experience any of the following: 
• 
Intolerable toxicity related to study treatment, including development of an 
immune-mediated adverse event determined by the investigator to be 
unacceptable given the individual patient’s potential response to therapy 
and severity of the event 
• 
Any medical condition that may jeopardize the patient’s safety if he or she 
continues study treatment 
• 
Investigator determines it is in the best interest of the patient 
• 
Pregnancy 
• 
Anaphylaxis or other severe hypersensitivity reaction 
• 
Loss of clinical benefit as determined by the investigator after an integrated 
assessment of clinical status (e.g., symptomatic deterioration such as pain 
secondary to disease) (see Section 3.1.1 for details) 
The primary reason for study treatment discontinuation should be documented 
in the patient’s medical records.  Patients who discontinue study treatment 
prematurely will not be replaced. 
4.6.1 
Patient Discontinuation from Study 
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: 
• 
Withdrawal of consent 
• 
Study termination or site closure 
• 
Patient non-compliance, defined as failure to comply with protocol 
requirements as determined by the Investigator 
 

 
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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 in the patient’s medical records.  If a patient requests to be 
withdrawn from the study, this request must be documented in the source 
documents and signed by the investigator.  Patients who withdraw from the study 
will be replaced. 
If a patient withdraws from the study, the study staff may use a public information 
source (e.g., county records) to obtain information about survival status. 
4.6.2 
Study Discontinuation 
The Investigator 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 
 
5. 
ASSESSMENT OF SAFETY 
5.1 
SAFETY PLAN 
The safety and efficacy of Xofluza has been investigated in otherwise healthy 
adult and adolescent populations as well as adult and adolescent patients at high 
risk of influenza-related complications.  Xofluza has been approved in several 
countries, including Japan and the United States.  The safety plan for patients in 
this study is based on clinical experience with Xofluza in completed and ongoing 
studies, as well as analysis of cumulative adverse events reporting from post-
marketing surveillance.  Please refer to the Xofluza Investigator's Brochure for a 
complete summary of safety information. 
Several measures will be taken to ensure the safety of patients participating in 
this study.  Eligibility criteria have been designed to exclude patients at higher 
risk for toxicities.  Patients will undergo safety monitoring during the study, 
including assessment of the nature, frequency, and severity of adverse events.  
In addition, guidelines for managing adverse events, including criteria for 
treatment interruption or discontinuation, are provided below. 
5.1.1 
Potential Risks Associated with Xofluza 
Xofluza is generally well tolerated, and no important identified or potential safety 
concerns associated with Xofluza have been identified from clinical studies 
conducted, to date.  

 
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5.1.1.1 
Hypersensitivity 
Hypersensitivity reactions have been observed in the post-marketing setting 
which include reports of anaphylaxis/anaphylactic reactions and less severe 
forms of hypersensitivity reactions including angioedema, and urticaria. 
Exclusion criteria for patients with known hypersensitivity to Xofluza or the drug 
product excipients are included in this protocol, as re-exposure must be avoided. 
5.1.1.2 
Increased Incidence of Treatment-Emergent Resistance in 
Patients Less Than 5 Years of Age 
Xofluza is not indicated in patients less than 5 years of age due to increased 
incidence of treatment-emergent resistance in this age group.  In clinical trials, the 
incidence of virus with treatment-emergent substitutions associated with reduced 
susceptibility to baloxavir (resistance) was higher in pediatric subjects younger 
than 5 years of age (43%, 36/83) than in pediatric subjects ≥ 5 years to < 12 
years of age (16%,19/117) or subjects ≥ 12 years of age (7%, 60/842).  The 
potential for transmission of resistant strains in the community has not been 
determined. 
Refer to the current USPI for XOFLUZA (baloxavir marboxil) for details.  
5.1.1.3 
Risk of Bacterial Infections 
There is no evidence of efficacy of Xofluza in any illness caused by pathogens 
other than influenza viruses.  Serious bacterial infections may begin with 
influenza-like symptoms or may coexist with, or occur as, a complication of 
influenza.  Xofluza has not been shown to prevent such complications.  
Prescribers should be alert to potential secondary bacterial infections and treat 
them as appropriate. 
Refer to the current USPI for XOFLUZA (baloxavir marboxil) for details. 
5.1.2 
Management of Patients Who Experience Adverse Events 
5.1.2.1 
Dose Modifications 
No dose modification will be permitted during the study. 
5.1.2.2 
Treatment Interruption 
Treatment interruption is not allowed in this study.  Study treatment should be 
discontinued in patients who meet the criteria listed in Section 4.1.2 
5.2 
SAFETY REPORTING OF ADVERSE EVENTS 
5.2.1 
Specification of Safety Variables 
Safety assessments will consist of monitoring and reporting adverse events 
(AEs) and serious adverse events (SAEs) per protocol.  This includes all events 
of death and any study-specific issue of concern.  

 
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5.2.2 
Adverse Events 
An AE is any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of an investigational medicinal product (IMP) or other 
protocol-imposed intervention, regardless of attribution. 
This includes the following: 
• 
AEs not previously observed in the subject that emerge during the protocol-
specified AE reporting period, including signs or symptoms associated with 
influenza that were not present prior to the AE reporting period. 
• 
Complications that occur as a result of protocol-mandated interventions 
(e.g., invasive procedures such as cardiac catheterizations). 
• 
If applicable, AEs that occur prior to assignment of study treatment 
associated with medication washout, no treatment run-in, or other protocol-
mandated intervention. 
• 
Preexisting medical conditions (other than the condition being studied) judged 
by the investigator to have worsened in severity or frequency or changed in 
character during the protocol-specified AE reporting period.  
 
5.2.3 
Serious Adverse Events 
An AE should be classified as an SAE if the following criteria are met: 
• 
It results in death (i.e., the AE actually causes or leads to death). 
• 
It is life threatening (i.e., the AE, in the view of the investigator, places the 
subject at immediate risk of death.  It does not include an AE that, had it 
occurred in a more severe form, might have caused death). 
• 
It requires or prolongs inpatient hospitalization. 
• 
It results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the subject’s ability to conduct normal life functions). 
• 
It results in a congenital anomaly/birth defect in a neonate/infant born to a 
mother exposed to the IMP. 
• 
It is considered a significant medical event by the investigator based on 
medical judgment (e.g., may jeopardize the subject or may require 
medical/surgical intervention to prevent one of the outcomes listed above). 
 
5.3 
METHODS AND TIMING FOR ASSESSING AND RECORDING 
SAFETY VARIABLES 
 
The investigator is responsible for ensuring that all AEs and SAEs that are observed or 
reported during the study are collected and reported to the FDA, appropriate IRB(s), and 
Genentech, Inc. in accordance with CFR 312.32 (IND Safety Reports). 
 

 
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5.3.1 
Adverse Event Reporting Period 
The study period during which AEs and SAEs as described in Section 5.4.2.10 where 
the patient has been exposed to Genentech product must be reported - reporting period 
begins after informed consent is obtained and initiation of study treatment and ends 14 
days following the last administration of study treatment or study 
discontinuation/termination, whichever is earlier.  After this period, investigators should 
only report SAEs that are attributed to prior study treatment (Modify statement 
depending up on AESI Section 5.4.2.7. 
5.3.2 
Assessment of Adverse Events 
All AEs and SAEs whether volunteered by the subject, discovered by study personnel 
during questioning, or detected through physical examination, laboratory test, or other 
means, will be reported appropriately.  Each reported AE or SAE will be described by its 
duration (i.e., start and end dates), regulatory seriousness criteria if applicable, 
suspected relationship to Xofluza (see following guidance), and actions taken. 
To ensure consistency of AE and SAE causality assessments, investigators should 
apply the following general guideline: 
Yes 
There is a plausible temporal relationship between the onset of the AE and 
administration of Xofluza, and the AE cannot be readily explained by the subject’s 
clinical state, intercurrent illness, or concomitant therapies; and/or the AE follows a 
known pattern of response to Xofluza or with similar treatments; and/or the AE abates or 
resolves upon discontinuation of Xofluza or dose reduction and, if applicable, reappears 
upon re-challenge. 
No 
Evidence exists that the AE has an etiology other than Xofluza (e.g., preexisting medical 
condition, underlying disease, intercurrent illness, or concomitant medication); and/or the 
AE has no plausible temporal relationship to Xofluza administration (e.g., cancer 
diagnosed 2 days after first dose of Xofluza). 
 
Expected adverse events are those adverse events that are listed or characterized in the 
Package Insert (P.I).  
 
Unexpected AEs are those not listed in the PI or current IB or not identified.  This 
includes AEs for which the specificity or severity is not consistent with the description in 
the PI or IB.  For example, under this definition, hepatic necrosis would be unexpected if 
the PI or IB only referred to elevated hepatic enzymes or hepatitis. 

 
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5.4 
PROCEDURES FOR ELICITING, RECORDING, AND 
REPORTING ADVERSE EVENTS 
5.4.1 
Eliciting Adverse Events 
A consistent methodology for eliciting AEs at all subject evaluation time points should be 
adopted.  Examples of non-directive questions include: 
• 
"How have you felt since your last clinic visit?" 
• 
"Have you had any new or changed health problems since you were last here?" 
 
5.4.2 
Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or 
SAEs.  Avoid colloquialisms and abbreviations. 
5.4.2.1 
Diagnosis vs. Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported 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, it is acceptable to report the information that is currently available.  If a 
diagnosis is subsequently established, it should be reported as follow-up information. 
5.4.2.2 
Deaths 
All deaths that occur during the protocol-specified AE reporting period (see Section 
Error! Reference source not found.), regardless of attribution, will be reported to the 
appropriate parties.  When recording a death, the event or condition that caused or 
contributed to the fatal outcome should be reported as the single medical concept.  If the 
cause of death is unknown and cannot be ascertained at the time of reporting, report 
“Unexplained Death.” 
5.4.2.3 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study.  Such 
conditions should be reported as medical and surgical history.  A preexisting medical 
condition should be re-assessed throughout the trial and reported as an AE or SAE only 
if the frequency, severity, or character of the condition worsens during the study.  When 
reporting such events, it is important to convey the concept that the preexisting condition 
has changed by including applicable descriptors (e.g., “more frequent headaches”). 
5.4.2.4 
Hospitalizations for Medical or Surgical Procedures 
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE.  If a subject is hospitalized to undergo a medical or surgical 
procedure as a result of an AE, the event responsible for the procedure, not the 
procedure itself, should be reported as the SAE.  For example, if a subject is 
hospitalized to undergo coronary bypass surgery, record the heart condition that 
necessitated the bypass as the SAE. 

 
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Hospitalizations for the following reasons do not require reporting: 
• 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for preexisting conditions 
• 
Hospitalization or prolonged hospitalization required to allow efficacy measurement 
for the study, or 
• 
Hospitalization or prolonged hospitalization for scheduled therapy of the target 
disease of the study 
 
5.4.2.5 
Assessment of Severity of Adverse Events 
The AE severity grading scale for the NCI CTCAE (v5.0) will be used for assessing AE 
severity.  Table below should be used for assessing severity for AES that are not 
specifically listed in the NCI CTCAE. 
Table 1 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE Grade Severity 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a. 
Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
b. 
Examples of self-care activities of daily living include bathing, dressing and undressing, feeding oneself, using 
the toilet, and taking medications, as performed by patients who are not bedridden 
c. 
If an event is assessed as a "significant medical event," it must be reported as a serious adverse event 
d. 
Grade 4 and 5 events must be reported as serious adverse events 
 
5.4.2.6 
Pregnancy 
If a female subject becomes pregnant while receiving Xofluza or within 14 days after the 
last dose of Xofluza, or if the female partner of a male study subject becomes pregnant 
while the study subject is receiving Xofluza or within 14 days, a report should be 
completed and expeditiously submitted to Genentech, Inc.  Pregnancies will be followed-
up until the outcome of the pregnancy is known, whenever possible, based upon due 
diligence taken to obtain the follow-up information.  Abortion, whether accidental, 

 
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therapeutic, or spontaneous, should always be classified as serious, and expeditiously 
reported as an SAE.  Similarly, any congenital anomaly/birth defect in a child born to a 
female subject exposed to Xofluza should be reported as an SAE. 
5.4.2.7 
Adverse Events of Special Interest 
Adverse events of special interest (AESIs) are a subset of events to monitor (EtMs) of 
scientific and medical concern specific to the product, for which ongoing monitoring and 
rapid communication by the Investigator to the Sponsor is required.  Such an event 
might require further investigation in order to characterize and understand it.  Depending 
on the nature of the event, rapid communication by the trial Sponsor to other parties 
(e.g., Regulatory Authorities) may also be warranted. 
AESIs 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: 
– 
Treatment-emergent ALT or AST  3  ULN in combination with total 
bilirubin  2  ULN. 
– 
Treatment-emergent ALT or AST  3  ULN in combination with clinical 
jaundice. 
 
• 
Data related to a suspected transmission of an infectious agent by the study 
drug (STIAMP), 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. 
 
There are no products specific AESIs for Xofluza. 
5.4.2.8 
Other Special Situations Reports 
The following other Special Situations Reports should be collected even in the absence 
of an Adverse Event and transmitted to Genentech: 
• 
Data related to the Product usage during breastfeeding 
• 
Data related to overdose, abuse, misuse or medication error (including potentially 
exposed or intercepted medication errors) 
• 
In addition, reasonable attempts should be made to obtain and submit the age or 
age group of the patient, in order to be able to identify potential safety signals 
specific to a particular population 
 

 
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5.4.2.9 
Product Complaints 
A product complaint is defined as any written or oral information received from a 
complainant that alleges deficiencies related to identity, quality, safety, strength, purity, 
reliability, durability, effectiveness, or performance of a product after it has been 
released and distributed to the commercial market or clinical trial. 
5.4.2.10 
Post-Study Adverse Events  
The investigator should expeditiously report any SAE occurring after a subject has 
completed or discontinued study participation if attributed to prior Xofluza exposure.  If 
the investigator should become aware of the development of cancer or a congenital 
anomaly in a subsequently conceived offspring of a female subject [add if applicable: 
(including pregnancy occurring in the partner of a male study subject)] who participated 
in the study, this should be reported as an SAE adequately to Genentech Patient Safety 
during the follow-up period. 
5.4.2.11 
Exchange of Single Case Reports with Genentech 
TriCore Laboratories will be responsible for collecting all protocol-defined Adverse 
Events (AEs)/Serious Adverse Events (SAEs), pregnancy reports (including pregnancy 
occurring in the partner of a male study subject), other Special Situation reports, AESIs 
and Product Complaints with an AE where the patient has been exposed to the Product.  
The Roche reporting Tool (AE reporting online “AERO”) should be sent to the 
Genentech contact specified below.  Transmission of these reports (initial and follow-up) 
will be either electronically via email or by fax and within the timelines specified below: 
Fax:  (650) 238-6067 
Email:  usds_aereporting-d@gene.com 
 
Batch ID/lot ID for biologics associated with AE/SSR/PC/AESI must be included when 
submitting the case reports to Genentech. 
All Product Complaints without an AE should call via: 
PC Hotline Number: (800) 334-0290 (M-F: 5 a.m. to 5 p.m. PST) 
Transmission of these reports (initial and follow-up) will be either electronically or by fax 
and within the timelines specified below: 
Type of Report  
Timelines 
Serious Adverse Events (related and not 
related to the Product) 
 
 
30 calendar days from awareness date 
Special Situation Reports (With or without 
AE and pregnancy) 
Product Complaints (With or without AE) 
AESI 
 

 
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Fax:  (650) 238-6067 / Email:  usds_aereporting-d@gene.com 
5.4.2.12 
Case Transmission Verification of Single Case Reports 
If Single Case Reports are exchanged via AERO, use the following: 
• 
Roche shall extract and review the AERO report listing on a quarterly basis.  If any 
Single Case Report(s) is not correctly transmitted, Roche will request TriCore to 
immediately re-send the missing Single Case Report(s) and follow-up until 
resolution. 
  
Monthly or quarterly line listings, Non-serious line listings, and cumulative/final CTV 
should be sent to: ctvistsa@gene.com  
5.5 
REPORTING REQUIREMENTS FOR ADVERSE EVENTS 
ORIGINATING FROM PATIENT-REPORTED OUTCOMES 
Although sites are not expected to review the PRO data, if physician/study personnel 
become aware of a potential adverse event during site review of the PRO questionnaire 
data, he/she will determine whether the criteria for an adverse event have been met and, 
if so, these must be reported using the Adverse Event and Special Situation Reporting 
Form or MedWatch form. 
5.6 
MEDWATCH 3500A REPORTING GUIDELINES 
In addition to completing appropriate patient demographics (Section A) and suspect 
medication information (Sections C & D), the report should include the following 
information within the Event Description (Section B.5) of the MedWatch 3500A form: 
• 
Protocol number and title description 
• 
Description of event, severity, treatment, and outcome if known 
• 
Supportive laboratory results and diagnostics (Section B.6) 
• 
Investigator’s assessment of the relationship of the adverse event to each 
investigational product and suspect medication 
 
5.6.1 
Follow-Up Information 
Additional information may be added to a previously submitted report by any of the 
following methods: 
• 
Adding to the original MedWatch 3500A report and submitting it as follow-up 
• 
Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500A form 
• 
Summarizing new information and faxing it with a cover letter including patient 
identifiers (i.e., D.O.B., initials, patient number), protocol description and number, if 
assigned, brief adverse event description, and notation that additional or follow-up 
information is being submitted (the patient identifiers are important so that the new 
information is added to the correct initial report) 
 

 
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MedWatch 3500A (Mandatory Reporting) form is available at 
https://www.fda.gov/media/69876/download 
5.7 
REPORTING TO REGULATORY AUTHORITIES, ETHICS 
COMMITTEES AND INVESTIGATORS 
Genentech, as the Marketing Authorization Holder, will be responsible for the reporting 
of individual case safety reports from the study to the regulatory authority in compliance 
with applicable regulations.  
TriCore as the Sponsor of the study will be responsible for the expedited reporting of 
safety reports originating from the study to the European Medicine Agency (EMA) 
through Eudravigilance Clinical Trial Module (EVCTM), where applicable.  
TriCore will be responsible for the expedited reporting of safety reports originating from 
the study to the Independent Ethics Committees/Institutional Review Boards (IEC/IRB) 
of the Concerned Member States, where applicable. 
TriCore as the Sponsor of the study will be responsible for the preparation of six-monthly 
Suspected Unexpected Serious Adverse Reaction (SUSAR) reports and their 
submission to Investigators, Regulatory Authorities, and the Institutional Review 
Board/Independent Ethics Committee (IRB/IEC), where applicable. 
TriCore will be responsible for the distribution of safety information to its own 
investigators, where relevant, in accordance with local regulations. 
And TriCore will be responsible for the distribution of safety information to site IRB: 
WCG IRB 
 
For questions related to safety reporting, please contact Genentech Patient 
Safety: 
Tel:  (888) 835-2555 
Fax:  (650) 225-4682 or (650) 225-4630 
 
5.8 
AGGREGATE REPORTS  
Development Safety Update Report 
The Parties agree that aggregate reporting obligations for the study (including 
Development Safety Update Report [DSURs] and/or Investigational New Drug [IND]) 
Annual Reports) in accordance with the applicable laws and regulations in the 
concerned countries will reside with TriCore, as the Sponsor of the study. 
Upon request, TriCore, agrees to share a copy of their own DSUR with Genentech as 
soon as reasonably possible after completion.  

 
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Genentech will forward to TriCore an executive summary of the Genentech DSUR upon 
request.  Furthermore, Genentech agrees that TriCore may cross-reference the 
executive summary of the Genentech DSUR, as applicable. 
Other Reports  
TriCore will forward a copy of the final study report to Genentech upon completion of the 
study.  
Note: Investigators should also report events to their IRB as required. 
5.9 
STUDY CLOSE-OUT 
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech.  This includes all IND annual reports and the Clinical Study Report (final 
study report).  Additionally, any literature articles that are a result of the study should be 
sent to Genentech.  Copies of such reports should be mailed to the assigned Clinical 
Operations contact for the study: 
xofluza-gsur-d@gene.com 
And to Genentech Patient Safety CTV oversight mailbox at:  ctvistsa@gene.com  
5.10 
QUERIES 
Queries related to the study will be answered by TriCore.  However, responses to all 
safety queries from Regulatory Authorities, Ethics Committees, and Institutional Review 
Board, or for publications will be discussed and coordinated between the Parties.  The 
Parties agree that Genentech shall have the final say and control over safety queries 
relating to the Product.  TriCore agrees that it shall not answer such queries from 
regulatory authorities and other sources relating to the Product independently but shall 
redirect such queries to Genentech. 
Both Parties will use all reasonable effort to ensure that deadlines for responses to 
urgent requests from Regulatory Authorities and/or IRB/IEC for information or review of 
data are met.  The Parties will clearly indicate on the request the reason for urgency and 
the date by which a response is required. 
5.11 
SIGNAL MANAGEMENT AND RISK MANAGEMENT 
Genentech is responsible for safety signal management (signal detection and/or 
evaluation) for their own Product.  However, it is agreed that TriCore, as Sponsor of the 
study, will be primarily responsible for assessment of the benefit-risk balance of the 
study. 

 
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If TriCore issues a safety communication relevant for Genentech (i.e., a safety issue that 
notably impacts the benefit-risk balance of the study and / or triggers any changes to the 
study) this will be sent to Genentech within five (5) business days of its internal approval. 
As needed, Genentech will reasonably assist TriCore with signal and risk management 
activities related to the Product within the study. 
Genentech will also provide TriCore with any new relevant information that may modify, 
or supplement known data regarding the Product (e.g., relevant Dear Investigator 
Letter). 
5.12 
COMPLIANCE WITH PHARMACOVIGILANCE AGREEMENT / 
AUDIT 
The Parties shall follow their own procedures for adherence to AE reporting timelines.  
Each Party shall monitor and, as applicable, request feedback from the other Party 
regarding AE report timeliness in accordance with its own procedures.  The Parties 
agree to provide written responses in a timely manner to inquiries from the other Party 
regarding AE reports received outside the agreed upon Agreement timelines.  If there is 
any detection of trends of increasing or persistent non-compliance to transmission 
timelines stipulated in this Agreement, both Parties agree to conduct an ad hoc or 
institute a regular joint meeting to address the issue. 
In case of concerns related to non-compliance of processes, other than exchange 
timelines, with this Agreement, the Parties will jointly discuss and collaborate on 
clarifying and resolving the issues causing non-compliance.  Every effort will be made by 
the non-compliant Party to solve the non-compliance issues and inform the other Party 
of the corrective and preventative actions taken. 
Upon justified request, given sufficient notice of no less than sixty (60) calendar days, an 
audit under the provisions of this Agreement can be requested by either Party.  The 
Parties will then discuss and agree in good faith upon the audit scope, agenda, and 
execution of the audit.  The requesting Party will bear the cost of the audit. 
 
6. 
STATISTICAL CONSIDERATIONS 
6.1 
DETERMINATION OF SAMPLE SIZE 
The algorithms that we use to determine the community of interest is based on meeting 
the hot-spot or testing desert criteria and a weighted value of the social vulnerability 
index (SVI) which defined from 0-1.0 and is determined at the census tract level. This 
includes factors such as socioeconomic status, household composition, race/ethnicity, 
housing and transportation access. Each census tract is composed of 2500-4000 
individuals and we anticipate enrolling 200-250 patients at each deployment resulting in 
approximately 5-10% of the census tract tested at each deployment. The 20 community 
centers that we will partner with have an average SVI pf 0.85 (0.55-1.0). There are 

 
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approximately 140 census tracts in the Albuquerque Metropolitan Area that will be 
tracked during this study. These high vulnerability locations are aggregated in six zip 
codes with the following demographic composition of race and ethnicity.  
 
While test positivity rate will change based on the current epidemiology, we expect 10-
20% positivity for Influenza during the treatment study period as we anticipate beginning 
the study period during respiratory virus season with increased viral positivity. Based on 
this, we expect 20-50 patients will be eligible for influenza treatment at each deployment 
with an additional 20-50 patients positive for COVID-19 who will receive referrals for 
COVID-19 treatment at other treatment locations. We expect that we will be able to 
provide treatment to approximately 430 individuals based on the assumption that 90% 
will be in the treatment window and 80% will test positive. 
 
The mobile testing unit will be deployed a minimum of 2 times per week following the 
determination of the influenza season by the New Mexico Department of Health. We 
expect to screen 50-100 patients per week for the duration of the influenza season 
(approximately 12 weeks) for a total of  600-1,2000 patients. With an anticipated 20-10% 
positivity rate for influenza, we expect at least 5-10 patients per week to be eligible for 
treatment for a total of 60-120 patients eligible over the course of the study. All subjects 
will be provided a survey to evaluated their ability to access respiratory virus testing and 
their acceptance of and trust in using a mobile unit for access to treatment and 
therapeutics. As per the New Mexico Test to Treat protocol, all patients will receive a 
follow-up phone call 24-48 hours following treatment. Additionally, all patients enrolled in 
the study will receive a follow-up phone call 14-days following the initial screening visit. 
 
 
Enrollment 
per 
deployment 
Number of 
Deployments 
Total 
Enrolled 
Positivity 
Rate 
(Influenza) 
Within 
Treatment 
Window 
Expected 
Treated 
(total 
study) 
Influenza Test to 
Treat  
50-100 
12 
600-1200 
10-20% 
(60-240) 
90% 
 
54-180 
6.2 
PLANNED EFFICACY EVALUATIONS 
This is an observational study of the population.  Individual patient efficacy will not be 
assessed.   
6.3 
SECONDARY EFFICACY VARIABLES 
Census tracts and hot spot/testing desert scores are the efficacy variables. 
6.4 
SAFETY ANALYSES 
The safety analysis population will consist of all patients who received at least one dose 
of study drug.  
6.5 
METHOD OF ANALYSIS 
The analysis population for the efficacy analyses will consist of measuring the hot spot 
score in SVI-paired census tracts not receiving intervention during the study. 

 
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7. 
INVESTIGATOR REQUIREMENTS 
7.1 
RETENTION OF RECORDS 
FDA regulations (21 CFR §312.62[c]) and the International Council for Harmonisation 
(ICH) Guideline for GCP (see Section 4.9 of the guideline) require that records and 
documents pertaining to the conduct of clinical trials and the distribution of 
investigational drug, patient records, consent forms, laboratory test results, and 
medication inventory records, must be retained for 2 years after the last marketing 
application approval in an ICH region or after at least 2 years have elapsed since formal 
discontinuation of clinical development of the investigational product.  All state and local 
laws for retention of records also apply.  
For studies conducted outside the U.S. under a U.S. IND, the Principal Investigator must 
comply with the record retention requirements set forth in the FDA IND regulations and 
the relevant national and local health authorities, whichever is longer. 
7.2 
STUDY MEDICAL MONITORING REQUIREMENTS 
This clinical research study will be monitored both internally by the PI and externally by 
the WCG IRB.  In terms of internal review, the PI will continuously monitor and tabulate 
AEs.  Appropriate reporting to the WCG IRB will be made.  The PI of this study will also 
continuously monitor the conduct, data, and safety of this study to ensure that: 
• 
Interim analyses occur as scheduled, 
• 
Stopping rules for toxicity and/or response are met, 
• 
Risk/benefit ratio is not altered to the detriment of the subjects, 
• 
Appropriate internal monitoring of AEs and outcomes is done, 
• 
Over-accrual does not occur, 
• 
Under-accrual is addressed with appropriate amendments or actions, and 
• 
Data are being appropriately collected in a reasonably timely manner. 
 
Routine monitoring will be carried out via a periodic team conference among 
investigators during which toxicity data, including all SAEs, will be reviewed and other 
issues relevant to the study such as interim assessment of accrual, outcome, and 
compliance with study guidelines, will be discussed.  Monitoring will be carried out on an 
ongoing basis.  The severity, relatedness, and whether or not the event is expected will 
be reviewed. 
7.3 
DATA COLLECTION 
The study coordinator and investigators are responsible for ensuring that the eligibility 
checklist is completed in a legible and timely manner for every patient enrolled in the 
study, and that data are recorded on the appropriate forms and in a timely manner.  Any 
errors on source data should be lined through, but not obliterated, with the correction 

 
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inserted, initialed, and dated by the study coordinator or PI.  All source documents will 
be available for inspection by the FDA and the WCG IRB. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
Patients who comply with the requirements of the protocol, are tolerating study 
treatment, and may be receiving benefit will be offered dosing beyond Cycle 1 at the 
investigator’s discretion after a careful assessment and thorough discussion of the 
potential risks and benefits of continued treatment with the patient.  Such patients may 
have the option to receive Xofluza treatment as long as they continue to experience 
clinical benefit in the opinion of the investigator until the earlier of unacceptable toxicity, 
symptomatic deterioration attributed to disease progression, or any of the other reasons 
for treatment discontinuation listed in Section 4.6. 
8.2 
INFORMED CONSENT 
The informed consent document must be signed by the subject or the subject’s legally 
authorized representative before his or her participation in the study.  The case history 
for each subject shall document that informed consent was obtained prior to participation 
in the study.  A copy of the informed consent document must be provided to the subject 
or the subject's legally authorized representative.  If applicable, it will be provided in a 
certified translation of the local language. 
Signed consent forms must remain in each subject’s study file and must be available for 
verification by study monitors at any time. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the informed consent document, and relevant supporting information must 
be submitted to the IRB for review and must be approved before the study is initiated.  
The study will be conducted in accordance with FDA, applicable national and local 
health authorities, and IRB requirements. 
The Principal Investigator is responsible for keeping the IRB apprised of the progress of 
the study and of any changes made to the protocol as deemed appropriate, but in any 
case, the IRB must be updated at least once a year.  The Principal Investigator must 
also keep the IRB informed of any significant AEs. 
Investigators are required to promptly notify their respective IRB of all adverse drug 
reactions that are both serious and unexpected.  This generally refers to SAEs that are 
not already identified in the Investigator’s Brochure and that are considered possibly or 
probably related to the molecule or study drug by the investigator.  Some IRBs may have 
other specific AE requirements to which investigators are expected to adhere.  
Investigators must immediately forward to their IRB any written safety report or update 

 
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provided by Genentech (e.g., IND safety report, Investigator’s Brochure, safety 
amendments and updates, etc.). 
8.4 
CONFIDENTIALITY 
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 to use and 
disclose personal health information) signed by the patient or 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 FDA and other regulatory agencies, national and local health 
authorities, Genentech representatives and collaborators, and the IRB/Ethics Committee 
(EC) for each study site, if appropriate. 

 
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9. 
REFERENCES 
Centers for Disease Control and Prevention (CDC), National Center for Immunization 
and Respiratory Diseases (NCIRD). Influenza Antivirial Medications: Summary for 
Clinicians. Retreived from 
https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm. Revised 
February 23, 2018. Accessed March 30, 2018. 
de Jong ME, Ison MG, Monto AS, et al. Evaluation of Intravenous Peramivir for 
Treatment of Influenza in Hospitalized Patients. Clin Infect Dis 
2014;59(12):e172-85. 
Fiore AE, Fry A, Shay D, et al. 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). 
MMWR Recomm Rep 2011;60:1−24. 
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;48:1003−32. 
Hu Y, Lu S, Song Z, et al. Association between adverse clinical outcome in human 
disease caused by novel influenza A H7N9 virus and sustained viral shedding and 
emergence of antiviral resistance. Lancet 2013;381:2273−9. 
Kitano M, Yamamoto A, Noshi T, et al. Synergistic antiviral activity of 
XOFLUZA/S-033447, a novel inhibitor of influenza virus cap-dependent 
endonuclease, in combination with neuraminidase inhibitors in vitro. Open Forum 
Infect Dis 2017;4(Suppl 1):S371. 
Lee N, Chan PK, Hui DS, et al. Viral loads and duration of viral shedding in adult 
patients hospitalized with influenza. J Infect Dis 2009,200:492−500. 
Lee N, Ison MG. Diagnosis, management and outcomes of adults hospitalized with 
influenza. Antivir Ther 2012;17(1 Pt B):143−57. 
Marty FM, Vidal-Puigserver J, Clark C, et al. Intravenous zanamivir or oral oseltamivir for 
hospitalised patients with influenza: an international, randomised, double-blind, 
double-dummy, phase 3 trial. Lancet Respir Med 2017;5(2):135-46. 
Muthuri SG, Venkatesan S, Myles PR, et al. Effectiveness of neuraminidase inhibitors in 
reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 
virus infection: a meta-analysis of individual participant data. Lancet Respir Med 
2014;2:395−404.  
Hayden FG, et al. Baloxavir Maroxil for Uncomplicated Influenza in Adults and 
Adolescents. N Engl J Med 2018; 379:913-923 
Paules C, Subbarao K. Influenza. Lancet 2017;390:697−708. 
Rothberg MB, Haessler SD. Complications of seasonal and pandemic influenza. Crit 
Care Med 2010;38:e91−7.  

 
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Royal College of Physicians. National early warning score (NEWS) 2 Standardising the 
assessment of acute-illness severity in the NHS. London: RCP, 2017. 
Borunda TB et al. Opportunity for Real-Time, Longitudinal Clinical Laboratory Data to 
Enhance Diabetes Disease Surveillance: A Cross-Sectional, Laboratory Database 
Enabled Population Study. J Appl Lab Med. 2020; 5(5): 967-977 
https://www.tricore.org/infectious_disease_reports 
Social vulnerability index (SVI): enters for Disease Control and Prevention/ Agency for 
Toxic Substances and Disease Registry/ Geospatial Research, Analysis, and 
Services Program. CDC/ATSDR Social Vulnerability Index 2018 Database 
NM. https://www.atsdr.cdc.gov/placeandhealth/svi/data_documentation_download.
html. Accessed on December 1, 2021. 
Oster AM, Kang GJ, Cha AE, et al. Trends in Number and Distribution of COVID-19 
Hotspot Counties — United States, March 8–July 15, 2020. MMWR Morb Mortal 
Wkly Rep 2020;69:1127–1132. 
Karaye IM, Horney JA. The Impact of Social Vulnerability on COVID-19 in the U.S.: An 
Analysis of Spatially Varying Relationships. Am J Prev Med. 2020 Sep;59(3):317-
325. doi: 10.1016/j.amepre.2020.06.006. Epub 2020 Jun 26. PMID: 32703701; 
PMCID: PMC7318979 
Dasgupta S, Bowen VB, Leidner A, et al. Association Between Social Vulnerability and a 
County’s Risk for Becoming a COVID-19 Hotspot – United States, June -July 25, 
2020. MMWR Morb Moral Wkly Rep 2020;69:1535-1541.  
Freese KE, Vega A, Lawrence JJ, Documet PI. Social Vulnerability Is Associated with 
Risk of COVID-19 Related Mortality in U.S. Counties with Confirmed Cases. J 
Health Care Poor Underserved. 2021;32(1):245-257. doi: 10.1353/hpu.2021.0022. 
PMID: 33678695. 
Selden TM, Berdahl TA. COVID-19 And Racial/Ethnic Disparities in Health Risk, 
Employment, and Household Composition. Health Affairs. 2020 
Hawkins D. Differential occupational risk for COVID-19 and other infection exposure 
according to race and ethnicity  Am J Ind Med 2020 63:917-820 
Rader B, Astley CM, Sy KTL, Sewalk K, Hswen Y, Brownstein JS, Kraemer MUG. 
Geographic access to United States SARS-CoV-2 testing sites highlights 
healthcare disparities and may bias transmission estimates. J Travel Med. 2020 
Nov 9;27(7):taaa076. 
https://globalepidemics.org/testing-targets/, Accessed November 29, 2021 
Swanson K et al. Improving the Delivery of Healthcare through Clinical Diagnostic 
Insights. (2018) J Appl Lab Med. 3(2): 1-11; Online ahead of print 

 
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Appendix 1  
Study Flowchart 
 
 
 
 

Appendix 1: Study Flowchart 
  
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Patient Case Report Form 
Study Number: ________   Patient DOB: _____________ 
ENROLLMENT INFORMATION: 
Informed Consent and assent form completed: ___ YES     ____ No  
Conforms with Inclusion and Exclusion Criteria: ___ YES     ____ No  
MUST HAVE CONSENT AND  PATIENT MUST MEET CRITERIA TO CONTINUE 
 
Physical assessment and medical history documented  
___ YES     ____ No 
 
TESTING:  
Cobas Liat SARS-CoV2 and Influenza A&B Test Result:  
 
Result 
Action Taken 
SARS CoV 2 
 
 
Patient counseling 
 Provider referral 
Influenza A 
 
 
Prescription provided 
 
Patient counseling 
 Provider referral 
Influenza B 
 
 
 
VISIT COMPLETION 
Survey returned: ___ YES     ____ No 
 
 
 

Appendix 1: Study Flowchart 
  
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Protocol ML44485, Version {Number} 
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14- Day Follow-Up   Survey 
 
Subject Number: __________ 
Did anyone else in your household test positive at the testing event: 
Influenza: ___ YES     ____ No        COVID: ___ YES     ____ No 
Did anyone else in your household test positive for influenza or 
COVID following the testing event: 
Influenza: ___ YES     ____ No  COVID: ___ YES     ____ No 
 
Did anyone else in your household have any of the symptoms above 
following the testing event?   ___ YES     ____ No 
Symptom assessment 
Present at First Visit 
Date Resolved 
Fever or chills 
___ YES     ____ No 
Cough 
___ YES     ____ No 
Sore throat 
___ YES     ____ No 
 
Runny or stuffy nose 
___ YES     ____ No 
 
Muscle or body aches 
___ YES     ____ No 
 
Headaches 
___ YES     ____ No 
 
Fatigue (tiredness) 
_
 
Did your illness cause you (or household members) to miss  
 
Self 
Household 
Member 
Days 
Missed 
Was there any 
additional requirement 
to allow return to 
activity? (I.e., required 
days at home or 
negative test) 
Work  
 
 
 
 
School 
 
 
 
 
Grocery 
Shopping 
 
 
 
 
Faith-
based 
activity 
 
 
 
 
Fitness 
 
 
 
 
Other: 
Name 
 
 
 
 
 

 
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Appendix 2  
Safety Reporting Fax Cover Sheet 
 
SAFETY REPORTING FAX COVER SHEET 
GENENTECH SUPPORTED RESEARCH 
AE / SAE FAX No: (650) 238-6067 
 
Genentech Study Number 
 
Principal Investigator 
 
Site Name 
 
Reporter name 
 
Reporter Telephone # 
 
Reporter Fax # 
 
 
 
Initial Report Date 
[DD] / [MON] / [YY] 
Follow-up Report Date 
[DD] / [MON] / [YY] 
 
Subject Initials 
(Enter a dash if patient has no 
middle name) 
[ ] - [ ] - [ ] 
 
 
SAE or Safety Reporting questions, contact Genentech Drug Safety: (888) 835-2555 
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS COVER 
SHEET 

 
Xofluza⎯TriCore 
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Appendix 3  
FDA MedWatch 3500 Form 
This form is included in the study start-up zip file to be sent to sites via email.

 
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Appendix 4  
Management Criteria for Abnormal Liver Function Tests 
Management Criteria for Abnormal Liver Function tests have been designed to ensure 
patient safety and evaluate liver event etiology (see Guidance for Industry Drug-Induced 
Liver Injury:  Premarketing Clinical Evaluation, FDA: 2009; available from: 
https://www.fda.gov/downloads/Guidances/UCM174090.pdf). 
Abnormal Liver Chemistry Criteria 
The investigator or subinvestigator must review study patient laboratories to identify if 
any levels meet the following criteria: 
• 
AST or ALT  5  upper limit of normal (ULN) 
• 
AST or ALT  3  ULN and total bilirubin (TBL)  2  ULN or INR  1.5, if INR is 
measured 
• 
AST or ALT  3  ULN with signs or symptoms compatible with hepatitis or 
hypersensitivity (e.g., fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, jaundice, fever, rash, eosinophilia [ 5%]) 
 
Action to be Taken by Investigator 
If any abnormal liver chemistry criterion is met, the investigator or subinvestigator must 
do the following: 
• 
Patients must be instructed to discontinue study medication immediately. 
• 
Following the initial observed elevation, every effort should be made to have the 
patient return to the clinic within 72 hours (if already discharged from hospital) to 
repeat liver function chemistries and for further hepatic evaluation. 
• 
Every effort should be made to have the patients monitored 2 to 3 times per week 
until liver function chemistries (i.e., ALT, AST, ALP, TBL) resolve, stabilize per  
• 
investigator judgement, or return to within the normal range or to baseline levels. 
• 
Consultation with a specialist, such as a hepatologist, and liver imaging 
(i.e., ultrasound, magnetic resonance imaging [MRI], computerized tomography) 
should be considered for worsening laboratory values or symptoms.