Clinical trial NCT05170009
Conditions: Influenza
Keywords: Influenza Bone marrow transplant Flu Baloxavir Marboxil Xofluza Oseltamivir
Sponsor: Weill Medical College of Cornell University
Start date: 2022-04-22; Completion date: 2024-02-07
Enrollment: 2 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, double-blind, placebo-controlled pilot study of the efficacy and safety of baloxavir in combination with oseltamivir (standard of care) for the treatment of influenza in allogeneic stem cell transplant patients. Although there are no data about this treatment option currently available, the investigator hypothesizes that combination therapy may be more effective in clearing influenza virus infection and decreasing the rate of emergence of resistant influenza in immunocompromised human hosts.

Detailed description:
This is a randomized double-blind placebo-controlled pilot study of the efficacy and safety of baloxavir in combination with oseltamivir (standard of care) for the treatment of influenza in allogeneic stem cell transplant patients. 30 SCT recipients will take part in the study. Participants with be randomly assigned (1:1) to either baloxavir + oseltamivir or baloxavir-matched placebo +oseltamivir. Before randomization, patients will be stratified by hospitalization status and influenza type A (yes/no).

Patients in the baloxavir combination arm will receive weight-adjusted baloxavir (40 mg for patients weighing \<80 kg and 80 mg for those weighing ≥80 kg) at baseline and at day 4 and day 7. They will also receive oseltamivir 75 mg twice daily for 10 days. Patients in the baloxavir-matched placebo + oseltamivir arm will receive baloxavir-matched placebo at baseline and at day 3 and day 7and oseltamivir 75 mg twice daily for 10 days.

Arms: arm 1: Active Baloxavir Marboxil and standard of care Oseltamivir arm 2: Placebo-matched Baloxavir Marboxil and standard of care Oseltamivir
Interventions: intervention 1: Baloxavir Marboxil intervention 2: Placebo intervention 3: Oseltamivir
Intervention descriptions: intervention 1: Weight-adjusted Baloxavir Marboxil (40 mg for patients weighing \<80 kg and 80 mg for those weighing ≥80 kg) at baseline, day 4, and day 7. intervention 2: Placebo at baseline, day 4, and day 7. intervention 3: Oseltamivir 75 mg twice daily for 10 days.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
Page 1 of 1 
 
Protocol Cover Sheet 
 
 
 
 
Protocol Title:  
Randomized double-blind, placebo-controlled pilot study of the efficacy 
and safety of baloxavir in combination with standard of care in stem cell 
transplant patients hospitalized for influenza 
 
Principal Investigator:  
Mirella Salvatore, MD 
 
NCT number:   
 
NCT05170009 
 
Document Date:  
 
October 05, 2023 
 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 1 of 47 
Protocol v3.0 dated 10/05/2023 
PROTOCOL 
TITLE: 
Randomized double-blind, placebo-controlled single center pilot 
study to evaluate the efficacy and safety of baloxavir in combination 
with oseltamivir in adult allogeneic bone marrow transplant 
recipients with influenza  
 
STUDY NUMBER: 
20-12023076 
VERSION NUMBER: 
3.0 
TEST PRODUCTS: 
Xofluza (baloxavir marboxil) (RO7191686) 
INDICATION: 
 
INVESTIGATOR: 
Mirella Salvatore 
1300 York Avenue Rm A479, BOX 125 
New York, NY 10065 
Telephone: 646-318-8506 
Fax: 212-746-8675 
E-mail: mis2053@med.cornell.edu 
 
 
SUPPORT PROVIDED BY  
Genentech, Inc. 
 
 
 
 
PROTOCOL DATE: 
October 5, 2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
This is a Weill Cornell Medicine 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 Weill Cornell Medicine. 
 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 2 of 47 
Protocol v3.0 dated 10/05/2023 
Table of Contents 
1. 
BACKGROUND ............................................................................................................................5 
1.1 
BACKGROUND ON INFLUENZA .......................................................................................................... 6 
1.2 
BACKGROUND ON XOFLUZA ............................................................................................................. 7 
1.2.1 
OVERVIEW OF XOFLUZA CLINICAL DEVELOPMENT .............................................................. 7 
1.2.1.1 
EFFICACY ....................................................................................................................... 8 
1.2.1.2 
SAFETY ........................................................................................................................... 8 
1.2.2 
POST-MARKETING SAFETY DATA .......................................................................................... 9 
1.3 
STUDY RATIONAL AND BENEFIT-RISK ASSESSMENT ......................................................................... 9 
2. 
OBJECTIVES AND ENDPOINTS .................................................................................................... 11 
2.1  
PRIMARY OBJECTIVE ....................................................................................................................... 11 
1.2.1 
EXPLORATORY EFFICACY OBJECTIVES ................................................................................. 13 
3. 
STUDY DESIGN .......................................................................................................................... 13 
3.1 
DESCRIPTION OF THE STUDY .......................................................................................................... 13 
3.2 
END OF STUDY AND LENGTH OF STUDY ......................................................................................... 14 
3.3 
RATIONALE FOR STUDY DESIGN ...................................................................................................... 14 
3.3.1 
RATIONALE FOR XOFLUZA DOSE ......................................................................................... 14 
3.3.2  
RATIONALE FOR PATIENT POPULATION ............................................................................. 14 
3.3.3 
RATIONALE FOR THE CONTROL GROUP .............................................................................. 15 
3.3.4 
RATIONALE FOR BIOMARKER ASSESSMENTS ..................................................................... 15 
3.3.5 
RATIONALE FOR PATIENT-REPORTED OUTCOME ASSESSMENTS ....................................... 15 
4. 
MATERIALS AND METHODS ...................................................................................................... 15 
4.1 
PATIENTS ......................................................................................................................................... 15 
4.1.1 
INCLUSION CRITERIA ........................................................................................................... 15 
4.1.2 
EXCLUSION CRITERIA........................................................................................................... 16 
4.2 
SAMPLE COLLECTION AND PROCESSING ........................................................................................ 17 
4.2.1 
NASOPHARYNGEAL SAMPLING AND VIROLOGICAL ASSAYS ............................................... 17 
4.2.2 
BLOOD SAMPLE FOR BIOMARKER ASSESSMENT ................................................................ 17 
4.3 
METHOD OF TREATMENT ASSIGNMENT ........................................................................................ 17 
4.3.1 
STUDY TREATMENT FORMULATION, PACKAGING, AND HANDLING .................................. 18 
4.3.1.1  Xofluza ............................................................................................................................... 18 
4.3.1.2  Placebo .............................................................................................................................. 18 
4.3.1.3 Oseltamivir ......................................................................................................................... 18 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 3 of 47 
Protocol v3.0 dated 10/05/2023 
4.3.2 
STUDY TREATMENT DOSAGE, ADMINISTRATION, AND COMPLIANCE ............................... 18 
4.3.2.1 Baloxavir and Oseltamivir .................................................................................................. 18 
4.3.2.2 Placebo and Oseltamivir .................................................................................................... 18 
4.4 
CONCOMITANT THERAPY, PROHIBITED FOOD, AND ADDITIONAL RESTRICTIONS ......................... 19 
4.4.1 
PERMITTED THRAPY ............................................................................................................ 19 
4.4.2 
CAUTIONARY THERAPY ....................................................................................................... 19 
4.4.3 
PROHIBITED THERAPY ......................................................................................................... 19 
4.5 
STUDY ASSESSMENTS ...................................................................................................................... 19 
4.5.1 
INFORMED CONSENT FORMS AND SCREENING LOG .......................................................... 19 
4.5.2 
MEDICAL HISTORY, CONCOMITANT MEDICATION, AND DEMOGRAPHIC DATA ................ 19 
4.5.3 
PHYSICAL EXAMINATION .................................................................................................... 20 
4.5.4 
VITAL SIGNS ......................................................................................................................... 20 
4.5.5 
INFLUENZA DIAGNOSTIC TEST ............................................................................................ 20 
4.5.6 
PHYSICIAN ASSESSMENTS ................................................................................................... 20 
4.5.7 
SELF ASSESSED MEASUREMENTS ........................................................................................ 22 
4.5.8 
LABORATORY, BIOMARKER, AND OTHER BIOLOGICAL SAMPLES ....................................... 23 
4.6 
TREATMENT, PATIENT, AND STUDY DISCONTINUATION ................................................................ 24 
4.6.1 
PATIENT DISCONTINUATION FROM STUDY ........................................................................ 25 
4.6.2 
STUDY DISCONTINUATION .................................................................................................. 25 
5. 
ASSESSMENT OF SAFETY ........................................................................................................... 25 
5.1 
SPECIFICATION OF SAFETY VARIABLES ........................................................................................... 25 
5.2 
 ADVERSE EVENTS ........................................................................................................................... 25 
5.3 
SERIOUS ADVERSE EVENTS ............................................................................................................. 26 
5.3.1 
METHODS AND TIMING FOR ASSESSING AND RECORDING SAFETY VARIABLES ................ 26 
5.3.2 
ADVERSE EVENT REPORTING PERIOD ................................................................................. 26 
5.3.3 
ASSESSMENT OF ADVERSE EVENTS .................................................................................... 26 
5.4 
PROCEDURES FOR ELICITING, RECORDING, AND REPORTING ADVERSE EVENTS ........................... 28 
5.4.1 
ELICITING ADVERSE EVENTS................................................................................................ 28 
5.4.2 
SPECIFIC INSTRUCTIONS FOR RECORDING ADVERSE EVENTS ............................................ 28 
5.4.2.1  Diagnosis vs. Signs and Symptoms .................................................................................... 28 
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 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 4 of 47 
Protocol v3.0 dated 10/05/2023 
5.4.2.5 
Assessment of Severity of Adverse Events ................................................................. 29 
5.4.3 
PREGNANCY ........................................................................................................................ 30 
5.4.4 
AEs OF SECIAL INTERESTS (AESIs) ....................................................................................... 30 
5.4.5 
OTHER SPECIAL SITUATIONS REPORTS ............................................................................... 31 
5.4.7 
POST-STUDY ADVERSE EVENTS ........................................................................................... 31 
5.4.8 
EXCHANGE OF SINGLE CASE REPORTS ................................................................................ 31 
5.4.9 
CASE TRANSMISSION VERIFICATION OF SINGLE CASE REPORTS ........................................ 32 
5.4.10 
REPORTING TO REGULATORY AUTHORITIES, ETHICS COMMITTEES AND INVESTIGATORS 33 
5.4.11 
AGGREGATED REPORTS ...................................................................................................... 33 
5.4.12 
STUDY CLOSE-OUT .............................................................................................................. 34 
6. 
STATISTICAL CONSIDERATIONS ................................................................................................. 36 
6.1 
EXPLORATORY ENDPOINTS ............................................................................................................. 36 
6.2 
METHOD OF ANALYSIS .................................................................................................................... 37 
7. 
INVESTIGATOR REQUIREMENTS ................................................................................................ 37 
7.1 
RETENTION OF RECORDS ................................................................................................................ 37 
7.2 
STUDY MEDICAL MONITORING REQUIREMENTS ........................................................................... 38 
7.3 
STUDY MEDICATION ACCOUNTABILITY .......................................................................................... 38 
7.4 
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............................................................................................................................ 39 
9. 
REFERENCES ............................................................................................................................. 40 
Appendix 1 - Study Flowchart ........................................................................................................... 42 
Appendix 2 - Safety Reporting Fax Cover Sheet ................................................................................. 45 
 
 
 
 
 
 
LIST OF ABBREVIATIONS AND DEFITIONS OF TERMS 
 
Abbreviation 
Definition 
CTCAE 
Common Terminology Criteria for Adverse Events 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 5 of 47 
Protocol v3.0 dated 10/05/2023 
Abbreviation 
Definition 
cfDNA 
Cell-Free DNA 
EC 
Ethics Committee 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
HA 
hemagglutinin complex  
HIPAA 
Health Insurance Portability and Accountability Act 
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 
LPLV 
last patient, last visit 
mITTI 
modified intent-to-treat (influenza) infected (population) 
NA 
neuraminidase 
NAI 
neuraminidase inhibitor 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
PK 
pharmacokinetic 
PRO 
patient-reported outcome 
SCT 
SOC 
Stem cell transplant 
standard of care 
TCID50 
50% tissue culture infectious dose 
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 
Vc/F 
apparent volume of distribution for the central compartment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. BACKGROUND 
 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 6 of 47 
Protocol v3.0 dated 10/05/2023 
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 (baloxavir), 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 (not approved 
in the US), and the NA inhibitors (i.e., oseltamivir, zanamivir, and peramivir). Many viral isolates 
causing seasonal influenza infection are resistant to amantadine and rimantadine, hence the use 
of these drugs 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. 
 
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). 
 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 7 of 47 
Protocol v3.0 dated 10/05/2023 
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 has a novel mechanism of action. In fact it 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. Currently, 
the drug is also approved for post-exposure prophylaxis, the reduction of influenza transmission, 
and otherwise healthy pediatrics ( 12 years of age).  
 
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). 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. In addition, Xofluza is approved in 
Thailand and Japan 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. Currently  baloxavir is approved for influenza treatment in more than 60 
countries). 
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. Multiple administrations of Xofluza (at 
day 1, 4 and 7) have been used in the Flagstone study for the treatment of hospitalized 
patients with influenza to maintain sustained efficacious plasma concentrations. 
 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 8 of 47 
Protocol v3.0 dated 10/05/2023 
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 with a difference of −26.5 hours for Xofluza 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 
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). 
 
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 
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 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. 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 9 of 47 
Protocol v3.0 dated 10/05/2023 
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. 
 
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 postmarketing 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 RATIONAL 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). Influenza virus infection can be especially severe in stem cell transplant (SCT) recipients. 
In these patients the clinical course is often prolonged with a higher frequency of progression of 
the disease to the lower respiratory tract, protracted viral shedding and increased death1,2. 
Neuraminidase inhibitors (NAI), including oseltamivir, are the mainstay of influenza therapy. 
However, because the paucity of initial symptoms and the frequent absence of fever3,4 the 
diagnosis of influenza is often delayed in this population, and treatment with NAI is often 
started later than 48-hours after the onset of influenza, that is the period during which NAI 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 10 of 47 
Protocol v3.0 dated 10/05/2023 
treatment is most effective. Moreover, while low rates of NAI resistance are reported in the 
general population, high viral replication associated with prolonged therapeutic courses favor 
the rapid emergence and transmission of NAI-resistant influenza in SCT recipients5. 
 
Baloxavir (XofluzaTM) is a first-in-class influenza antiviral that blocks influenza virus RNA 
replication by inhibiting cap-dependent endonuclease activity (Omoto et al 2018). Baloxavir has 
a prolonged half-life allowing the administration in single dosing and it was recently approved 
for use in the US for the treatment of uncomplicated influenza. In the Phase III CAPSTONE-1 
double-blind randomized study in otherwise healthy patients (Hayden et al 2018), a single 
treatment of baloxavir (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 
reduced 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 
 
Although it was shown that baloxavir is effective against oseltamivir--resistant influenza strains 
in vitro (Taniguchi et al 2019), and it was effective in treating influenza in the 
immunocompromised mouse model (Fukao et al 2019), no randomized--controlled trials are 
available on the use of baloxavir in SCT recipients or in other immunocompromised patients. In 
a pilot study, we administered baloxavir to 5 SCT recipients who were still symptomatic and 
shedding influenza after treatment with oseltamivir. Two of these patients had the codon 
variant H275Y, that is known to confer resistance to oseltamivir. We found that after one or two 
administrations of baloxavir, the patients   could clear the virus and improve the influenza 
symptoms. One of the patients developed the I38T variant in the PA subunit of the IAV 
polymerase. High rates of the I38X PA variant have emerged during baloxavir treatment in 
clinical trials, and it has been associated with resistance to the drug (Hayden et al 2018). Despite 
the limitations of a small number of patients and lack of control group, our preliminary data 
(Salvatore et al 2020) suggest that baloxavir may be a useful treatment option for infections 
with influenza SCT patients, although the low barrier to resistance and the potential for 
transmissibility of baloxavir-resistant influenza virus raises concern.   
 
Combination treatment with baloxavir and oseltamivir in vitro and in mice produced synergistic 
responses against influenza virus infections. In this model, a suboptimal dose of baloxavir 
marboxil (0.5 mg/kg twice daily) in combination with oseltamivir phosphate provided additional 
efficacy compared with monotherapy in terms of virus-induced mortality, elevation of 
cytokine/chemokine levels and pathological changes in the lung suggesting that treating humans 
with the combination may be beneficial (Fukao et al 2019 b). Despite this treatment option may 
be more effective in clearing influenza virus infection and decrease the rate of emergence of 
resistant influenza in immunocompromised hosts no data about combination therapy in human 
are currently available. This study was therefore designed with the primary objective to 
compare the efficacy of the combination therapy of baloxavir with oseltamivir with oseltamivir 
plus placebo.  
 
In the Flagstone study, the incidence of adverse events was comparable between the two 
treatment arms regardless of the number of Xofluza or placebo doses that were received. One 
serious adverse event (orthostatic hypotension) in the placebo arm was considered treatment 
related. 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 11 of 47 
Protocol v3.0 dated 10/05/2023 
 
Table 4: FLAGSTONE – Incidence of Adverse Events* 
Baloxavir + SoC 
NAI (n=239) 
Placebo + SoC NAI 
(n=124) 
All Patients 
(n=363) 
Patients with ≥1 AE 
108 (45.2%) 
62 (50.0%) 
170 (46.8%) 
Total number of AEs 
279 
180 
459 
Deaths 
4 (1.7%) 
7 (5.6%) 
11 (3.0%) 
Patients withdrawn from treatment due to AE 
3 (1.3%) 
4 (3.2%) 
7 (1.9%) 
Serious AEs, patients (%) 
29 (12.1%) 
19 (15.3%) 
48 (13.2%) 
Treatment-related serious AEs, patients (%) 
0 
1 (0.8%) 
1 (0.3%) 
Treatment-related AEs, patients (%) 
8 (3.3%) 
8 (6.5%) 
16 (4.4%) 
Notes: *Safety population. Investigator text for AEs encoded using the MedDRA version 23.0. Related AEs are related to 
study drug only. 
Abbreviations: AE(s)=adverse event(s); MedDRA=Medical Dictionary for Regulatory Activities; NAI=neuraminidase 
inhibitor; SoC=standard of care 
 
Our study will randomize SCT recipients with influenza to receive baloxavir + oseltamivir (SOC) or 
oseltamivir + baloxavir matching placebo and assess if the combination of baloxavir with 
oseltamivir will translate in a more rapid decrease of viral load and faster symptoms resolutions 
when compared to oseltamivir alone. It will also test if combination therapy may lower the 
incidence of drug-resistant influenza variants.  
 
In summary, there is a strong rationale and a positive benefit-risk assessment for studying 
Xofluza combination therapy in SCT recipients. Safety and efficacy results suggest that Xofluza 
has an acceptable clinical safety profile and could benefit in immunocompromised patients. 
Given the poor treatment responses to single therapy in SCT, this population is considered 
appropriate for trials of combination therapy. The benefit-risk ratio for Xofluza in combination 
with oseltamivir is expected to be acceptable in this setting. 
2. OBJECTIVES AND ENDPOINTS 
 
2.1  PRIMARY OBJECTIVE 
The primary objective is to evaluate the efficacy of both the combination therapy of baloxavir 
with oseltamivir and that of oseltamivir plus placebo in SCT patients with influenza as measured 
by changes in influenza viral RNA loads at day 10 from baseline (day 1) and compare between 
arm differences in decline of viral load 
 
The co-primary efficacy endpoints are: 
 
• 
Change of influenza viral RNA loads from baseline (day 1) at the end of treatment (day 10) 
as measured by quantitative real time polymerase chain reaction (qRT-PCR, nucleic acid). 
 
• 
Between-treatment-arm difference in the change of influenza viral RNA loads from baseline (day 
1) at the end of treatment (day 10) as assessed by quantitative real time polymerase chain 
reaction as measured by (qRT-PCR, nucleic acid) and by Influenza plaque assay (replicating virus). 
 
 
 
 
 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 12 of 47 
Protocol v3.0 dated 10/05/2023 
The secondary efficacy endpoints are:  
 
1. Change of influenza viral RNA load from baseline (day 1) at day 4 and day 7 and 10 as 
measured by quantitative real time polymerase chain reaction (qRT-PCR, nucleic acid) in 
each treatment arm. 
2. Difference in change of influenza viral loads from baseline (day 1) at day 4, 7 and 10 
between the two treatment arms as measured by quantitative real time polymerase 
chain reaction (qRT-PCR, nucleic acid)  
3. Change of influenza viral loads from baseline (day 1) at day 4, 7 and 10 as measured by 
Influenza plaque assay (replicating virus) in each treatment arm. 
4. Difference in change of influenza viral loads from baseline (day 1) at day 4, 7 and 10 
between the two treatment arms as measured by Influenza plaque assay (replicating 
virus). 
5. Time to Improvement of Individual Influenza Symptoms [Time Frame: From Day 1 pre-
treatment up to Day 30] defined as the time from the initiation of the study treatment 
to the improvement of influenza symptoms as assessed by patient-reported outcome 
measures on a single scale as specified in section 4.5.7 . Time to improvement of 
symptoms is defined as the time from the start of treatment to the time when each of 
the influenza symptoms will be alleviated, maintained, or improved, for a duration of at 
least 24 hours. 
Participants will assess the severity of 7 influenza-associated symptoms (cough, sore 
throat, headache, nasal congestion, feverishness/chills, muscle/joint pain, and fatigue) 
on a 4-point scale (0 = no symptoms, 1= mild, 2 = moderate, and 3 = severe) as specified 
in section 4.5.7. Improvement is defined as: improvement pre-existing symptoms (i.e 
cough, fatigue, or muscle/join pain that existed prior to influenza) that were worse at 
baseline and improve at least 1 point from baseline; pre-existing symptoms not worse at 
baseline that maintain baseline severity; and new symptoms that are alleviated, defined 
as a symptom score of non (0) or mild (1). 
 
Once all patient’s influenza symptoms are alleviated, maintained, or improved 
(hereafter all will be called ‘improvement’) as defined above, the endpoint will be 
reached. 
6. Percentage of patients who experience each influenza-related complication 
(hospitalization, death, sinusitis, otitis media, bronchitis, and radiologically-confirmed 
pneumonia) as an adverse event after the initiation of study treatment symptoms 
[symptoms [Time Frame: From Day 1 pre-treatment up to Day 30]. 
7. Time to Return to Preinfluenza Health Status [Time Frame: From Day 1 pre-treatment 
up to Day 30]. Participants will be asked to record their preinfluenza health status on a 
scale from 0 (worst possible health) to 10 (normal health [for someone same age and 
condition]), and their health status at baseline and every day after initiation of study 
treatment on the same scale as specified in section 4.5.7. Return to preinfluenza health 
status is defined as time from the initiation of the study treatment to the first time 
when the health status score was equal to or higher than the preinfluenza health status 
score. 
8. Time to viral clearance, as assessed by difference in Percentage of Participants Positive 
by Influenza plaque assay and qPCR at each time-point (in each treatment group) The 
definition of the time to sustained cessation of infectious virus detection is the time 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 13 of 47 
Protocol v3.0 dated 10/05/2023 
between the start of treatment and when virus titer remained below the detection limit 
on all subsequent sampling time points.   
9. Measure treatment-emergent variants of neuraminidase and polymerase known to 
confer antiviral resistance to oseltamivir  in each arm by direct next-generation 
sequencing symptoms [Time Frame: From Day 1 pre-treatment up to Day 30] 
10. Safety and tolerability of Baloxavir in Combination with SOC treatment as assessed by 
Percentage of Participants with Adverse Events (AEs) [Time Frame: From first dose of 
study drug to Day 15] 
 
1.2.1 
EXPLORATORY EFFICACY OBJECTIVES 
1. To evaluate the use of cell-free DNA as surrogate for organ damage and treatment 
response 
 
The exploratory efficacy endpoint is:  
1. Measure change in organ damage and response to treatment by using cell-free DNA as 
surrogate. 
 
3. STUDY DESIGN 
 
3.1 DESCRIPTION OF THE STUDY 
This is a randomized double-blind placebo-controlled pilot study of the efficacy and safety of 
baloxavir in combination with oseltamivir (SOC) for the treatment of influenza in allogeneic stem 
cell transplant patients.  
 
30 SCT recipients with influenza  will take part in the study. Participants with be randomly 
assigned (1:1) to either baloxavir + oseltamivir or baloxavir-matched placebo +oseltamivir. 
Randomization will be performed by research pharmacy using an interactive web randomizer. 
Before randomization, patients will be stratified by hospitalization status (yes or no), influenza 
type A (yes or no).  
 
Patients in the baloxavir combination arm will receive weight-adjusted baloxavir (40 mg for 
patients weighing <80 kg and 80 mg for those weighing ≥80 kg) at baseline and at day 4 and day 
7. They will also receive oseltamivir 75 mg twice daily for 10 days.  
 
Patients in the baloxavir-matched placebo + oseltamivir arm will receive baloxavir-matched 
placebo at baseline and at day 4 and day 7 and oseltamivir 75 mg twice daily for 10 days.  
 
Nasopharyngeal swabs will be collected on days 1 (at diagnosis, pre-meds), 2, (optional visit), 4, 
7 and 10 for viral quantitation and viral sequencing. Influenza virus polymerase and 
neuraminidase sequencing will be also performed in all patients. Patients will have follow-up 
visits day 15 (+/- 2 days) and day 30 (+/- 2 days, EOT). Patients who will not clear the virus by 
day 10 will perform additional NP swabs at these visits.  
 
Paracetamol (acetaminophen; maximum 3000 mg per day) or NSAIDS can be given for severe 
discomfort or fever. No other antiviral drugs for the treatment of influenza, will be permitted, 
except antibiotics for the treatment of suspected bacterial infections. 
 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 14 of 47 
Protocol v3.0 dated 10/05/2023 
For the first 10 days, patients will receive a daily call from one member of the study team to 
review symptoms and severity scale. 
To assess the time to improvement of individual influenza symptoms (with modification for 
preexisting symptoms), participants will be given a diary to self-assess the severity of seven 
influenza-associated symptoms on a four-point scale.  To evaluate patient-reported time to 
return to pre-illness health status, patients will also rate daily the interference of influenza 
symptoms in daily activities on a 5-point severity scale. 
 
Oral temperature will be measured by the patient (in the outpatient setting) or by the staff for 
inpatients in the am and pm daily until day 10.  
 
To evaluate incidence of complications associated with influenza after the start of study 
treatment, at each study visit investigators will assess whether each of the complications 
(sinusitis, otitis, bronchitis, pneumonia) is present or not. If present, the report form shown in 
section will be completed. For pneumonia, a radiological confirmation will be required.  
 
On days 1, 7 and 15 safety laboratory tests (CBC, blood chemistry with LFTs) will be done. 
 
3.2 END OF STUDY AND LENGTH OF STUDY 
The end of this study is defined as the date when the last patient, last visit (LPLV) has occurred, 
patient has become lost to follow up, patient has withdrawn consent, or patient has completed 
at least 1 months of follow-up after randomization. The end of the clinical part of the study is 
expected to occur two months after the last patient is enrolled. After that the study will be open 
for analysis only. 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 24 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 results of Study  
1601T0831 (CAPSTONE-1). This study compared the effects of a single dose of  
Xofluza (40 mg for patients <80 kg and 80 mg for patients ≥80 kg administered as 20 mg 
tablets) with placebo or oseltamivir in otherwise healthy patients with influenza aged 
≥12 to ≤64 years of age. Study 1601T0831 demonstrated that a single 40 mg/80 mg dose 
on Day 1 was well tolerated and significantly reduced the time to alleviation of 
symptoms. This dose and regimen were also effective at reducing viral load. In the 
Flagstone study, baloxavir dosing at day 0, 4 and optional day 7 was used for treatment 
of influenza on hospitalized patients. Since SCT recipients are immunocompromised and 
have severe and prolonged disease we will use the same dose of baloxavir that is used 
for hospitalized patients in SCT with influenza treated both as outpatients or inpatients. 
 
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 
determine if adding baloxavir to oseltamivir will translate into a reduction in viral titer 
and symptoms. 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 15 of 47 
Protocol v3.0 dated 10/05/2023 
 
3.3.3 
RATIONALE FOR THE CONTROL GROUP 
This is a placebo+oseltamivir -controlled study because oseltamivir is standard of care 
treatment for influenza in SCT. Since SCT patients usually are unable to clear infection 
after 5 day-course of oseltamivir, we will use a 10-day course that is the standard of 
care (SOC) in the Weill Cornell Medicine BMT clinic. Comparison with placebo + 
oseltamivir will enable the analysis of the effect of combination therapy with baloxavir 
on influenza viral titers and clearance. 
 
3.3.4 
RATIONALE FOR BIOMARKER ASSESSMENTS 
Short fragments of cell-free DNA (cfDNA) circulate in blood. These molecules are the 
circulating debris of the genomes of dead cells, and their importance in diagnostic 
medicine has been widely established. The value of cfDNA as a quantitative marker of 
tissue and organ injury was first recognized in solid-organ transplantation, where the 
level of transplant donor derived cfDNA in the blood is now widely used as a marker of 
transplant rejection. More recently, several approaches have been developed to 
quantify the cell-, tissue-, and organ-of-origin of cfDNA and to thereby monitor injury to 
any cell, tissue or organ types. This is achieved by profiling of cell-, tissue-, or organ-
specific epigenetic marks within cfDNA by quantitative molecular measurement 
technologies such as DNA sequencing. Here, we will test the hypothesis that profiling 
the cfDNA tissues-of-origin would enable identifying specific tissue cell types that are 
directly or indirectly targeted and injured by influenza infection, and follow their 
recovery under therapy. 
 
3.3.5 
RATIONALE FOR PATIENT-REPORTED OUTCOME ASSESSMENTS 
PROs provide an understanding of the impact a treatment has on a patient. As for 
previous Baloxavir studies we will use patient-reported outcome measurements.  
4. MATERIALS AND METHODS 
 
4.1 PATIENTS 
 
Approximately 30 patients with allogeneic bone marrow transplant will be enrolled in this study.  
 
4.1.1 
INCLUSION CRITERIA 
 
 
Patient 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 
• 
Age  18 years at the time of signing the Informed Consent Form/Assent 
Form 
• 
Ability to comply with the study protocol, in the investigator’s judgment 
• 
Be defined as immunocompromised*, as defined by: 
1. Have received allogeneic bone marrow transplant, or 
2. Is currently receiving treatment with chemotherapy and/or 
CAR-T cell therapy for hematologic malignancies (e.g., 
leukemia, myeloma, lymphoma), or 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 16 of 47 
Protocol v3.0 dated 10/05/2023 
3. Received treatment with chemotherapy and/or CAR-T cell 
therapy for hematologic malignancies (e.g., leukemia, 
myeloma, lymphoma) within the past 1 year. 
• 
Tested positive for influenza infection after the onset of symptoms 
using a polymerase chain reaction (PCR)-based diagnostic assay.  
• 
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 diagnosis of influenza 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. 
 
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. 
 
*This study will enroll a minimum of 10 patients who have received allogeneic bone marrow 
transplant. 
 
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 Baloxavir for the current influenza infection 
• 
Known contraindication to neuraminidase inhibitors  
• 
Patients weighing  40 kg 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 17 of 47 
Protocol v3.0 dated 10/05/2023 
• 
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:  
o ALT or AST level >5 times the upper limit of normal (ULN) 
OR 
o 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 antimicrobial 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 baloxavir marboxil or the drug product 
excipients 
• 
Known COVID-19 coinfection 
• 
Unwilling to undergo nasopharyngeal (NP) swabs as per study schedule 
 
4.2 SAMPLE COLLECTION AND PROCESSING 
 
 
4.2.1 
NASOPHARYNGEAL SAMPLING AND VIROLOGICAL ASSAYS 
Two nasopharyngeal swabs will be collected at each visit and put immediately into viral 
transport medium and frozen. Pharyngeal swabs will be collected when if it is not 
possible to collect nasopharyngeal swabs. At the end of the clinical study period, 
samples will be used for viral sequencing and virological assessment.   
 
Viral RNA in pre- and last post-treatment swab samples will be extracted using 
conventional RNA extraction kit without virus amplification and used for viral RNA 
quantification by q-PCR and for viral sequencing. Swabs will also be used to calculate 
viral titers by plaque assays on MDCK cells. 
 
 
4.2.2 
BLOOD SAMPLE FOR BIOMARKER ASSESSMENT  
This will be collected at each visit, plasma will be separated by PBMC PI laboratory and 
samples will be kept frozen at -80C until use.  
 
 
 
4.3 METHOD OF TREATMENT ASSIGNMENT 
Participants will be and randomly assigned (1:1) to either the baloxavir + oseltamivir group, or 
the placebo + oseltamivir group. Before randomization, patients will be stratified by 
hospitalization (yes or no), influenza type A (yes or no). To maintain blinding, patients in the 
oseltamivir group will receive baloxavir-matched placebo. 
 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 18 of 47 
Protocol v3.0 dated 10/05/2023 
The design randomization schema will be developed and managed by the Weill Cornell 
investigational pharmacy. Unblinding will be done when last patient completed the study follow 
up period.  
 
Study Treatment: The investigational medicinal product (IMP) for this study is baloxavir in 
combination with oseltamivir.  
 
 
4.3.1 
STUDY TREATMENT FORMULATION, PACKAGING, AND HANDLING 
 
4.3.1.1  Xofluza 
Xofluza will be supplied by the Genentech, Inc. as tablets.  
For information on the formulation and handling of Xofluza, see the Xofluza 
Investigator’s Brochure. 
 
4.3.1.2  Placebo 
Baloxavir-matched placebo will be supplied by Genentech, Inc. as tablets.  
 
4.3.1.3 Oseltamivir 
Oseltamivir will be supplied by Genentech, Inc. as 75 mg tablets for oral 
administration. For information on the formulation, packaging, and handling of 
Oseltamivir see the local prescribing information for Oseltamivir.  
 
4.3.2 
STUDY TREATMENT DOSAGE, ADMINISTRATION, AND COMPLIANCE 
 
 
The treatment regimens are summarized in Section 3.1.  
 
 
 
 
Treatment will be self-administered in case of outpatient, the first dose will be taken 
during the clinic visit.  
 
For hospitalized patients, treatment will be administered by a trained nursing 
professional.  
 
Any overdose or incorrect administration of baloxavir or oseltamivir 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 Baloxavir and Oseltamivir 
The treatment regimens are summarized in Section 3.1.  
  
Patients in the baloxavir combination group will receive an oral dose of baloxavir at 
baseline (40 mg for patients weighing <80 kg and 80 mg for those weighing ≥80 kg) 
and at day 4 and 7. They will also receive oseltamivir 75 mg twice daily for 10 days.  
 
4.3.2.2 Placebo and Oseltamivir  
Patients in the standard-of-care group will receive oseltamivir 75 mg twice daily 
for 10 days and an oral dose of baloxavir-matched placebo at baseline and at 
day 4 and 7.  


 
Xofluza—Weill Cornell Medical College                                                                                              Page 19 of 47 
Protocol v3.0 dated 10/05/2023 
 
4.4 CONCOMITANT THERAPY, PROHIBITED FOOD, AND ADDITIONAL RESTRICTIONS 
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 initiation of study treatment to 
the treatment discontinuation visit. All such medications should be reported to the investigator 
and recorded in the patient’s medical records. 
 
 
4.4.1 
PERMITTED THRAPY 
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). 
 
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. 
 
4.4.3 
PROHIBITED THERAPY 
 
 
Use of the following concomitant therapies is prohibited as described below:  
• 
Investigational antimicrobial 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 
• 
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. 
 
 
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 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 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 20 of 47 
Protocol v3.0 dated 10/05/2023 
history, fertility history, and puberty history, will be recorded at baseline. 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 until 
30 days after the final dose of study drug 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 EXAMINATION 
A complete physical examination, will be performed at screening and other specified 
visits. Any abnormality identified at baseline will be recorded in the patient’s medical 
records. 
 
Limited, symptom-directed physical examinations should be performed at specified 
postbaseline visits and as clinically indicated. Changes from baseline abnormalities 
should be recorded in patient notes. New or worsened clinically significant 
abnormalities should be recorded as adverse events in the patient’s medical records. 
 
4.5.4 
VITAL SIGNS 
Vital signs will include measurements of respiratory rate, pulse rate, and systolic and 
diastolic blood pressure, and temperature and will be performed at specified timepoints 
as outlined in the schedule of activities (see Appendix 1). They may be performed by a 
MN professional. 
 
4.5.5 
INFLUENZA DIAGNOSTIC TEST 
For patients to be eligible for this study, a RT-PCR is required to be performed to inform 
a diagnosis of influenza. If a site has performed a RT-PCR test within the 24 hours prior 
to screening, the local RIDT or RT-PCR result can be used. Screening test for COVID-19 
will also be performed before enrollment. 
 
4.5.6 
PHYSICIAN ASSESSMENTS 
1. Time to improvement of respiratory status. This is defined as decreased or no 
need for oxygen supplementation to maintain optimal O2 saturation (>94%) 
2. Measurement of the incidence of influenza complications 
We will record the incidence of following influenza complications associated 
with influenza after the start of study treatment: 1. Sinusitis; 2. Otitis Media; 3. 
Bronchitis; 4. Radiologically Confirmed Pneumonia, and 5. Hospitalization. At 
each study visit investigators will ask whether Sinusitis, Otitis Media, Bronchitis, 
Radiologically Confirmed Pneumonia and Hospitalization is present or not. If any 
of these is present, a specific report form shown below will be completed. 
 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 21 of 47 
Protocol v3.0 dated 10/05/2023 
 
 
 
 
 
3. Hospital Recovery Scale 
We will use the hospital recovery scale to assess participant’s clinical status 
from day 1 to day 30. The hospital recovery scale provides 6 mutually exclusive 
conditions ordered from best to worst, and the score reflects the subject’s 
worst situation on the day of assessment: 
1. Not hospitalized 
2. Non-ICU hospitalization, not requiring supplemental oxygen 
3. Non-ICU hospitalization, requiring supplemental oxygen 
4. Admitted to the ICU, not requiring invasive mechanical ventilation 
5. Requiring invasive mechanical ventilation 
6. Death 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 22 of 47 
Protocol v3.0 dated 10/05/2023 
 
4.5.7 
SELF ASSESSED MEASUREMENTS 
 
1. 
TIME TO SYMPTOMS IMPROVEMENT 
This is defined as time from the start of treatment to patient reported improvement in all seven 
influenza-associated symptoms for a duration of at least 24 hours. Symptoms that were present 
before the development of influenza symptoms will have to improve by at least one level. If patient 
was not experiencing any symptom, all symptoms will have to be rated as mild or absent. Patients 
will be given a diary to self-assess daily the severity of the following influenza-associated symptoms 
on a 4 points scale, at baseline and then for the first 15 days of the study. 
 
 
 
 
 
 
At baseline (i.e., the predose examinations), patients will be asked if preexisting symptoms existed 
(within the last 30 days) and if they were worsened by influenza. Patients will be asked to rate the 
severity at baseline 
that needs to improve. The modification for preexisting symptoms will be done as follows (ISON et al 
2020, DOI:https://doi.org/10.1016/S1473-3099(20)30004-9) 
 
A. Symptoms that existed prior to developing influenza that are judged by the patient to be worse at 
baseline (before therapy) must improve from baseline severity 
 
o Improvement in baseline severity is defined as follows: 
  Severe to moderate, mild, or absent 
Moderate to mild or absent 
Mild to mild or absent 
Absent to mild or absent 
 
B. Symptoms that existed prior to developing influenza that were judged by the patient to NOT be 
worse at baseline (before therapy) must have their baseline severity maintained 
 
o Maintenance of baseline severity is as follows: 
Severe is defined as severe or less than severe 
Moderate is defined as moderate or less than moderate 
Mild is defined as mild or absent 
Absent is defined as mild or absent 
 
• For new symptoms at baseline (before therapy), alleviation of symptoms assessment must be 
achieved 
 
Date 
 
No symptoms 
Score 0 
Mild symptoms 
Score 1 
Moderate symptoms 
Score 2 
Severe symptoms 
 Score 3 
cough  
 
 
 
 
sore throat  
 
 
 
 
headache  
 
 
 
 
nasal congestion 
 
 
 
 
feverishness  
 
 
 
 
chills 
 
 
 
 
muscle or joint pain 
 
 
 
 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 23 of 47 
Protocol v3.0 dated 10/05/2023 
o Alleviation of symptoms is defined as follows: 
Severe is mild or absent 
Moderate is mild or absent 
Mild is mild or absent 
Absent is mild or absent 
 
Time to improvement of influenza symptoms is defined as the time from the initiation of the study 
treatment to the improvement of influenza symptoms for a duration of at least 24 hours. Once the 
patient’s influenza symptoms will be alleviated, maintained, or improved (hereafter all will be called 
‘improvement’) as defined above, the endpoint for that patient will be reached. 
Patients who did not experience improvement of symptoms will be censored at the last observation 
time point. 
 
 
2. TIME TO RETURN TO PRE-INFLUENZA HEALTH AND ACTIVITIES 
Participants will be asked to record their preinfluenza health status on a scale from 0 (worst possible 
health) to 10 (normal health [for someone your age and condition]), and their health status at 
baseline and every day after initiation of study treatment on the same scale. Return to preinfluenza 
health status is defined as time from the initiation of the study treatment to the first time when the 
health status score was equal to or higher than the preinfluenza health status score.  
 
3. PATIENT GLOBAL ASSESSMENT OF INTERFERENCE OF FLU IN DAILY ACTIVITIES 
This scale will be used by the patient for self-assessment of the interference in daily activities due to 
influenza symptoms during that day. Return to daily activities will be assessed once daily by means 
of the subject’s response to the question ‘Over the past 24 hours, how much has influenza (flu) 
interfered with your ability to carry out your daily activities?'  
Answer will be recorded using the following scale: 
 
1. Not at all 
2. A little bit 
3. Somewhat 
4. Quite a bit 
5. Very much 
 
4.5.8 
LABORATORY, BIOMARKER, AND OTHER BIOLOGICAL SAMPLES 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis as routinely done for standard of care: 
• 
Hematology: WBC count, RBC count, hemoglobin, hematocrit, platelet count 
• 
Chemistry panel (serum or plasma): sodium, potassium, magnesium, chloride, 
glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, 
total bilirubin, alkaline phosphatase, ALT, AST 
• 
Pregnancy test 
o All women of childbearing potential will have a serum pregnancy test at 
screening 
o 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 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 24 of 47 
Protocol v3.0 dated 10/05/2023 
than menopause), and has not undergone surgical sterilization (removal 
of ovaries and/or uterus). 
 
The following samples will be sent to the Investigator or a designee for analysis:  
• 
NP swabs 
• 
Blood samples for exploratory research on biomarkers 
o Exploratory biomarkers will include analysis of cfDNA, analysis of genes 
or gene signatures associated with influenza severity or recovery from 
influenza. This research will involve extraction of DNA, and genomic 
profiling through use of next-generation sequencing of a comprehensive 
panel of genes. NGS methods will not include whole genome 
sequencing (WGS). 
o Unless the patient gives specific consent for his or her leftover samples 
to be stored for optional exploratory research, biological samples will be 
destroyed when the final Clinical Study Report has been completed, 
with the following exception: 
o Blood samples collected for biomarker research will be 
destroyed no later than 10 years after the final Clinical Study 
Report has been completed.  
 
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. Given the complexity and exploratory nature of exploratory 
biomarker analyses, data derived from these analyses will generally not be provided to 
study investigators or patients unless required by law. The aggregate results of any 
conducted research will be available in accordance with the effective Investigator policy 
on study data publication. 
 
       4.6 TREATMENT, PATIENT, AND STUDY DISCONTINUATION 
Patients must permanently discontinue study treatment (Xolfuza and oseltamivir) 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) 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 25 of 47 
Protocol v3.0 dated 10/05/2023 
 
The primary reason for study treatment discontinuation should be documented in the patient’s 
medical records. Patients who discontinue study treatment prematurely will 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 
 
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 may 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 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 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. 
 
       5.2  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 SCT patients with influenza 
that were not present prior to the AE reporting period.  
• 
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. 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 26 of 47 
Protocol v3.0 dated 10/05/2023 
 
       5.3 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 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). 
 
5.3.1 
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) 
 
5.3.2 
ADVERSE EVENT REPORTING PERIOD 
The study period during which AEs and SAEs as described in section J 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 30 days 
following the first 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. 
 
5.3.3 
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 the baloxavir combination therapy (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 the baloxavir combination therapy 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 the baloxavir combination 
therapy or with similar treatments; and/or the AE abates or resolves upon 
discontinuation of the baloxavir combination therapy or dose reduction and, if 
applicable, reappears upon re- challenge. 
 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 27 of 47 
Protocol v3.0 dated 10/05/2023 
NO 
Evidence exists that the AE has an etiology other than the baloxavir combination 
therapy (e.g., preexisting medical condition, underlying disease, intercurrent illness, or 
concomitant medication); and/or the AE has no plausible temporal relationship to 
baloxavir combination therapy administration (e.g., cancer diagnosed 2 days after first 
dose of study drug). 
 
Expected adverse events are those adverse events that are listed or characterized in the 
Package Insert (P.I) 
or current Investigator Brochure (I.B). 
 
Unexpected adverse events are those not listed in the P.I or current I.B or not identified. 
This includes adverse events for which the specificity or severity is not consistent with 
the description in the P.I. or I.B. For example, under this definition, hepatic necrosis 
would be unexpected if the P.I. or I.B. only referred to elevated hepatic enzymes or 
hepatitis. 
 
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
 
 
5.3.4 
Management Criteria for Abnormal Liver Function Tests and Data and Safety 
Monitoring Plan (DSMP) 
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). 
The Weill Cornell Medicine DSMB will be used for this investigator-initiated study. The 
following information will be submitted to the WCM DSMB: 
 
Laboratory results 
• 
Blood hematology and chemistry 
• 
Blood liver chemistry 
 
Adverse Events and Stopping Rules 
The following adverse events will be submitted to the WCM DSMB and may cause the 
subject to terminate protocol treatment, at the discretion of the PI: 
1. AST or ALT  5  upper limit of normal (ULN) 
2. AST or ALT  3  ULN and total bilirubin (TBL)  2  ULN or INR  1.5, if INR 
is measured 
3. Severe drug reaction, including rash or fever (as determined by the PI) 
4. 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 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 28 of 47 
Protocol v3.0 dated 10/05/2023 
If any abnormal liver chemistry criterion is met, the investigator or sub investigator must 
do the following:  
• 
consider discontinuation only if transaminase elevation is not otherwise 
explained 
• 
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. 
 
WCM IRB policies will be followed for this study, including the Immediate Report Policy. 
Any SAEs will be reported to the IRB following these policies, and will also be reported 
to the funding source (Genentech Inc.) within 30 days of the study team learning of the 
SAE. The WCM DSMB comments/review will be submitted to the IRB at the time of 
continuing review and submitted to the funding source (Genentech, Inc.) at the time of 
each WCM DSMB completion. 
 
 
       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 clinical 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. 
 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 29 of 47 
Protocol v3.0 dated 10/05/2023 
 
 
5.4.2.2 Deaths 
All deaths that occur during the protocol-specified AE reporting period (see 
Section I), 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. 
 
Hospitalizations for the following reasons do not require reporting:  
o Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study or 
o 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 adverse event severity grading scale for the NCI CTCAE v 5.0 Update current 
versions) will be used for assessing adverse event severity. Below Table should 
be used for assessing severity for adverse events that are not specifically listed 
in the NCI CTCAE. 
 
 
 
 
 
 
 
 
 
 
 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 30 of 47 
Protocol v3.0 dated 10/05/2023 
 
 
 
Adverse Event Severity Grading Scale for Events Not Specifically Listed in NCI CTCAE 
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 v 5,0 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 
 
5.4.3 
PREGNANCY 
If a female subject becomes pregnant while receiving the study drug or within 90 days 
after the last dose of study drug, or if the female partner of a male study subject 
becomes pregnant while the study subject is receiving the study drug or within 90 days 
after the last dose of study drug, a report should be completed and expeditiously 
submitted to Genentech, Inc. Follow-up to obtain the outcome of the pregnancy should 
also occur. Abortion, whether accidental, 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 the study drug 
should be reported as an SAE. 
 
5.4.4 
AEs OF SECIAL INTERESTS (AESIs) 
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. 
 
Adverse events of special interest for this study include the following:  


 
Xofluza—Weill Cornell Medical College                                                                                              Page 31 of 47 
Protocol v3.0 dated 10/05/2023 
• 
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: 
o 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. 
 
5.4.5 
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. 
 
5.4.7 
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 baloxavir 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 drug Safety 
during follow up period. 
 
5.4.8 
EXCHANGE OF SINGLE CASE REPORTS 
Weill Cornell Medical College 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. Weill Cornell Medical College will submit SAEs, AESIs, Special Situations, 
and any pregnancy to Genentech using the MedWatch Form. 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 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 32 of 47 
Protocol v3.0 dated 10/05/2023 
 
All Product Complaints without an AE should call via: 
PC Hotline Number: (800) 334-0290 (M-F: 5 am to 5 pm 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 
 
5.4.9 
CASE TRANSMISSION VERIFICATION OF SINGLE CASE REPORTS 
• 
The parties will verify that all single case reports have been adequately received 
by Genentech by emailing Genentech a Quarterly line-listing documenting single 
case reports sent to Genentech in the preceding time period.  
• 
The periodic line-listing will be exchanged within seven (7) calendar days of the 
end of the agreed time period. Confirmation of receipt should be received 
within the time period mutually agreed upon. 
• 
If discrepancies are identified, the Sponsor and Genentech will cooperate in 
resolving the discrepancies. The responsible individuals for each party shall 
handle the matter on a case-by-case basis until satisfactory resolution. The 
sponsor shall receive reconciliation guidance documents within the ‘Activation 
Package’. 
• 
Following Case Transmission Verification, single case reports which have not 
been received by Genentech shall be forwarded to Genentech within five (5) 
calendar days from request by Genentech. 
 
At the end of the study, a final cumulative Case Transmission Verification report will be 
sent to Genentech: ctvis_drugsafety@gene.com 
 
MEDWATCH 3500a REPORTING GUIDELINES 
In addition to completing appropriate patient demographic (Section A) and suspect 
medication information (Section 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 
 
Follow-Up Information 
• 
Additional information may be added to a previously submitted report by any of 
the following methods:  


 
Xofluza—Weill Cornell Medical College                                                                                              Page 33 of 47 
Protocol v3.0 dated 10/05/2023 
o Adding to the original MedWatch 3500A report and submitting it as 
follow-up 
o Adding supplemental summary information and submitting it as follow-
up with the original MedWatch 3500A form 
o Summarizing new information and faxing it with a cover letter including 
patient identifiers (i.e. D.O.B. initial, 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) 
MedWatch 3500A (Mandatory Reporting) form is available at: 
https://www.fda.gov/media/69876/download 
 
 
5.4.10 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. WCMC, as the Sponsor of the Study, will be 
responsible for the expedited reporting of safety reports originating from the study to 
the EMA through Eudravigilance Clinical Trial Module (EVCTM), where applicable. 
 
WCMC will be responsible for the expedited reporting of safety reports originating from 
the Study to the Ethics Committees and Institutional Review Boards (IRB), where 
applicable. 
 
WCMC 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 
WCMC will be responsible for the distribution of safety information to its own 
investigators, where relevant, in accordance with local regulations. 
 
5.4.11 AGGREGATED REPORTS 
 
 
 
 
 
Development Safety Update Reports 
WCMC as the Sponsor of the Study, will be responsible for the preparation of their own 
Development Safety Update Report (DSUR) for the Study and for the submission of the 
report to the regulatory authorities and Ethics Committees of the concerned Member 
States, where applicable. WCMC agrees to share a copy of their own DSUR with 
Genentech as soon as reasonably possible after completion. 
 
Genentech agrees to forward to WCMC an executive summary of the Genentech DSUR 
upon request. Furthermore, Genentech agrees that WCMC may cross-reference the 
executive summary of the Genentech DSUR, as applicable. 
 
Other Reports 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 34 of 47 
Protocol v3.0 dated 10/05/2023 
WCMC will forward a copy of the Publication to Genentech upon completion of the 
Study.  
 
5.4.12 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: 
 
 
Ron Obmaces 
obmaces.ronald@gene.com 
 
And to Genentech Drug Safety CTV oversight mail box at: ctvist_drugsafety@gene.com 
 
Queries 
Queries related to the Study will be answered by WCMC. However, responses to all 
safety queries from regulatory authorities 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. WCMC 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 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. 
 
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 WCMC, as Sponsor of the 
Study, will be primarily responsible for assessment of the benefit-risk balance of the 
Study. 
 
If WCMC 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 Roche within five (5) business days of its internal approval. 
 
As needed, Genentech will reasonably assist WCMC with signal and risk management 
activities related to the Product within the Study. 
 
Genentech will also provide WCMC with any new relevant information that may modify 
or supplement known data regarding the Product (e.g., relevant Dear Investigator 
Letter).  
 
Compliance with Pharmacovigilance Agreement / Audit 
The Parties shall follow their own procedures for adherence to AE reporting timelines. 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 35 of 47 
Protocol v3.0 dated 10/05/2023 
 
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 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. 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 36 of 47 
Protocol v3.0 dated 10/05/2023 
STATISTICAL CONSIDERATIONS  
The study plans to enroll a total of 30 allogeneic bone marrow transplant patients who will be 
randomized at 1:1 to the two study arms. The primary endpoint data will be analyzed on the basis of 
a modified intention-to-treat (ITT) principle for patients with viral loads measurements at both the 
baseline and day 10.  
For the first co-primary objective, the effects of the study drugs will be evaluated separately for 
each study arm by estimating the change in viral RNA loads from baseline (day1) at the end of 
treatment (day10) as measured by qRT-PCR. Summary statistics including mean, standard deviation, 
median and range of the primary endpoints will be calculated for each arm. Difference in log 
transformed viral RNA loads measuremed at the end of treatment and at baseline will be evaluated 
using paired t-test or the Wilcoxon signed rank test for each arm separately. For the second co-
primary endpoint, efficacy of the baloxavir + oseltamivir will be assessed through estimating the 
differences in the magnitude of change in viral RNA loads from baseline at the end of treatment 
between the two treatment arms along with the 95% confidence intervals. Given the pilot nature of 
the study, the sample size is primarily based on feasibility and logistic considerations. However, 
based on prior studies [ref: Infect Dis Ther (2019) 8:613–626], the expected baseline viral RNA loads 
for the immunocompromised patients would be around 6.5 log10 vp/mL with standard deviation 
around 3 log10 vp/mL. With 15 patients in a study arm, we would have 80% power to detect a 
difference of 2.33 log10 vp/mL in viral RNA loads at the end of treatment vs. at the baseline 
assuming similar level of standard deviation at the end of treatment with a two-sided 0.05 
significance level using a paired t-test. We expect to have adequate power to detect this level of 
change for both the study arms since prior study has observed a decrease of at least 3 log10 vp/mL 
with Oseltamivir alone in immune compromised patients [ref: Infect Dis Ther (2019) 8:613–626]. For 
the second co-primary endpoint, i.e., the between arm differences in change in viral loads, 15 
patients per arm will allow 80% power to detect effects size as small as 1.1 standard deviation at a 
two-sided 0.05 significance level. It is likely the study is under-powered but is expected to generate 
meaningful preliminary efficacy data [Machin, D, Campbell, M.J., Tan, S.B, Tan, S.H. 2018. 'Sample 
Sizes for Clinical, Laboratory and Epidemiology Studies, Fourth Edition', Chapter 16. John Wiley and 
Sons. Hoboken, New Jersey.].     
For secondary viral loads related endpoints, summary statistics in terms of mean, standard 
deviation, median and range will be calculated for each arm at each time points among patients 
with relevant measurements. Longitudinal analyses using mixed effects repeated measures will be 
used to model the mean viral loads overall time. Contrasts of interest including between arm 
differences will be explored using simultaneous tests of general linear hypotheses. If normality is a 
concern, log-transformed and standardized viral load data will be used. Longitudinal analysis will be 
carried out among patients with at least one relevant viral load measurement. Kaplan-Meier 
estimates will be generated for time to events endpoints such as time to Improvement of Individual 
Influenza Symptoms, the time to viral clearance and time to return to preinfluenza health status for 
each study arm.  Between study arm difference in these endpoints will be explored using the 
generalized Wilcoxon test.  
Categorical data such as the occurrence of treatment-emergent variants of neuraminidase and 
polymerase by direct next-generation sequencing and AE’s will be summarized in terms of counts 
and proportions separately for each arm.  


 
Xofluza—Weill Cornell Medical College                                                                                              Page 37 of 47 
Protocol v3.0 dated 10/05/2023 
Between arm difference in the categorical variable will be explored using Fisher’s exact test.  The 
study is likely will not have adequate power to detect between arm differences and all the between 
arms comparisons are considered exploratory. Summary statistics generated for study endpoints for 
each arm will provide useful information for planning future studies.  
The power calculations were performed using PASS 15 Power Analysis and Sample Size Software 
(2017). NCSS, LLC. Kaysville, Utah, USA, ncss.com/software/pass. All comparisons will be two-tailed, 
with a significance level at 0.05 and 95% confidence intervals will also be reported. All analyses will 
be performed in SAS Version 9.4 (2019), SAS Institute, Inc., Cary, NC; and R  Version 4.0.4 (2021).  
Note: The statistical considerations section was written by Kaylee Ho, MS, and revised by Xi Kathy 
Zhou, PhD, in the Division of Biostatistics, Department of Population Health Sciences, Weill Cornell 
Medicine. 
Influenza sequence analysis will be performed by Elodie Ghedin, Director of 
Systems Genomics Section at the Laboratory of Parasitic Diseases of NIAID/NIH and expert in 
Influenza evolution. 
No interim analysis is planned for this study 
 
6.1 EXPLORATORY ENDPOINTS 
Non-invasive methods for monitoring health-related biomarkers in liquids such as plasma 
(“liquid biopsy”) have already been successfully introduced in a wide range of contexts. cfDNA is 
extremely dynamic and responsive, providing strong indicators of immune response or infection, 
also revealing the cells of origin undergoing apoptosis or necrosis. We will profile cfDNA isolated 
from plasma samples before, during, and after influenza therapy to evaluate the utility of cfDNA 
as a means to monitor damage caused by viral infection as response to therapy. cfDNA analysis 
will be performed by our collaborator Iwijn De Vladmick 
 
5.2 METHOD OF ANALYSIS 
Plasma from patients of each arm was centrifuged at 16,000 g for 10 minutes. cfDNA extraction 
will be performed according to manufacturer recommendations (QIAGEN MinElute Circulating 
Nucleic Acid Kit, reference #55204 or QIAGEN EZ1 Virus Mini Kit v2.0 955134) at 0.4-1 mL 
plasma input. DNA sequencing of bisulfite-treated cfDNA will be used to reveal methylation 
patterns with single nucleotide resolution. Because these patterns are cell, tissue, and organ 
types specific, they can inform the origins of cfDNA. Levels of cdDNA and tissue of origins will be 
compared for patients in each arm begore during and after therapy as described(Bezdan, 
Grigorev et al. 2020) 
 
6. INVESTIGATOR REQUIREMENTS 
 
7.1 RETENTION OF RECORDS 
FDA regulations (21 CFR §312.62[c]) and the 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. 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 38 of 47 
Protocol v3.0 dated 10/05/2023 
 
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. 
 
6.2 STUDY MEDICAL MONITORING REQUIREMENTS 
This clinical research study will be monitored both internally by the PI and externally by the 
Weill Cornell Medicine IRB. In terms of internal review, the PI will continuously monitor and 
tabulate AEs. Appropriate reporting to the Weill Cornell Medicine 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. 
 
6.3 STUDY MEDICATION ACCOUNTABILITY 
The Sponsor Investigator of the study will ensure maintenance of complete and accurate 
records of the receipt, dispensation, and disposal or return of all study drug in accordance with 
21 Code of Federal Regulations (CFR), Part 312.57 and 312.62 and Genentech requirements. 
 
All unused remaining product at the end of the study should be disposed of at the study site 
according to institutional standard operating procedure. If there is no SOP at the site for drug 
destruction, return study drug with the Inventory of Returned Clinical Material form as directed 
by Genentech. 
 
6.4 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 inserted, initialed, and 
dated by the study coordinator or PI. All source documents will be available for inspection by 
the FDA and the Weill Cornell Medicine IRB. 
 
 
 
 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 39 of 47 
Protocol v3.0 dated 10/05/2023 
7. 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 
MPDL3280A 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.  
 
7.2 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.  
 
7.3 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 provided by Genentech (e.g., IND safety 
report, Investigator’s Brochure, safety amendments and updates, etc.). 
 
 
7.4 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. 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 40 of 47 
Protocol v3.0 dated 10/05/2023 
 
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. 
 
8. REFERENCES 
Burnham, P. Khush K., and De Vlaminck I., “Myriad applications of circulating cell-free DNA in precision 
organ transplant monitoring,” Ann. Am. Thorac. Soc., vol. 14, 2017. 
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. 
De Vlaminck I. et al., “Noninvasive monitoring of infection and rejection after lung transplantation,” 
Proc. Natl. Acad. Sci. , vol. 112, no. 43, pp. 13336–13341, Oct. 2015. 
De Vlaminck I. et al., “Circulating cell-free DNA enables noninvasive diagnosis of heart transplant 
rejection,” Sci. Transl. Med., vol. 6, no. 241, 2014. 
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. 
Fukao K, Ando Y, Noshi T, et al. Baloxavir marboxil, a novel cap-dependent endonuclease 
inhibitor potently suppresses influenza virus replication and represents therapeutic 
effects in both immunocompetent and immunocompromised mouse models. PLoS One 
2019;14:e0217307. (a) 
Fukao K, Noshi T, Yamamoto A, et al. Combination treatment with the cap-dependent 
endonuclease inhibitor baloxavir marboxil and a neuraminidase inhibitor in a mouse 
model of influenza A virus infection. J Antimicrob Chemother 2019;74:654-62. (b) 
Hayden FG, Sugaya N, Hirotsu N, et al. Baloxavir Marboxil for Uncomplicated Influenza in 
Adults and Adolescents. N Engl J Med 2018;379:913-23. 
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  
 
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. 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 41 of 47 
Protocol v3.0 dated 10/05/2023 
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.  
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.  
Royal College of Physicians. National early warning score (NEWS) 2 Standardising the assessment of 
acute-illness severity in the NHS. London: RCP, 2017. 
Salvatore M, Laplante JM, Soave R, Orfali N, Plate M, van Besien K, St George K. Baloxavir for the 
treatment of Influenza in allogeneic hematopoietic stem cell transplant recipients previously 
treated with oseltamivir. Transpl Infect Dis. 2020 Aug;22(4):e13336. doi: 10.1111/tid.13336. 
Epub 2020 Jun 10. PMID: 32449254. 
Taniguchi K, Ando Y, Nobori H, et al. Inhibition of avian-origin influenza A(H7N9) virus by the 
novel cap-dependent endonuclease inhibitor baloxavir marboxil. Sci Rep 2019;9:3466. 
 
 
 
 
 
 
 
 
 
 
 
 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 42 of 47 
Protocol v3.0 dated 10/05/2023 
Appendix 1 - Study Flowchart 
 
Day(s) 
D1 
D2a 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
 
 
D10 
D11 – 
D14 
D15b 
 
 
EOS 
D30b,c 
Unsched Visit 
 On-site study visit 
x 
(x) 
x 
 
x 
 
 
x 
 
x 
x 
 
Phone Visit  
 
x 
x 
 
 
x 
x 
 
 
x 
 
x 
 
 
 
 
 
Screening  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent and assent  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization d 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication monitoring 
x 
 
 
x 
 
 
x 
 
 
x 
 
x 
x 
x 
Physical examination e 
x e 
 
x 
 
x 
 
 
x 
 
 
x 
 
x f 
xf 
x g 
Body weight 
x 
 
 
 
 
 
 
 
 
 
 
 
xf 
 
 
Vital sign measurementsh 
x 
 
Daily through Day 10 
 
xf 
xf 
x g 
Presence or absence of respiratory 
supporti 
x 
 
x 
 
x 
 
 
x 
 
 
x 
 
xf 
xf 
x g 
Blood hematology and chemistryj, 
x 
 
 
 
x f 
 
 
x 
 
 
x 
 
x f 
x f 
x g 
Blood liver chemistryk 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
x f 
x f 
 
Blood for exploratory biomarkers 
x 
x 
 
x 
 
 
x 
 
 
x 
 
x 
x 
 
NP swabl 
x 
x 
 
x 
 
 
x 
 
 
x 
 
x 
x 
x a 
Chest X-ray/CT Scanm 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 43 of 47 
Protocol v3.0 dated 10/05/2023 
Day(s) 
D1 
D2a 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
 
 
D10 
D11 – 
D14 
D15b 
 
 
EOS 
D30b,c 
Unsched Visit 
 On-site study visit 
x 
(x) 
x 
 
x 
 
 
x 
 
x 
x 
 
Phone Visit  
 
x 
x 
 
 
x 
x 
 
 
x 
 
x 
 
 
 
 
 
Pregnancy testn 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
x 
 
x 
 
 
x 
 
 
x 
 
x 
x 
x 
Patient self assessmento 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Xofluza/Placebo p 
x 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
NAI SOC (Oseltamivir) q 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
CT = computed tomography; D = day; EOS = end of study; Hosp = Hospitalized; NAI = neuraminidase inhibitor; Random =Randomization; 
RIDT = Rapid 
Influenza 
Diagnostic 
Test; 
RT-PCR = reverse 
transcription 
polymerase 
chain 
reaction; 
SOC = standard-of-care; 
Unsched = Unscheduled; V = visit; VHP = Voluntary Harmonization Procedure. 
a. 
Optional visit  
b. 
A visit window of  2 days applicable.  
c. 
The EOS visit should occur approximately 20 days after the last dose of study drug. 
d. 
Randomization should occur as soon as possible, after screening and informed consent. 
e. 
A complete physical examination should be conducted at screening. At post baseline visits and as clinically indicated, limited, symptom directed 
physical examinations should be performed.  
f. 
Clinical procedures may be undertaken at investigator’s discretion if symptoms and signs persist beyond the treatment period or if viral shedding 
is detected beyond Day 10. 
g. 
Perform assessments at any unscheduled visits based upon clinician’s discretion. 
h. 
During the study treatment period (Day 1/Visit 1 to Day 10), all vital sign measurements (i.e., respiratory rate, pulse rate, peripheral oxygen 
saturation, systolic and diastolic blood pressures, and body temperature) should be recorded when on-site. For all other visits, the only vital 
signs measurement taken will be temperature. After day 10 vital sign measurements and specific assessments are to be recorded at the 
investigators’ discretion (e.g., if symptoms and signs persist during follow-up). 
i. 
Presence or absence and type of respiratory support; oxygen saturation. 
j. 
See Section X for tests included in laboratory panels. 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 44 of 47 
Protocol v3.0 dated 10/05/2023 
k. 
Liver function test results to be reviewed by the investigator before Xofluza, or its matching placebo, is administered. On Day 1, prior blood 
results if tests conducted within 24 hours prior to screening. On Day 4 and day 7, blood liver chemistry panel should be reviewed before the 
patient will receive Xofluza or matching placebo on this study day. 
l. 
Nasopharyngeal swabs for RT-PCR: RT-PCR for influenza and covid-19 should be performed at screening.  
m. If a chest X-ray has not been taken within the 24 hours prior to screening, it will be performed per clinical provider decision. If the SOC is a chest 
CT scan, this can be used as alternative to the chest X-ray per clinical provider decision. 
n. 
All women of childbearing potential will have a pregnancy test at screening (urine or serum).  
o. 
Self-assessment of seven influenza-associated symptoms (cough, sore throat, headache, nasal congestion, feverishness or chills, muscle or joint 
pain, and fatigue) on a four-point scale (with 0 indicating no symptoms, 1 mild symptoms, 2 moderate symptoms, and 3 severe symptoms) 
twice daily from enrolment (day 1) until day 9 and once daily on days 10–15, and record their results in the patient diary. 
p. 
Baloxavir treatment or Baloxavir-matched placebo dosing will occur on Day 1 and Day 4, with a further dose at Day 7  
q. 
The SOC NAI (Oseltamivir) will be administered from Day 1 through Day 10.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 45 of 47 
Protocol v3.0 dated 10/05/2023 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 46 of 47 
Protocol v3.0 dated 10/05/2023 
 


 
Xofluza—Weill Cornell Medical College                                                                                              Page 47 of 47 
Protocol v3.0 dated 10/05/2023