Clinical trial NCT04141930
Conditions: Influenza Respiratory Viral Infection
Keywords: influenza flu antiviral baloxavir Xofluza rapid delivery self-test
Sponsor: University of Washington
Start date: 2019-11-01; Completion date: 2020-04-01
Enrollment: 481 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will evaluate a home-based approach to influenza infection control, using prepositioned home-based influenza self-test kits, telemedicine services, and rapid delivery of Xofluza (Baloxavir marboxil) for administration within 48 hours of symptom onset.

Detailed description:
Households represent an important location for transmission of influenza. Rapid delivery of Xofluza may reduce household exposures to influenza among susceptible individuals.This study is a pilot study of a home-based approach to influenza infection control, utilizing self-test kits and rapid home delivery of an antiviral. Households with at least 3 individuals residing there at least 4 days a week, including at least 2 household members that are eligible to take antiviral, will be monitored throughout the influenza season for the onset of a cough or two or more acute respiratory infection symptoms. This study will be conducted in households in the Seattle, WA area for one influenza season, beginning November 1, 2019 and ending April 1, 2020. Household will self-monitor for onset of symptoms throughout the influenza season. When symptoms develop, the participant will self-test for influenza infection using a prepositioned home-testing kit. If negative, the ill participant will provide one self-collected nasal swab specimen. If positive, the ill participant will connect with a healthcare provider via the tele-health app on their smartphone to confirm the influenza diagnosis. Next, if eligible to receive Xofluza, the influenza-positive individual will receive a rapid home delivery of Xofluza within 2-6 hours of the positive test result. All influenza-positive participants will provide a self-collected nasal swab specimen at Study Day 0, Study Day 2-3, and Study Day 5-7. For all illness episodes, the ill individual will complete a questionnaire regarding symptom duration and severity, as well as behavioral changes due to illness.

Arms: arm 1: Baloxavir given in 40 mg and 80 mg tablets for single-dose oral consumption during the first influenza infection for that participant
Interventions: intervention 1: Baloxavir Marboxil
Intervention descriptions: intervention 1: Individuals willing and able, will receive a weight-based oral dose of baloxavir within 48 hours of symptom onset

Protocol documents:
Prot_000.pdf: 
1 
 
 
Title: Pilot of a Cohort of Households for Influenza Monitoring and Evaluation in Seattle 
(pCHIMES) 
 
Home-based testing and administration of baloxavir within 48 hours of influenza 
diagnosis in Seattle, WA 
 
Protocol version: 3.1  
Date updated: January 14, 2020 
 
Funding: Anonymous 
 
Trial Sponsor: University of Washington 
 
Role of funders and sponsors: 
The funders and sponsors had no role in design of this study.  
 
Summary 
Background: Households represent an important location for transmission of influenza. Rapid 
delivery of antiviral may reduce household exposures to influenza among susceptible 
individuals. 
Design: This study is a pilot study of a home-based approach to influenza infection control, 
utilizing self-test kits and rapid home delivery of baloxavir (BXM).  
Population: Households with at least 3 individuals residing there at least 4 days a week, 
including at least 2 household members that are eligible to take BXM, will be monitored 
throughout the influenza season for the onset of a cough.  
Study size and duration: This study will be conducted in 250 households in the Seattle, WA 
area for one influenza season, beginning November 1, 2019 and ending May 1, 2020.  
Intervention: Household will self-monitor for onset of a cough or 2 or more respiratory 
symptoms throughout the influenza season. When symptoms develop in a study participant, the 
participant will self-test for influenza infection using a prepositioned home-testing kit, as well as 
collect a separate nasal swab specimen at Study Day 0. Additionally, if eligible, the sick 
participant will connect with a healthcare provider via the 98point6 app on their smartphone to 
discuss their respiratory symptoms, and the provider will determine whether antiviral treatment 
is appropriate. If determined to be a probable influenza illness, the individual will receive a rapid 
home delivery of BXM, and the ill participant will provide a self-collected nasal swab specimen 
Study Day 2-3 and Study Day 5-7. For all illness episodes, the ill individual will complete a 
questionnaire regarding symptom duration and severity, as well as behavioral changes due to 
illness.  
Primary aim: Determine the percentage of drug-eligible, individuals with a diagnosed influenza 
infection who initiate antiviral therapy within 48 hours of symptom onset.  
Secondary arm: Determine the social and technical infrastructure that would be required to 
rapidly detect and interrupt influenza transmission at the household level; determine whether a 
home-based self-test and antiviral delivery strategy would be feasible in the context of a 
pandemic; and assess the prevalence of antiviral resistance in post-treatment nasal swab 
specimens.  
 
 
 
 
 


2 
 
 
I. 
Background 
Acute respiratory infections (ARIs) are a major cause of morbidity worldwide.1 In the United 
States, the estimated annual economic burden of influenza to the healthcare system and society 
is $11.2 billion ($6.3-$25.3 billion), and the Centers for Disease Control and Prevention (CDC) 
estimates that influenza has resulted in 140,000-960,000 hospitalizations and 12,000-79,000 
deaths annually since 2010.2,3 Current influenza prevention and treatment options available to 
the general population include seasonal vaccination and antivirals for both treatment and 
prophylaxis. Despite these options, lack of durable immunity and variable influenza vaccine 
effectiveness contribute to large-scale epidemics each season.4-6 This highlights a need for 
additional evidence-based prevention and treatment strategies to increase preparedness.   
 
Current Antiviral Receipt Process: Traditionally, influenza infection is diagnosed during a 
clinic visit and if antiviral treatment is prescribed, a subsequent visit to a pharmacy to receive 
the antivirals is required. This multi-step process leads to delays in receipt of antivirals and 
potentially exposes other individuals in clinics and pharmacies to influenza. This practice is 
problematic since viral shedding occurs during this time frame, and it is well-established that 
antiviral therapy is most effective when started within 48 hours of symptom onset.7-12 
Additionally, this process may deter individuals from seeking care and thus further the spread of 
influenza within households and communities.  
 
Household Transmission: Households play a key role in the overall spread of influenza 
because the frequency and intensity of contacts between household members are greater than 
contacts that occur within the broader community.13 Historically, household studies aimed to 
provide information on age-specific incidence and characteristics of respiratory infections; 
however, newer laboratory methods make it possible to define illness etiology and better 
understand household transmission dynamics.14-17 It is estimated that approximately 1/3 of all 
influenza transmissions occur within households.14 Therefore, the household represents an 
important point for intervention or control strategies to decrease influenza spread, particularly 
during a pandemic.  
 
Previous studies that focused on the use of antivirals like zanamivir and oseltamivir to block 
influenza transmission between household members found this strategy efficacious or effective, 
though efficacy and effectiveness varied by study design, type of antiviral used, and time from 
symptom onset to start of antiviral therapy.18-23 A small number of studies report insignificant 
results for antiviral use in stopping secondary influenza transmission, though these studies had 
small sample sizes and may have lacked the statistical power necessary to identify an effect on 
transmission.24,25 Additionally, the randomized controlled trials conducted in households for 
zanamivir and oseltamivir are limited in that antivirals were used for treatment and prophylaxis 
or just prophylaxis, making it difficult to clearly define to role of antiviral use in ill individuals.18-21 
Furthermore, this combined strategy for treatment and prophylaxis may contribute to increased 
levels of antiviral resistance and may not be practical in pandemic situations when drug supplies 
are limited.   
 
Antiviral Treatment: Home-based influenza self-testing and subsequent rapid treatment with 
antivirals has not been previously evaluated in antiviral clinical trials. Home-based start of 
antivirals has the potential to decrease exposure risk in the community and decrease time from 
symptom start to initiation of therapy, thereby decreasing illness duration and risk of 
transmission to other household members. Current advances in technology, including tele-
medicine services (tele-health) and rapid 1-2 hour delivery services (Amazon Now, Uber, Lyft, 
FedEx), make this strategy feasible to study.   
    


3 
 
 
Baloxavir (BXM) is a single dose oral agent licensed for treatment of influenza for individuals 
aged 12 years and older. Unlike oseltamivir, a neuraminidase inhibitor, BXM functions as a cap-
dependent endonuclease inhibitor and prevents influenza genome synthesis. In a phase III 
randomized controlled trial, BXM showed equivalence to oseltamivir in time to alleviation of 
influenza symptoms.26 Additionally, BXM was associated with significantly lower infectious viral 
titer one day after initiation as well as reductions in viral RNA loads and shorter median duration 
of virus detection compared to both oseltamivir and placebo. Furthermore, initial findings from a 
phase IIIb clinical efficacy study report that household contacts of index patients who were given 
BXM were significantly less likely to develop influenza relative to household contacts of index 
patients who were given placebo (1.9% vs 13.6%), despite a wide-range of times to initiation of 
therapy.27 Therefore, in contrast to other antiviral medications, BXM may be better suited to stop 
person-to-person transmission.  
 
The present study seeks to use a home-based approach to influenza infection, utilizing self-
testing and rapid household delivery of BXM within 48 hours of symptom onset to treat cases of 
probable influenza. We aim to study the feasibility of this strategy to better understand the social 
and technical infrastructure required to rapidly detect and interrupt influenza transmission at the 
household level to increase pandemic preparedness. 
 
Equipoise: There remain important unanswered questions regarding the usability of influenza 
self-tests, transmission dynamics, and antiviral resistance in households. It is established that 
the likelihood of infection following an exposure in the household is greater than the likelihood of 
infection following an exposure in the community due to differences in the frequency and 
intensity of contacts.13 However, the feasibility of a home-based strategy where individuals self-
test and rapidly receive antiviral therapy within 48 hours of symptom onset remains unknown. 
Likewise, the impact of this strategy on community transmission dynamics is unknown, but it is 
anticipated that this study will provide valuable knowledge and insights for citywide pandemic 
preparedness given that the current process for antiviral receipt remains problematic. Therefore, 
there is an unmet need to evaluate the feasibility of home-based approach to influenza infection.   
 
II. 
Study design 
This is a pilot study that will evaluate the feasibility of a home-based approach to influenza 
infection for households in the Seattle, WA area, utilizing an influenza self-test, followed by 
telehealth consultation for diagnosis and rapid home delivery of antivirals. Households with 3 or 
more of the same members at least 4 days per calendar week will be eligible to enroll, as long 
as there are at least 2 members in household eligible to take BXM. Individuals 12 years or older, 
weighing at least 40 kg, will eligible to take BXM, and thus, are able to enroll as drug eligible 
participants. Individuals that are not able to take BXM will be able to enroll in the study as drug 
ineligible participants. Individuals within an eligible household will be enrolled prior to or during 
the annual influenza season and monitored throughout the influenza season for the 
development of a cough or 2 or more respiratory symptoms. If a drug ineligible study participant, 
meaning a household member who does not meet BXM criteria, develops symptoms, they will 
use an influenza self-test; however, regardless of the result, they will not be able to receive 
BXM. Nevertheless, the drug ineligible study participant will provide one self-collected or 
parent/permanent legal guardian-collected nasal swab specimen that will be mailed back to the 
laboratory for further testing.  
 
If a drug eligible study participant in the household develops a cough or 2 or more respiratory 
symptoms, he/she will use a prepositioned influenza self-test kit as soon as possible. 
Additionally, the individual will connect with a healthcare provider through the 98point6 app to 


4 
 
 
review the participant’s medical information and provide an influenza diagnosis based on clinical 
judgement. If probable influenza is diagnosed, the 98point6 provider will confirm that antiviral 
treatment is appropriate. If appropriate, drug eligible study participant will subsequently receive 
a single dose of BXM delivered to their household via rapid delivery service for therapy initiation 
within 48 hours of symptom onset. Concurrently, the ill individual will collect a Study Day 0 nasal 
swab sample that will be mailed back to the laboratory for further testing. Additional nasal swabs 
will be collected at Study Day 2-3 and Study Day 5-7. If influenza is not diagnosed, the ill 
individual will provide one self-collected or parent/permanent legal guardian-collected nasal 
swab specimen that will be mailed back to the laboratory for further testing, and the household 
will remain enrolled and all study participants in the household will continue to self-monitor for 
presence of symptoms. Once an eligible study participant receives BXM, no additional 
household members will be eligible to receive BXM; the household will be able to continue 
monitoring for onset of symptoms, as well as self-testing and swabbing when symptoms 
develops, but the household will no longer be able to receive BXM delivery.      
 
Figure 1. Study schema  
 
 


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Symptom Table  
Feeling Feverish 
Muscle or Body Aches 
Headache 
Rash 
Sore Throat or Itchy/Scratchy Nose 
Runny/stuffy nose  
Feeling More Tired Than Usual 
Muscle or body aches 
Nausea or Vomiting 
Increased trouble with breathing 
Ear Pain or Ear Discharge 
Diarrhea  
 
The study is being conducted in the Seattle, WA area over one influenza season. The goal is to 
have 250 households comply with full study procedures. Of these, 25% are estimated to have 
an individual in the household diagnosed with influenza based on estimates from previous 
household studies.23, 28-29 
A table for influenza attack rates by household size is provided below. 
 
Household 
attack rate 
Total 
households 
enrolled 
Primary 
cases 
Secondary cases 
(mean household 
size 5) 
Secondary cases 
(mean household 
size 4) 
Secondary cases 
(mean household 
size 3) 
25% 
250 
63 45-96 
34-72 
23-48 
20% 
250 
50 36-76 
27-57 
18-38 
10% 
250 
25 18-38 
14-29 
9-19 
Mean household size includes case.  
Secondary attack rate 18-38%, secondary cases presented as a range based on these high and low 
bounds.30-32  
  
 
The University of Washington is the sponsor of the study which is supported by an anonymous 
funder who does not have any ownership over the management and conduct of the study, the 
data, or the rights to publish.  
 
III. 
Objectives 
The objective of the study is to measure the proportion of individuals who are initiated on 
antiviral therapy within 48 hours of symptom onset using a home-based self-test, followed by a  
telehealth consultation to diagnose influenza and home delivery of antivirals 
 
Primary Outcome Measures 
The primary outcome measure will be the proportion of eligible individuals who initiate antiviral 
therapy at home within 48 hours of symptom onset utilizing a home-based test and the tele-
health app for influenza diagnosis and rapid home-delivery of antivirals. It will be calculated 
using binomial regression with log link, where the number of drug eligible influenza-diagnosed 
individuals, defined as the number of individuals eligible to receive BXM with both self-test 
positive influenza and laboratory-confirmed influenza, reporting administration of the study drug 
within 48 hours of symptom onset is divided by the total number of drug eligible individuals with 
both self-test positive influenza and laboratory-confirmed influenza.  


6 
 
 
 
Secondary endpoints: 
• 
Proportion of individuals who test positive for influenza using the home-based test within 48 
hours of symptom onset  
• 
Proportion of individuals with a positive home-based influenza self-test who have a positive 
test confirmed by the central laboratory 
• 
Sensitivity and specificity of a self-test compared to a laboratory-based molecular influenza 
test 
• 
Proportion of individuals who are delivered antivirals within 48 hours of symptom onset 
• 
Proportion of individuals who self-report administration antiviral therapy within 48 hours of 
symptom onset 
• 
Symptom duration and severity among drug eligible and drug ineligible influenza-positive 
individuals 
• 
Proportion of families with influenza infection diagnosed within 7 days of an index case 
(another influenza-positive household member) 
• 
Viral quantity and duration of viral RNA detection among drug eligible and drug ineligible 
influenza-positive participants  
• 
Proportion of drug ineligible study participants seeking medical care for respiratory 
illness  symptoms 
• 
Proportion of individuals who choose to take a self-test among those who are eligible to take 
a self-test 
• 
Within-host variation in influenza strains between the first and the third viral swab 
• 
Cost effectiveness, assessed using health resource utilization (visit to clinic, hospital, 
pharmacy, emergency department) and school and work absenteeism 
• 
Proportion with antiviral resistance, assessed by genetic sequencing of influenza strains 
from the drug eligible and drug ineligible study participants  
 
Hypothesis 
Primary hypothesis: 
● A home-based approach to influenza infection control will result in a large percentage of 
drug eligible individuals diagnosed with influenza initiating antiviral therapy within 48 
hours of symptom onset.  
 
Secondary hypotheses:   
● Home-based approach to influenza infection control and rapid delivery of antiviral 
therapy will decrease symptom severity in the drug eligible individuals diagnosed with 
influenza that administer antiviral therapy within 48 hours of symptom onset compared to 
drug eligible, influenza-infected individuals that administer antiviral therapy greater than 
48 hours after symptom onset.  
● Home-based approach to influenza infection control and rapid delivery of antiviral 
therapy will decrease the duration of viral RNA detection in the drug eligible, influenza-
infected individuals that administer antiviral therapy within 48 hours of symptom onset 
compared to drug eligible, influenza-infected individuals that administer antiviral therapy 
greater than 48 hours after symptom onset.  
 
IV. 
Study Population  
The study will be conducted in households with at least 3 members, where at least 2 of these 
members must be eligible to receive BXM, in the Seattle area. Participants aged 12 years or 
older, weighing at least 40 kg, will be drug eligible. Participants of any age that reside in the 
same household as the case at least 4 days per calendar week will be drug ineligible study 
participants. Drug eligible study participants will receive baloxavir intervention when appropriate, 


7 
 
 
and all drug eligible and drug ineligible participants will receive a 7-day follow-up from the study 
team per illness episode.    
 
Study size 
The study is being conducted in the Seattle, WA area over one influenza season. The goal is to 
enroll 250 households, with enrollment occurring prior to and during the annual influenza 
season.  
 
Household enrollment criteria 
The household must meet all the following enrollment criteria: 
 
Household inclusion criteria 
● Group of at least 3 individuals of any ages defined as at least 3 persons residing at the 
same address for at least 4 days per calendar week  
● Household group utilizes common household areas  
● At least 2 household members meeting all individual inclusion/exclusion criteria listed below 
and willing to participate (e.g. at least two members of the household are 12 years of age or 
older) 
● At least one member of the household has a smartphone  
 
Household exclusion criteria 
Within eligible households, individuals meeting any of the following criteria will be excluded: 
● Previous documentation of an influenza infection prior to or during the annual influenza 
season in any household member prior to enrollment  
 
Study participants 
Inclusion criteria for eligible study participants include: 
 
Inclusion criteria for drug eligible study participants: 
● Resident of a household with 3 or more members (including eligible cases) for 4 or more 
days a calendar week 
● Age 12 years or older weighing at least 40 kg (greater than 88 pounds) 
● Willing and able to take study medication 
● Willing to comply with all study procedures  
● English-speaking 
● Able to provide written, informed consent and/or assent (if applicable)  
● Permanent mailing address that is available for study staff to mail necessary materials  
 
Inclusion criteria for drug ineligible study participants: 
● Resident of a household with 3 or more members (including eligible cases) for 4 or more 
days a calendar week 
● Willing to comply with all study procedures  
● English-speaking 
● Able to provide written, informed consent and/or assent (if applicable)  
 
Exclusion criteria 
Individuals meeting any of the following criteria will be excluded from being drug-eligible, but 
may still participate in the study by submitting swabs: 


8 
 
 
● Any serious or uncontrolled medical disorder or active infection that, in the opinion of the 
investigator, may increase the risk associated with study participation or study drug 
administration 
● Individuals with hypersensitivity to baloxavir   
● Any individual that has one or more of the following conditions:  
o Pregnant 
o Currently lactating 
o Immunosuppressed or immunocompromised (by disease or medication)  
o Cancer  
o Liver disease 
o Kidney disease  
 
Individuals meeting the following criteria will be excluded from being drug-eligible, and will not 
participate in submitting swabs:  
● Age younger than 3 months   
 
Withdrawal criteria 
All household members and/or their parent or permanent legal guardians are free to withdraw 
from the study at any time. Household members can also withdraw from sample collection but 
allow continued collection of symptom data. Additionally, it is within the rights of the PI to 
withdraw any participant or household from participation in this study without their consent at 
her discretion.  
 
Additional consent concerns 
Staff enrolling households will verbally summarize the consent form for any participant who 
requests it either in-person or via telephone. If ability to provide consent or assent is a concern 
for any staffer when engaging a household member, the staff member will not enroll that 
individual.  
 
V. 
Study procedures 
 
Study Timeline 
The study will be conducted during one influenza season, defined in this study as November 1 
to May 1. Households will be eligible to enroll in the study prior to the start of the influenza 
season. Additionally, households that have not had a previously documented case of influenza 
during the season of proposed enrollment will be eligible to enroll during the annual influenza 
season.  
 
Recruitment and screening  
Recruitment of households will be conducted via media advertising campaigns directed at 
households with children. Strategies will include but are not limited to:  
● Web-based marketing (positioning of advertising on childcare sites such as care.com or 
WebMD.com) 
● Recruitment materials through an online portal on the overall Seattle Flu Study website 
(seattleflu.org) 
● Targeted recruitment materials sent by mail to households with children  
● Use of geolocation to target social messaging advertisements via Facebook or other sites to 
individuals at locations frequented by households with children (e.g. community centers, 
libraries, the zoo and aquarium) 
● Post flyers at public locations including community centers, libraries, and childcare facilities 


9 
 
 
 
Households will be screened for eligibility through a web-based portal via a standardized 
screening questionnaire to ensure that all individual and household inclusion and exclusion 
criteria are met. An additional screening over the phone or an in-person meeting with a member 
of the study team will also occur to ensure all individual and household inclusion and exclusion 
criteria are met.  
 
Obtaining Consent  
Consent will be obtained from an individual and their household members at time of enrollment 
by study staff only after a full explanation has been given, and time allowed for consideration 
and questions. This process will mainly occur over the phone with individuals consenting via 
REDCap questionnaires. Though for families unable or not willing to consent via REDCap, and 
in-person consent visit with the study team can be scheduled. Individuals under 18 years of age 
will have consent provided by their parent or legal guardian. In addition to consent by their legal 
guardian, study staff will attempt to obtain assent from individuals 7 to18 years of age when 
applicable. Following the consent process, all household members will receive a paper or 
electronic copy of the consent form.  
 
All subjects who consent to participate will also be asked to approve the storage of their 
biospecimens (nasal swabs).  Persons who consent to the study, but who do not want their 
biospecimens stored may still participate in the study.  Their biospecimens will be tested as per 
protocol, but the remaining aliquots will be destroyed once test results of sufficient quality are 
reported. 
 
Study Personnel 
Given the scale of this project and the necessity to collect data of the highest quality, an 
extensive organizational structure is necessary to ensure that adequate supervision is provided 
at all levels of organization. For this study, the organizational structure will fall into five 
categories: 
 
● Enrollment and Follow-up team: This team will be responsible for completing the 
screening and obtaining consent from all study participants. This team will be comprised 
of study staff who will be directly supervised by the research lead team. All members of 
the enrollment team will receive extensive training in the specifics of this protocol prior to 
the start of participant enrollment. Members of this group will be responsible creating the 
participant trainings (excluding the Ellume home-testing video) for this study. 
Additionally, members of this group will be responsible for going to the households when 
in-person training is requested. This team will also be responsible for sending the weekly 
reminders to households (see Weekly Monitoring section), and reviewing adverse event 
questionnaires to determine whether there is evidence of short-term reaction to the study 
drug.  
 
● Data management team: This team will be primarily responsible for checking the 
completeness and quality of the data being reported by study participants. This team will 
be comprised of study staff who have relevant data management experience and will be 
directly supervised by the research lead team. The additional responsibilities for this 
team include sending participant gift cards electronically, tracking the study drug, and 
maintaining the log of study drug delivery.      
 


10 
 
 
● Research Lead team: This team will be responsible for overseeing the enrollment and 
follow-up team and the data management team. The primary responsibilities for this 
team include overseeing the day to day operations of the study, working with the 
enrollment and follow-up team and the data management team, and answering 
questions from participants regarding the study. Additionally, this team will act as 
troubleshooters for any minor problems that come along during the course of the study. 
This team will also function as the daily supervisors for the study and will act as a link 
between the previous two teams and the medical expert team.  
 
● The Bedford team: Located at Fred Hutchinson Cancer Research Center, will 
contribute to the analysis of the data from this study through development and 
maintenance of a database to store study data (both survey and lab data), the 
production of this data into a “flu-map” of Seattle, which displays current influenza 
prevalence based on census tract, and a phylogenetic analysis of samples collected 
through the study (including genome assembly). As part of this, the Bedford team will 
have access to PHI such as participant address.  
 
● Medical expert team: This team will be composed of a study research nurse, as well as 
the principal investigator, co-principal investigators, and the study Safety Officer. This 
team will act as overall supervisors for the study, and as troubleshooters for any major 
problem that comes along during the course of the project. They will be responsible for 
dissemination of data to study partners, and will participate in the interviewing and hiring 
of personnel at all levels below them.  
 
All members of the study staff or research team have completed institution approved human 
subjects training. Additionally, for staff or research team members that interact directly with 
participants, Good Clinical Practice (GCP) training has been complete. This training as well as 
project-specific training will be required for any newly hired staff. This will involve presentations 
and discussions on the importance of voluntary participation, informed consent, confidentiality, 
data security, and sensitivity to the participants in the research. Quality control procedures will 
also be emphasized during the project-specific training and this training will be reviewed on a 
regular basis by study investigators.  
 
Individual and Household Enrollment Process  
 
1. Check eligibility: Individuals will be screened for eligibility over the phone, in-person, or 
through a web-based portal via a standard screening questionnaire to ensure that all 
individual and household inclusion criteria are met. Individuals or households that meet 
any of the exclusion criteria will not be eligible to participate in this study (See IV. Study 
Population section).  
 
2. Consent: If eligible, all household members will provide informed consent at the time of 
enrollment. For children, consent will be provided by their parent or permanent legal 
guardian and assent will be obtained by study staff as applicable. This process can also 
be done electronically (e-consent) (See Obtaining consent section).   
 
3. Enrollment Questionnaire: The household will then complete a REDCap survey that 
will collect information about the participants or household that is not expected to change 
for the duration of the study. Data collected on the enrollment questionnaire may include, 
but are not limited to, information about address and living situation, birthdate, past 


11 
 
 
medical history, health insurance, household structure, the preferred method of 
communication for the participant, and socioeconomic status.  
 
4. Participant Training: Following consent and completion of enrollment, all enrolled 
household members will watch informational videos or receive informational pamphlets 
regarding how to properly complete study tasks. These videos will be created by the 
study staff and will be available to participants via the Seattle Flu Study website during 
the study. However, households will have the option to request an in-person training by 
study staff on how to properly complete these tasks. Study participants will also be 
provided with a phone number and email address for the study where additional 
questions can be directed. A comprehensive list of the trainings each household must 
complete prior to being enrolled is provided below.  
 
● Nasal self-swab collection – pamphlet 
● Symptom monitoring logs – pamphlet  
● Illness questionnaire – pamphlet 
● Study drug information and risks – pamphlet  
● Ellume home-testing – video   
● tele-health app access – pamphlet  
 
During this time, households will also receive information regarding how and when they 
will receive their thank you gift cards.  
 
5. Receipt of standardized nasal swab kit and completion of baseline nasal swab kit: 
Via a delivery service, all enrolled households will receive two types of standardized 
nasal swab kits, one type that will be used to establish baseline health and the other 
type will be stored in their home until nasal swab collection is needed. For the 
standardized nasal swab kits that will be used following the onset of an acute cough or 
two or more respiratory symptoms. These kits will contain nasal swabs and standard 5 
mL tubes for the nasal swabs that contain universal transport media (UTM). The swabs 
will be collected via self-swab or parent/permanent legal guardian-swab. The number of 
swabs and tubes sent to each household will vary depending on the size of the 
household, but all kits will contain enough of these materials for non-drug-eligible study 
participants to collect a nasal swab following the development of an acute cough or two 
or more respiratory symptoms, for drug-eligible study participants to collect a nasal swab 
following an when influenza infection is not diagnosed,  and for drug-eligible participants 
to collect a nasal swab specimens at Study day 0, Study day 2-3, and Study day 5-7 
when influenza is diagnosed. Additionally, each kit will contain biohazard bags for 
packaging of each individual tube, larger plastic bags as well as absorbent sleeves for 
collective packaging of all nasal swab specimens at each time point. The standardized 
nasal swab kits will also contain pre-paid shipping labels and return boxes, which will 
allow the participants to mail the nasal swab specimens back to the laboratory the day of 
or the day after collection (as soon as possible). The baseline nasal swab kit will contain 
all the same materials as the standardized nasal swab kit but in a quantity of one.   
 
After completing the required study trainings, all household members, regardless of 
whether they are drug eligible, will provide a nasal swab sample, which will be collected 
by self-swab or parent/legal guardian-swab. These swabs will then be packaged and  
returned to the laboratory for storage and eventual testing. This process will be done as  
a trial run to ensure that participants will be able to successfully collect and return nasal  
swabs following a positive influenza self-test result and may help determine baseline  


12 
 
 
viral and bacterial nasal carriage for each participant.  
 
6. Receipt of a thermometer: Via a delivery service, all enrolled households will receive a 
standard digital thermometer as well as a supply of corresponding plastic probes, which 
can be used to orally measure participant body temperature throughout the study.  
 
7. Receipt of home-based influenza test: Via a delivery service, all enrolled households 
will receive influenza home-testing kits. The number of testing kits sent to the household 
will vary depending on the size of the household. The household will store these tests 
until the onset of a cough or two or more respiratory symptoms. All households will have 
access to the contact information for the study team, via phone number or email, which 
they will contact if they are in need of additional home-testing kits.  
 
8. Tele-health app access: All drug eligible study participants will download the tele-health 
app onto their smartphone. Next, drug eligible participants will register for an account 
with tele-health. Upon completing the enrollment questionnaire, the data management 
team will share participant information necessary for a tele-health account via a HIPAA 
compliant transfer method. This information includes participant and household study ID 
number, name, birthdate, age, sex, last four digits of social security number (SSN) for 
drug eligible adults, and address. This process will be done to ensure only drug eligible 
participants can register for a tele-health account. After registering for an account, drug 
eligible participants will follow the steps provided in the tele-health training pamphlet to 
ensure they understand how to connect with a tele-health provider. Drug eligible study 
participants will be able to use their tele-health account until 30 days after the conclusion 
of the study.  
 
 
Weekly Monitoring 
At the start of influenza season, defined in this study as November 1, pre-enrolled households 
will receive weekly reminders via text message, email, or phone call to complete their symptom 
monitoring logs regarding the presence or absence of cough or 2 or more respiratory symptoms. 
Additionally, households will be reminded to self-test for influenza as soon as symptoms 
develop in a member of the household. The household will complete a symptom monitoring log 
via REDCap online or text-message, regardless of age, for the duration of the influenza season 
(November 1-May 1). Once a household has a drug eligible participant who is diagnosed with 
probable influenza by a telehealth provider and that participant has received and administered 
BXM, weekly monitoring will still occur, but the household is no longer eligible to receive BXM 
delivery.    
 
For households that enroll during the influenza season, they will receive weekly reminders via 
text message, email, or phone call to complete their symptom monitoring logs starting the day of 
enrollment. These reminders will be identical to the reminders the pre-enrolled household 
receive. The household will complete a weekly symptom monitoring log via REDCap online or 
text-message, regardless of age, for the duration of the influenza season (November 1-May 1). 
Once a household has a drug eligible participant who is diagnosed with probable influenza by a 
telehealth provider and that participant has received and administered BXM, weekly monitoring 
will still occur, but the household is no longer eligible to receive BXM delivery.   
 
 
Onset of Symptoms  


13 
 
 
Immediately following the onset of an acute cough or 2 or more respiratory symptoms in a drug 
ineligible participant, the following procedures will occur: 
1. The participant will self-test for influenza using the prepositioned home-testing kit as long 
as the following criteria are met: 
● Symptom duration <48 hours 
● Cough present or 2 or more respiratory symptoms present  
2. The individual will provide a nasal swab specimen collected via self-swab or 
parent/permanent legal guardian-swab, which will be mailed back to the laboratory for 
testing and further characterization (See VI. Laboratory Procedures section).  
3. Next, the ill individual will complete day 0 of the illness questionnaire in REDCap, which 
will ask information about respiratory and systemic symptoms, recent travel history, and 
absenteeism.  
4. Additionally, one week later, the ill individual will complete day 7 of the illness 
questionnaire, which will ask information about respiratory and systemic symptoms, 
recent travel history, and absenteeism in 7 calendar days following the onset of a cough 
in the ill participant.  
 
Immediately following the onset of an acute cough or 2 or more respiratory symptoms in a drug 
eligible participant, the following procedures will occur:  
1. The person will self-test for influenza using the prepositioned home-testing kit as long as 
the following criteria are met: 
● Symptom duration <48 hours 
● Cough present or 2 or more respiratory symptoms present 
i. Qualification for receipt of study drug will be determined based on a 
review of medical information with the tele-health provider. If the 
individual meets the required criteria (symptom duration <48 hours) and is 
diagnosed with probable influenza by a healthcare provider, this will 
trigger subsequent delivery of the intervention, if deemed appropriate. 
2. Next, the ill individual will collect a nasal swab sample via self-swab or parent/legal 
guardian-swab as soon as possible. These specimens will then be packaged and 
shipping back to the laboratory via a delivery service for testing and further 
characterization. Additionally, the ill individual will complete day 0 of illness questionnaire 
in REDCap, which will ask information about respiratory and systemic symptoms, recent 
travel history, and absenteeism.  
3. Concurrently, the participant will connect with a provider via the tele-health app 
previously downloaded on their smartphone. The provider will review the participant’s 
symptoms and determine whether influenza infection is likely to be the underlying cause 
of the symptoms. If probable influenza is diagnosed, the tele-health provider will 
prescribe a weight-based dose of BXM. If antiviral treatment is not deemed appropriate 
by the tele-health provider, this information will be documented in the post-visit Care 
Plan for the study participant and subsequently shared with the study team. 
4. Next, the study pharmacy will be notified that the participant is being prescribed BXM.  
5. Following the prescription, the study pharmacist will dispense and package the BXM. 
Additionally, an informational hand out regarding the BXM dosing instructions will be 
included in this package. Furthermore, the individual will receive a post-visit Care Plan 
through the tele-health app, which will include reminders about the next steps for the 
study. 
6. Following packaging of the study drug, a rapid delivery service will be notified that the 
intervention is available for delivery.   


14 
 
 
7. Next, rapid delivery service will pick up the study drug and deliver it in-person to the 
household of the case.  
8. After delivery, the case will take the study drug and record the time of ingestion in the 
illness questionnaire in REDCap.  
 
Follow-up 
Following drug receipt, individuals will be screened 48 hours later to determine whether there is 
evidence of short-term reaction to the drug. Any short-term evidence reaction to the drug will be 
treated promptly by consultation with a member of the study medical expert team. In addition, 
the household will receive the contact information for a medical professional for follow-up 
questions after initiation of the intervention. Furthermore, the drug eligible participant will also be 
able to direct drug related questions to a tele-health provider via the tele-health app.     
 
All sick individuals, meaning those drug eligible and those drug ineligible, will complete an 
illness questionnaire in REDCap 7 days after they report the illness. This questionnaire will 
collect information on the presence or absence of respiratory and systemic symptoms during the 
7 days after reporting the illness. Data will also be collected on childcare, school, and work 
absenteeism, and subsequent visits to health care providers. Additionally, the influenza-
diagnosed individual will provide nasal swab specimens collected via self-swab or parent/legal 
guardian-swab at Study day 2-3 and Study day 5-7. These swabs will be returned to the 
laboratory via a delivery services the day of or the day after collection (See VI. Laboratory 
Procedures section).  In addition to the illness questionnaire, the drug eligible, influenza infected 
participant will complete a standard questionnaire at 7 and 14 days following study drug receipt 
to monitor for the occurrence of adverse events (AEs) or serious adverse events (SAEs). These 
questionnaires will be monitored by a member of the study team. Additionally, any provider 
consultations with tele-health following drug administration will be reported to the study team to 
monitor for the occurrence of adverse events (AEs) or (SAEs). Any reported adverse events will 
be assessed to determine if related to drug treatment and whether unexpected or not and 
subsequently reported to the IRB using a standardized AE and SAE form. After the self-
collected nasal swabs have been tested in the laboratory, the case will have to ability to view 
the results of their swab on the Seattle Flu Study website.  
 
For all individuals that provide nasal swab specimens for testing and further characterization, 
they will have the ability to view whether influenza or respiratory syncytial virus (RSV) was 
detected from their swab(s) on the Seattle Flu Study website (See VI. Laboratory Procedures).  
 
Data collection 
Data will be collected electronically in REDCap online via a computer or mobile device or 
through a text-message accessible app. The major data collection activities will occur at the 
following times (See Table 1).  
● At household enrollment, which can occur prior to and during the influenza season, 
the household will submit an enrollment questionnaire. This questionnaire will collect 
information that is not expected to change through the duration of the influenza season. 
Questions in the enrollment questionnaire may include information about address and 
living situation, birthdate, past medical history, health insurance, household structure, 
the preferred method of communication, and socioeconomic status. Additionally, at this 
time, informed consent will be obtained from each household participant willing to take 
part in the study, and the household will complete the required study training (see V. 
Study Procedures section). All eligible study participants in the household will also 
provide a baseline nasal swab specimen.          


15 
 
 
● On a weekly basis during the influenza season, the household will complete a 
symptom log where they will report on the occurrence of a cough or 2 or more 
respiratory symptoms in enrolled participants for that week in order to monitor for onset 
of new or worsening cough or two or more respiratory symptoms among study 
participants.  
● Monthly during the influenza season, the household will complete a questionnaire 
where they will report any changes to household structure or changes in influenza 
vaccine status for participating household members.  
● Following the onset of a cough or two or more respiratory symptoms, the ill 
participant, regardless of whether they are drug eligible or not, will use an prepositioned 
influenza self-test. 
o  For drug ineligible participants, they will provide one nasal swab specimen 
collected via self-swab or parent/permanent legal guardian-swab, which will be 
mailed back to the laboratory. Additionally, the ill participant will complete an 
illness questionnaire at day 0, then again at day 7. The household will remain 
enrolled and continue to monitor for the development of a cough or 2 or more 
respiratory symptoms via the weekly symptom monitoring log.  
o If the ill participant is drug eligible, they connect with a telehealth provider 
using their smartphone as soon as possible.  
▪ 
If influenza is not diagnosed, the sick participant will provide one nasal 
swab collected via self-swab or parent/permanent legal guardian-swab, 
which will be mailed back to the laboratory. Additionally, the ill participant 
will complete an illness questionnaire at Study day 0, then again at Study 
day 7. The household will remain enrolled and continue to monitor for the 
development of a cough or 2 or more respiratory symptoms via the 
weekly symptom monitoring log.  
▪ 
If influenza is diagnosed, ill participant will provide a nasal swab sample 
collected via self-swab or parent/legal guardian-swab. Also, following a 
positive test result, the ill participant will complete Study day 0 of the 
illness questionnaire. This questionnaire will collect information regarding 
the presence, duration, and severity of respiratory and systemic 
symptoms in the ill participant.  Additional information such as recent 
travel history, childcare, school, or work absenteeism as well as data on 
subsequent medical care will be collected on the questionnaire. 
Additionally, the 98point6 provider will confirm antiviral treatment is 
appropriate, and write a BXM prescription. Next, BXM will be delivered 
home of the case within 6 hours via a rapid delivery service.  
● Following delivery and therapy initiation, the case will document the time of 
consumption.   
● At Study day 2-3 and Study day 5-7 after a positive test result, the drug eligible, 
influenza-infected participant will provide nasal swab samples collected via self-swab or 
parent/legal guardian-swab. All nasal swabs will be mailed back to the laboratory for 
further testing the same day or the day following collection (see VI. Laboratory 
Procedures section). Also, the ill participant will complete an illness questionnaire 7 days 
after antiviral treatment. This questionnaire will collect information regarding the 
presence, duration, and severity of respiratory and systemic symptoms. Additional 
information such as recent travel history, childcare, school, or work absenteeism as well 
as data on subsequent medical care will be collected through the questionnaire.  
● Within 48 hours after drug receipt, individuals will be screened for evidence of 
reaction to the drug using a standardized questionnaire in REDCap.  


16 
 
 
● 7 days and 14 days after drug receipt, individuals will be screened for evidence of 
reaction to the drug using a standardized questionnaire. 
 
Table 1. Timing of Data Collection  
Data Items 
Enrollmen
t 
Weekly 
during 
Influenz
a 
Season 
Monthly 
during 
Influenz
a 
Season 
Influenza 
not 
diagnosed, 
drug 
eligble 
group 
Influenza 
diagnosed
, drug 
eligible 
group 
Sick, 
drug 
ineligible 
group 
Informed 
consent 
X 
 
 
 
 
 
Baseline 
health and 
demographic 
data 
collected  
X 
 
 
 
 
 
Baseline 
nasal swab 
collection  
X 
 
 
 
 
 
Self-monitor 
cough or 2 or 
more 
respiratory 
symptoms  
 
X 
 
 
 
 
Report 
changes in 
household 
structure or 
influenza 
vaccine 
status 
 
 
X 
 
 
 
Nasal swab 
collection 
(Study day 0) 
 
 
 
X 
X 
X 
Nasal swab 
collection 
(Study day 2-
3) 
 
 
 
 
X 
 
Nasal swab 
collection 
(Study day 5-
7) 
 
 
 
 
X 
 
Illness 
questionnair
e (Study day 
0, Study day 
7)  
 
 
 
X 
X 
X 


17 
 
 
Record 
timing of 
drug receipt  
 
 
 
 
X 
 
Standard 
questionnair
e for AEs 
and SEAs 
(48 hours , 7 
&14 days 
post-
treatment) 
 
 
 
 
X 
 
 
 
Medication management 
 
Baloxavir (BXM) 
Drug eligible, influenza-infected study participants will receive a one-time oral dose of baloxavir 
(Xofluza) based on weight. For individuals weighing 80kg or more, they will receive 80mg of 
BXM. For individuals weighing 40-80kg, they will receive 40mg of BXM (See Table 2). The drug 
will be delivered to the individual’s home within 2-6 hours of an influenza diagnosis. The case 
will be instructed to take the medication immediately on receipt and record the time of ingestion 
using the REDCap app or by text message. The description of the antiviral from the product 
monograph is as follows:  
 
XOFLUZATM is a polymerase acidic (PA) endonuclease inhibitor indicated for the 
treatment of acute uncomplicated influenza in patients 12 years of age and older 
who have been symptomatic for no more than 48 hours.  
Limitations of Use: Influenza viruses change over time, and factors such as the 
virus type or subtype, emergence of resistance, or changes in viral virulence 
could diminish the clinical benefit of antiviral drugs. Consider available 
information on drug susceptibility patterns for circulating influenza virus strains 
when deciding whether to use XOFLUZA.  
 
 
Medication storage and packing   
BXM blister packs will be provided to the study team prior to the start of the influenza season by 
the drug manufacturer or purchased from the manufacturer. According to the manufacturer, 
baloxavir should be stored in its blister package at 20°C to 25°C (68°F to 77°F); excursions 
permitted to 15°C to 30°C (59°F to 86°F). Additional storage recommendations are provided 
below.  
● 20 mg white to light yellow, oblong shaped film-coated tablets debossed with “Θ772” on 
one side and “20” on the other side available as: 
o 2 x 20 mg tablets per blister card in secondary packaging: NDC 50242-828-02 
o 4 x 20 mg tablets per blister card in secondary packaging: NDC 50242-828-02 
● 
40 mg white to light yellow, oblong shaped film-cated tablets debossed with “BXM40” on 
one side available as: 
o 
1 x 40 mg tablet per blister card in secondary package: NDC 50242-860-01 
o 
2 x 40 mg tablets per blister card in secondary packaging: NDC 50242-860-02 
 


18 
 
 
Upon receiving a prescription for antiviral medication from a tele-health provider, a study 
pharmacist will pull the blister pack or packs from the correct weight bin, which will be organized 
prior to the start of the influenza season, and dispense the medication.  
 
Following the packaging and labeling of the intervention, an informational hand out about the 
study drug will be included in this packaging along with the contact information for a licensed 
medical professional associated with the study who is available to answer any follow-up 
questions the participant may have regarding the intervention. Furthermore, the drug eligible 
participant will also be able to direct drug related questions to a 98point provider via the tele-
health app.     
 
 
Medication delivery and counseling  
After the intervention is dispensed, the rapid delivery service will be notified that the study drug 
is available for delivery. Next, the rapid delivery service will pick up the intervention and deliver 
the package to the household of the case within 2-6 hours of an influenza diagnosis . Once the 
medication leaves the storage facility, delivery tracking will be performed by a member of the 
study staff and a log recording successful medication delivery will be kept as additional quality 
assurance measure.       
 
Upon enrollment in the study, all eligible study participants in the enrolled household will receive 
information regarding the potential risks of the study drug as well as information regarding 
prohibited medications/treatments. Once the medication is received by the case, there will also 
be an informational hand out included in the delivery package as well as the contact information 
for a licensed medical professional associated with the study who is available to answer any 
follow-up questions the participant may have regarding the intervention. Finally, after reviewing 
this information and administering the medication, cases will record the time of medication 
administration via REDCap.   
 
Prohibited medications/treatments 
Prohibited medications/treatments during the study include concurrent use of any anti-influenza 
medication.  The concurrent use of BXM with the intranasal live attenuated influenza vaccine 
(LAIV) has not been evaluated; concurrent administration may inhibit viral replication of LAIV 
and thereby decrease the effectiveness of LAIV vaccination. Co-administration with polyvalent 
cation-containing products may decrease plasma concentrations of BXM which may reduce 
efficacy. Medications containing calcium, magnesium, iron, selenium, or zinc, such as Tums, 
are not to be taken within 2 hours of taking BXM. Additionally, participants should avoid co-
administration with dairy products, calcium-fortified beverages, polyvalent-cation containing 
laxatives or antacids. This information will be given to the participant at enrollment, and will be 
provided in the informational handout with the medication.  
 
Table 2. Medication Information  
Patient Body Weight (kg) Recommended Oral Dose 
40 kg to less than 80 kg 
Single dose of 40 mg 
At least 80 kg 
Single dose of 80 mg 
 
Compensation 


19 
 
 
Households that participate in this study will not receive compensation; however, as a thank you 
gift for the time spent completing study tasks households will receive with a $20 gift card for 
enrollment. In addition, households will receive a $5 gift card for completion of study participant 
training (See V. Study Procedures section), and a $5 gift card for completion of a baseline nasal 
swab kit from eligible cases. Furthermore, enrolled households will receive a $5 gift card per 
household for completion of each weekly symptom monitoring log for the duration of the 
influenza season and a $10 gift card for using the influenza self-test. For drug eligible, influenza-
infected cases, they will also receive an additional $30 for study drug receipt. Participants will 
also receive $5 per follow-up nasal swab sequence collected and successfully returned to the 
laboratory. Gift cards, with summed amounts, will be sent electronically to each household and 
to each household member (when applicable) twice a month, with the first gift card being 
processed within the first two weeks of the month and the second gift card being processes 
within the last two weeks of the month. A log of previously sent and currently owed gift card 
amounts will be kept on a password protected network (See VIII. Data management section), 
and member of the study staff will update this log on a weekly basis. An overview of thank you 
gifts for this study is shown below (Table 3).  
 
Table 3. Overview of participant thank you gifts  
 
Study 
Enrollment  
Completion 
of training 
and 
baseline 
swab kit  
Completion 
of weekly 
symptom 
log  
Completion 
of self-test 
for 
influenza 
Receipt of 
study drug  
Completion 
and return of 
nasal swab 
specimens  
Individual  
- 
- 
- 
$10 
$30 
$5 
Household  $20 
$10 
$5 
- 
- 
- 
Frequency  
Once 
Once 
Per week 
Per illness 
Once 
Per swab 
sequence 
 
VI. 
Laboratory Procedures 
 
Ellume Home-Test: Following the onset of a cough or two or more respiratory symptoms, the 
individual will unpack their prepositioned home-testing kit and follow the in-box instructions to 
perform the test. The general process for completion of this test is as follows:  
1. The participant will self-collect a nasal swab.  
2. The nasal swab will be placed into a dropper that already contains media. 
3. The participant will then connect the test strip to their smartphone via Bluetooth.  
4. 
Once connected, the participant will drop the media that has been mixed with the 
nasal swab sample from the dropper onto the target area of the test strip.  
 
Additional nasal swabs, from a standardized nasal swab kit, will be collected from the 
participants. For drug ineligible and for drug eligible, participants not diagnosed with influenza, 
only one nasal swab will be collected at Study day 0 via self-swab or parent/legal guardian-
swab. For drug eligible, participants diagnosed with influenza nasal swab specimens will be 
collected at Study day 0, Study day 2-3, and Study day 5-7 via self-swab or parent/legal 
guardian-swab following an influenza diagnosis from the telehealth provider. After collection, the 
swab will be placed directly into a 5 mL tube containing universal transport media (UTM) that is 
included in the standardized nasal swab kit, and a barcode unique to the participant will be 
placed on the outside of the tube. Next, the tube will be enclosed in a biohazard bag, then 
packaged with an absorbent sleeve and placed into one of the provided return shipping boxes, 
with an attached pre-paid shipping labels. Previous testing has demonstrated that respiratory 


20 
 
 
viral RNA is stable at room temperature in UTM for up to one week. Nevertheless, these 
specimens will be placed into the mail as soon as possible so that the nasal swabs can be 
returned to the laboratory via delivery services the day of or the day after collection for testing 
and further characterization. This same process for specimen return will occur at Study day 2-3 
and Study day 5-7.  
 
Initial Results: Once delivered to the laboratory, the boxes will be unpackaged and any errors 
that occurred during specimen return will be noted during this time in a spreadsheet accessible 
to all study staff. Next, the barcode for each specimen as well as a testing cartridge will be 
scanned into the multiplex PCR instrument (Cepheid) used for detection of influenza A/B or 
RSV in order to link testing results to each participant. Then, for each specimen, 300 µL of UTM 
will be transferred to the testing cartridge and run on the Cepheid instrument. On the computer 
attached to the instrument, testing results are displayed in the GeneXpert Dx System 
qualitatively as a positive or negative for the three respiratory targets (influenza A, influenza B, 
and RSV), and quantitatively as Ct values. These results will then be manually entered into a 
centralized laboratory database, which can later be linked to clinical data for analysis.  
 
Further Characterization: The remaining UTM for each nasal swab sample will be aliquoted 
under a sterile hood into three matrix 1.0 mL tubes, with each tube containing 650 µL of UTM. A 
log of the sample information such as collection date, test status, and aliquot date is kept in an 
excel sheet in a password protected network, which links this information to each participant. 
One tube will remain in the freezer as backup sample for the duration of the trial (See Future 
Use in VIII. Data Management section). Another tube will be sent an off-site archive for deep 
storage. Next, using standard aseptic techniques, 200 µL from the non-storage tube will be 
transferred to a cartridge to undergo standard viral RNA extraction via the MagNA Pure 96 
System using the MagNA Pure 96 DNA and Viral NA Small Volume Kit 2.0. This extraction 
process will occur in batches, with 94 samples being processed per batch. The output plate will 
contain 50 µL of purified nucleic acid per sample. Following standard laboratory procedures, the 
extracted nucleic acid samples will be added to a PreAmp reaction master mix containing 
TaqPath 1-Step RT-qPCR Master Mix CG, TaqMan PreAmp pool respiratory tract microbiota, 
and TaqMan Universal Xeno RT control (ThermoFisher). RT-PCR (TaqMan Open Array) cycling 
conditions will be according to the manufacturer’s recommendations for a total of 40 cycles. 
Positive and negative controls will be included in each extraction and PCR run. Samples will be 
considered positive if they meet a priori criteria for paired Crt, Cq, and amplification scores 
(initially set by ThermoFisher). Pathogen detection results will be TaqMan Open Array, which 
will be uploaded to a central data capture system and subsequently stored in the password 
protected network. These results can later be linked to clinical data for analysis. (See SFS 
Protocol for full laboratory details).  
 
     Return of Results: Some of these results, such as whether the nasal specimens test 
positive for the following viral respiratory pathogens: Influenza A and B, and RSV, will be 
available to the participant after initial laboratory testing via the Cepheid on the Seattle Flu 
Study website. Results will be reported in easy-to-understand language explaining in lay terms 
the name of the virus, usual symptoms, and basic advice about preventing the spread of 
infection. Additionally, participants will be able to see where their sample is located on a 
phylogenetic tree specific to the respiratory viruses their specimen was positive for. Participants 
will be able to access these results by entering the barcode present on their Study Day 0 nasal 
swab into the results section of the Seattle Flu Study website, which will show their specific 
results page.  
    


21 
 
 
VII. 
Risks and Benefits 
 
Study participants will benefit from the receipt of a thermometer. Additionally, influenza-infected 
participants that receive baloxavir may benefit from a reduction in the duration and severity of 
their respiratory and systematic symptoms.  
 
 
Nasal swab collection is a minimal risk event; it may be uncomfortable and may cause watery 
eyes or sneezing; in rare cases, it may cause slight bleeding of the nose (<1:4,000). Given that 
participants will be self-swabbing, a nose bleed is very unlikely to occur. However, the 
information on the proper steps for how to treat a nose bleed (i.e. pressure applied to the septal 
area continuously for 5 to 20 minutes) will be provided to the participants during the self-swab 
training video.  
 
 
Incidences of adverse events occurring in !"#$%&$'()*+,-'$.+,+/0/12$BXM in prior randomized 
controlled trials of acute, uncomplicated influenza in adults and adolescents have included: 
● Diarrhea  
● Bronchitis  
● Nausea  
● Nasopharyngitis  
● Headache 
 
 
There is minimal risk of breach of confidentiality in this study. This risk is minimal because there 
are multiple safeguards in place (see VIII. Data Management section) to ensure participant 
confidentiality is protected.  
 
 
There are very few risks to others who are not study subjects. Nevertheless, it should be noted 
that there is the potential for the transmission of BXM resistant influenza strains from person-to-
person, though there are not currently enough data available to determine the likelihood of this 
event.33 Non-study subjects that reside in enrolled households may benefit from a reduced risk 
of secondary transmission of influenza by cases that receive BXM. Similarly, non-study subjects 
that are part of the social network of household where the case receives BXM may benefit from 
reduced risk of secondary influenza transmission. All risks and benefits of the intervention will 
be clearly communicated during the consent process to all study participants prior to enrollment.  
 
 
Cost of participation  
 
There is no cost to subjects for participation in this study.  
 
 
Payment for Participation 
 
There is no payment for participation in this study.   
 
VIII. 
Data Management 
 
 
Data security and privacy   
 
All information from the study subjects will be kept confidential. All forms and specimens will 
have a participant identification number, given to the participant upon enrollment in the study, 
that will be used in the place of names whenever possible. Data will be collected electronically 
in REDCap either online or through a text-message accessible app. REDCap’s survey app is 
Title 21 CFR Part 11 compliant, password protected and auditable database. The list linking the 
participant to the ID number will be stored separately from the REDCap database. Access to 
identifiable information will be limited to the study staff and the study pharmacist (for drug 
dispensing and delivery purposes); their grounds for employment regarding this study will be 


22 
 
 
contingent on maintaining the security of study records and any identifiable information. 
Electronic files will be secured via logon password protection for study accounts. Any datasets 
that include identifiable information will be stored on in a HIPAA-compliant manner. No 
identifying information will be included on any data sent to the broader study team or any other 
data-sharing repositories. All data files transferred for the purpose of this study will be 
transferred via encrypted software and the original files will be kept on our server.  
 
Identifiable numbers will be kept on biospecimens (nasal swabs) while the laboratory processing 
occurs. All subjects who consent to participate will also be asked to approve the storage of their 
biospecimens (nasal swabs). Backup aliquots will be kept until we are sure all laboratory assays 
are completed with adequate quality control. Persons who consent to the trial, but who do not 
want their biospecimens stored may still participate in the trial. Their biospecimens will be tested 
as per protocol, but the remaining aliquots will be destroyed. 
 
 
Identifiers will be kept on all data files until the study is closed out. Primary data collection 
sources will be kept for at least 5 years following the publication of the primary result from this 
study. Once this time elapses and the electronic data files are fully cleaned, any paper forms will 
be destroyed.  
 
 
Data quality  
 
Data will be checked for missing or unusual values and checked for consistency within 
individual participants and households by study staff in the centralized data capture system. 
Computerized checks will be conducted weekly to identify missing, inconsistent or out of range 
data. Any suspect data will be raised as data queries. Examples of suspect data (while not an 
exhaustive list) will include: 
● Invalid or improbable dates of birth (e.g. dates in the future, dates greater than 100 years 
in the past) 
● Unlikely changes in symptom reporting (e.g. a participant reports experiencing 5 
symptoms one day and then no symptoms the following day) 
● Unusual or unlikely household variation (e.g. participants in the same household 
reporting different household structures) 
 
The study coordinator will investigate data queries to provide an explanation and possible 
resolution of discrepancies on a weekly basis using the data quality module overview on 
REDCap. The study coordinator will raise queries and share them with the study staff who are 
involved in the household enrollment process or are involved in data collection and 
management. The study staff will contact participants via their preferred method of 
communication to clarify instances of suspect data. Following this communication, the data 
items will be marked as “verified,” and an additional review will be conducted by the study 
coordinator then the query will be closed. When there are no longer any open queries on a 
survey it can be locked by the study coordinator. See the SFS Data Management Plan (DMP) 
for full details.  
 
 
Protection against risks  
 
All identifying data will be stored at the University of Washington using standard security 
techniques. Hard copies of data collection materials that have identifiers will be locked in the 
office of the study PI or a room with limited access by specific individuals. When possible, 
redacted (de-identified) versions of the data will be used for coding and data analysis. Personal 
identifiers will be stored in the database on a password protected network that is HIPAA-
compliant, and only accessible to specific individuals. Transfer or storage on portable devices 


23 
 
 
(e.g., laptops, flashdrives) will be encrypted. The devices on which this information is stored will 
be accessible only to individuals who need access to the data.  
 
 
The project will be approved by the Institutional Review Board (IRB) at the University of 
Washington. This study will be conducted according to Good Clinical Practice (GCP) guidelines 
at that are appropriate for use of already approved drugs. We will appoint an independent 
Safety Officer who is not involved in this study.  
 
 
To reduce distress, study participants will be given the opportunity to skip any questions that 
they are not comfortable answering. Additionally, all participants will be reminded that 
participating in research is always optional, and they may terminate their participation at any 
time without consequences. All members of the research team will be required to complete the 
Good Clinical Practice (GCP) and the Protecting Human Research Participants training offered 
before enrollment of participants begins. Only those research team members with login 
credentials and passwords will be granted access to the centralized data capture system, where 
data are stored and audited. As previously stated, to mask participant identity, participants will 
be assigned unique study identifiers (participant ID numbers) at the time of enrollment. Only 
specific members of the study team and the study pharmacist (for cases) will be able to link to 
the participant ID to the participant’s name. 
 
 
Future Use 
 
As the genome of influenza viruses (and other respiratory viruses) can change even within a 
season, it is critical that backup samples be kept that can be used with the latest primers to 
account for this drift. The samples will be held in a freezer at the University of Washington to 
serve as this backup.  
 
 
Nasal swab specimens will be provided by the case following an illness. Following self-
collection, specimens will be shipped back to the laboratory the day of or the day after collection 
via delivery services. Aliquots from consenting participants, will be held in freezers at the 
University of Washington for potential other, new influenza assays that may be used in the 
study, if they prove to be less expensive, easier to do and are accurate. We will amend this 
application if such opportunity presents itself.  
 
 
We do not currently expect to share specimens with outside investigators, but if compelling 
opportunities arise that will advance the overall objectives of this research, the Executive 
Committee (See IX. Data Safety and Monitoring section) of the study will consider such 
requests. They alone have the authority to make such decisions.  
 
 
All biospecimens (nasal swabs) will be coded and identifiable through the study’s main 
database. Any specimens shared with external investigators (if deemed appropriate by the 
Executive Committee) will have identifiers removed prior to sharing.  
 
IX. 
Data Safety and Monitoring  
 
There are three standing committees that will provide organizational structure for this project. 
These are the Executive Committee, the Operations Committee, and the Data and Safety 
Monitoring Board.   
 
 
Executive Committee: The Executive Committee has overall scientific and administrative 
responsibility for the conduct of the project. The other two committees will report their 
recommendations to the Executive Committee where final decisions will be made. All changes 


24 
 
 
or alterations to the protocol, or issues related to financing or administrative conduct of the study 
must be approved by the Executive Committee. The Executive Committee will also serve as the 
Publications Review Committee and all publicity, presentations, or manuscripts from the study 
must receive approval at this level. The Executive Committee will meet on a regular basis; the 
frequency will be decided based on the needs of the study.  
 
 
Operations Committee: The Operations Committee will have primary responsibility for the 
implementation of the study protocol under the direction of the Executive Committee. They will 
develop and test all necessary study forms and procedures and produce a Manal of Operations 
that will document all procedures and methodology for the project. This committee will make 
recommendations to the Executive Committee regarding any proposed additions or alterations 
to the study protocol. The Operations Committee will meet on a regular basis, the schedule will 
be determined by the requirements of the study.  
 
 
Data and Safety Monitoring Board: The purpose of the Data and Safety Monitoring Board 
(DSMB) is to provide external, objective advice to the Executive Committee regarding the safety 
and efficacy of the intervention being evaluated. This committee will be responsible for 
reviewing the data from the study on a regular basis, summarizing their conclusions and advice 
in a written set of minutes, and communicating this information to the Executive Committee. The 
PI will then forward these minutes to the Institutional Review Board at the University of 
Washington. The DSBM has specific responsibility to determine if there are problems relating to 
the safety of the intervention, to the degree the study should be stropped, and to determine if 
the study should be stopped early because the benefit of the interventions has proved to be 
stronger than originally anticipated. The Data and Safety Monitoring Board will meet just prior to 
the pre-season enrollment of households to review the final protocol, and after the conclusion of 
the influenza season. Voting membership on the Data and Safety Monitoring Board is limited to 
persons external to the investigative team. Senior members of the investigative team will serve 
as ex-officio members without voting rights. In addition to the voting members of the DSMB, 
study investigators will act as resources to the DSMB in a non-voting capacity.  
   
 
Plan for reporting unanticipated problems/adverse events: 
Serious Adverse Events: Serious adverse events (SAEs) under Good Clinical Practice (GCP) 
guidelines include death, a life-threatening reaction the study drug (or placebo) or other study 
procedure, hospitalization, or significant or persistent disability or impairment. Other events may 
also be considered a serious adverse event if, based on medical judgement, the event 
jeopardized the patient to the point of requiring medical or surgical intervention to 
 
 
Other Adverse Events: This will include any untoward medical event that occurs in a 
participant, any unfavorable sign or symptom disease temporally associated with the provision 
of the intervention, or any noxious or unintended response to the study drug. These other 
adverse events can be anticipated based on what we know about reactions to antiviral 
medications, or unanticipated. Examples of anticipated adverse events include (but are not 
limited to) instances of nausea, headache, or diarrhea.  
 
 
Unanticipated adverse events are those that are either unexpected in terms of nature, severity, 
and frequency especially if they indicate that there is greater risk of harm than previously 
recognized.  
 
Within 48 hours of taking the study drug, cases will be screened via REDCap for evidence of 
short-term reaction. Additionally, drug eligible, influenza-positive study participants will be 


25 
 
 
monitored at 7 and 14 days after receipt of the intervention using a standardized questionnaire. 
Any potential AE or SAE based on post-drug tele-health consultation will be reported to the 
study team as soon as possible, which will be entered into the standardized questionnaire. 
These questionnaires will be monitored by the data management team, such that adverse 
events will be reported as soon as possible. All SAEs (regardless of causality), and any grade 3 
and 4 AEs which are deemed related or possibly related to the study drug, will be logged in AE 
database and reported using an official Adverse Event Report Form to the designated principal 
investigator (Dr. Helen Chu) for review within 48 hours. This review will determine if there is any 
indication for the event being related to the study intervention or procedures. The medical expert 
team will review the file and make a determination regarding attribution to study procedures or 
the intervention. 
  
 
If the adverse event is considered by the medical expert team to be minor in severity, it will be 
logged in the centralized data capture system and a summary of such events will be reported to 
the DSMB. If the severity of the adverse event is considered to be moderate or severe by      
Principal and Co-Principal Investigators,  it should be reported to the safety officer (DSMB)  and 
the cognizant IRB immediately.  All study-related SAEs will be reported to the IRB within 14 
days.  
 
 
The following are a list of anticipated and unanticipated adverse events we expect to be 
attributable to the study procedures or the intervention:  
 
 
Anticipated Events: Mild-moderate systemic reactions, these include diarrhea, bronchitis, 
nausea, nasopharyngitis, and headache.   
 
 
Unanticipated Events: By definition these are unexpected in terms of their nature, (see above 
for anticipated events) severity, and frequency, especially if they indicate that there may be 
greater risk of harm than previously recognized.  
 
X. 
Definitions  
 
Acute Respiratory Illness/infection (ARI): We will use the CDC definition of ARI that includes 
disease that typically involves the airways within the nose and throat and may or may not 
include fever. ARI is generally defined by the presence of two or more symptoms such as fever, 
cough, runny nose or nasal congestion, or sore throat. ARI is more sensitive (broader) than ILI 
to describe illness consistent with influenza because fever/feverishness are not required.  
 
Drug eligible, influenza-infected study participant: A drug eligible study participant in the 
household that is diagnosed with influenza from a 98point6 provider based on a clinical review 
of the sick participant’s symptoms.  
 
Drug ineligible participant: A study participant in the household that is not able to receive 
BXM. 
 
 
Influenza-like Illness in Adults and Adolescents (ILI): We will use the CDC definition of ILI 
that requires reported or measured fever (>37.8°C) plus either cough or sore throat on one or 
more days preceding consultation with a tele-health physician.  
 


26 
 
 
 
Laboratory-confirmed influenza infection: We will use the CDC definition that is an individual 
who tests positive for influenza via an approved laboratory test, which will be the multiplex PCR 
(Cepheid) in this study.  
 
 
Person-to-person transmission: We will use the CDC definition for influenza transmission that 
refers to the ability of an influenza virus to spread from one person to another, most commonly 
through large or small droplets containing influenza virus that are expelled when a sick person is 
coughing or sneezing.  
 
XI. 
Statistical Analyses  
The primary objective is to precisely estimate the proportion of drug eligible individuals with an 
influenza diagnosis who initiate treatment within 48 hours. We define precision in terms of the 
width of a 95% confidence interval. The width of a 95% CI will be less than or equal to 
±1.96*.5/sqrt(n) where n is the number of individuals who test positive for flu. With 250 
households participating and an attack rate of 25% we expect 63 individuals with confirmed 
influenza infection. This will give a 95% CI for the proportion initiating treatment of ±0.12 or less. 
 
The proportion of drug eligible individuals receiving the drug and initiating treatment within 48 
hours of symptom onset using home-based self-test and delivery methods will be estimated. 
Binomial regression with log link will be used to calculate the relative risk of receiving and 
initiating treatment within 48 hours by demographic and clinical factors, including age, sex, 
race/ethnicity, symptom types, symptom severity, and duration of symptoms.  The RR, 95% 
confidence intervals and p-values will be reported.   
 
For the secondary endpoints of symptom duration and severity, drug eligible and drug ineligible 
participants will be analyzed separately. Symptom severity will be measured on a 4-point scale 
(0 = no symptoms, 1 = mild, 2 = moderate, 3 = severe) for each influenza-associated symptom 
the participant reports experiencing. Influenza-associated symptoms the participant does not 
report as experiencing will be coded as 0. An additional analysis will be conducted comparing 
secondary endpoints for drug eligible, influenza-infected study participants that received and 
initiated treatment within 48 hours of symptom onset and those that initiated treatment later than 
48 hours. Kaplan-Meier curves will be used to present and analyze time to resolution of 
symptoms, defined as the time when the influenza-positive participant reports experiencing no 
respiratory or systemic symptoms. For study participants who received BXM, a Cox proportional 
hazards model will be used to calculate the hazard ratio, 95% confidence interval, and p-value 
for symptom duration by group (therapy within 48 hours of symptom onset, and therapy after 48 
hours of symptom onset). The analysis of drug ineligible study participants will use a similar 
approach but will cluster by household and use a robust variance for computing confidence 
intervals and p-values. For BXM recipients, symptom severity will be compared between groups 
(therapy within 48 hours of symptom onset, and therapy after 48 hours of symptom onset) using 
proportions for categorical measures of severity and Pearson’s chi-square test, as well as using 
ordinal regression. As above, the analysis using ordinal regression of drug ineligible study 
participants will cluster by household and use a robust variance for computing confidence 
intervals and p-values.  
 
For the secondary endpoints of maximum viral titer and duration of viral RNA detection, we will 
use t-tests or nonparametric alternatives and linear regression to assess maximum viral titer 
and Kaplan-Meier curves and Cox proportional hazards models to assess duration of viral RNA 
detection.  
 
Interim Analysis 


27 
 
 
This study is being conducted over the course of one influenza season. Therefore, an interim 
analysis will not be performed.  
 
Antiviral resistance analysis 
The secondary outcome data regarding emergence of BXM resistance will be reviewed at the 
end of the influenza season via genome sequencing of the viral RNA.  
 
Health economic analysis 
The economic analysis will include a ‘within-study’ cost-effectiveness analysis to compare the 
costs and health outcomes accrued over the follow-up period for individuals that initiated the 
therapy within 48 hours of symptom onset and after 48 hours of symptom onset. Results will be 
presented as an incremental cost-effectiveness ratio, assessed using health resource utilization 
and school and work absenteeism, for baloxavir treatment compared at these two time points. 
 
Translational analysis 
Samples will be sent to the central laboratory for storage and analysis. The goals of the 
translational research will be to determine the association between influenza infection and: (1) 
influenza strain (by genetic sequencing), (2) viral kinetics (maximum titer, duration viral RNA 
detection). It will also monitor for the emergence of antiviral resistance among strains. Additional 
testing and sequencing of non-influenza respiratory pathogens will also occur.  
 
XII. 
End of study 
The end of study is defined as when the last household has had their last data collected during 
the final influenza season of the study period. Active household recruitment and enrollment will 
take place prior to and during each annual influenza season, and the study itself will take place 
over the course of one influenza season: November 2019-May 2020. Overall, enrollment will 
begin October 2019; active participation is projected to start November 2019, and the study is 
projected to end in May 2020.  
 
XIII. 
References  
1. Troeger C, Forouzanfar M, Rao PC, et al. Estimates of the global, regional, and national 
morbidity, mortality, and aetiologies of lower respiratory tract infections in 195 countries: a 
systematic analysis for the Global Burden of Disease Study 2015. Lancet Infect Dis. 
2017;17(11), 1133-1161. doi:10.1016/S1473-3099(17)30396-1 
2. Putri WCWS, Muscatello DJ, Stockwell MS, Newall AT. Economic burden of seasonal 
influenza in the United States. Vaccine. 2018;36(27),3960-3966. 
doi:10.1016/j.vaccine.2018.05.057 
3. Centers for Disease Control and Prevention. Estimated Range of Annual Burden of Flu in 
the U.S. https://www.cdc.gov/flu/about/burden/index.html. Updated February 19, 2019. 
Accessed July 21, 2019.  
4. Lewnard JA, Cobey S. Immune history and influenza vaccine effectiveness. Vaccines 
(Basel). 2018;6(2):28. doi:10.3390/vaccines6020028 
5. Young B, Sadarangani S, Jiang L, Wilder-Smith A, Chen MI. Duration of influenza vaccine 
effectiveness: a systematic review, meta-analysis and meta-regression of test-negative 
design case-control studies. J Infect Dis. 2018;217(5):731-741. doi:10.1093/infdis/jix632  
6. Russell K, Chung JR, Monto AS et al. Influenza vaccine effectiveness in older adults 
compared with younger adults over five seasons. Vaccine. 2018;36(10):1272-1278. doi: 
7. Carrat F, Vergu E, Ferguson M, et al. Time lines of infection and disease in human 
influenza: a review of volunteer challenge studies. Am J Epidemiol. 2008;167(7):775-785. 
doi:10.1093/aje/kwm375 


28 
 
 
8. Hayden FG, Osterhaus AD, Treanor JJ, et al. Efficacy and safety of the neuraminidase 
inhibitor zanamivir in the treatment of influenzavirus infections. GG167 Influenza Study 
Group. N Engl J Med. 1997;337(13):874-880. doi:10.1056/NEJM199709253371302 
9. Monto AS, Fleming DM, Henry D et al. Efficacy and safety of the neuraminidase inhibitor 
zanamivirin the treatment of influenza A and B virus infections. J Infect Dis. 
1999;180(2):254-261. doi:10.1086/314904 
10. Treanor JJ, Hayden FG, Vroomn PS, et al. Efficacy and safety of the oral neuraminidase 
inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. US Oral 
Neuraminidse Study Group. JAMA. 2000;283(8):1016-1024. doi:10.1001/jama.283.8.1016 
11. Dobson J, Whitley RJ, Pocock S, Monto AS. Oseltamivir treatment for influenza in adults: a 
meta-analysis of randomised controlled trials. Lancet. 2015;385(9979):1729-1737. 
doi:10.1016/S0140-6736(14)62449-1  
12. Malosh RE, Martin ET, Heikkinen T, Brooks WA, Whitley RJ, Monto AS. Efficacy and safety 
of oseltamivir in children: systematic review and individual patient data meta-analysis of 
randomized controlled trials. Clin Infect Dis. 2018;66(10):1492-1500. 
doi:10.1093/cid/cix1040 
13. Cauchemez S, Carrat F, Viboud C, Valleron AJ, Boëlle PY. A Bayesian MCMC approach to 
study transmission of influenza: application to household longitudinal data. Stat Med. 
2004;23(22):3469-3487. doi:10.1002/sim.1912 
14. Monto AS. Studies of the community and family: acute respiratory illness and infection. 
Epidemiol Rev. 1994;16(2):351-373. doi:10.1093/oxfordjournals.epirev.a036158 
15. Monto AS, Koopman JS, Longini IM Jr. Tecumseh study of illness. XIII. Influenza infection 
and disease, 1976-1981. Am J Epidemiol. 1985;121(6):811-822. 
doi:10.1093/oxfordjournals.aje.a114052  
16. Templeton KE, Scheltinga SA, Beersma ME, Kroes AC, Claas EC. Rapid and sensitive 
method using multiplex real-time PCR for diagnosis of infections by influenza a and 
influenza b viruses, respiratory syncytial virus, and parainfluenza viruses 1, 2, 3, and 4. J 
Clin Microbiol. 2004;42(4):1564-1569. doi: 10.1128/jcm.42.4.1564-1569.2004 
17. Monto AS, Malosh RE, Evans R, et al. Data resource profile: Household Influenza Vaccine 
Evaluation (HIVE) Study. Int J Epidemiol. 2019;dzy086. doi:10.1093/ije/dyz086 
18. Hayden FG, Gubareva LV, Monto AS, et al. Inhaled zanamivir for the prevention of influenza 
in families. Zanamivir Family Study Group. N Engl J Med. 2000;343(18):1282-1289. 
doi:10.1056/NEJM200011023431801 
19. Monto AS, Pichichero ME, Blanckenberg SJ, et al. Zanamivir prophylaxis: an effective 
strategy for the prevention of influenza types A and B within households. J Infect Dis. 
2002;186(11):1582-1588. doi:10.1086/345722 
20. Hayden FG, Belshe R, Villanueva C, et al. Management of influenza in households: a 
prospective, randomized comparison of oseltamivir treatment with or without postexposure 
prophylaxis. J Infect Dis. 2004;189(3):440-449. doi:10.1086/381128 
21. Welliver R, Monto AS, Carewicz O, et al. Effectiveness of oseltamivir in preventing influenza 
in household contacts: a randomized controlled trial. JAMA. 2001;285(6):748-754. doi: 
10.1001/jama.285.6.748 
22. Leung YH, Li MP, Chaung SK. A school outbreak of pandemic (H1N1) 2009 infection: 
assessment of secondary household transmission and the protective role of oseltamivir. 
Epidemiol Infect. 2011;139(1):41-44. doi:10.1017/S0950268810001445 
23. Fry AM, Goswami D, Nahar K, et al. Efficacy of oseltamivir treatment started within 5 days of 
symptom onset to reduce influenza illness and virus shedding in an urban setting in 
Bangladesh: a randomised placebo-controlled trial. Lancet Infect Dis. 2014;14(2):109-118. 
doi:10.1016/S1473-3099(13)70267-6 


29 
 
 
24. Cheung DH, Tsang TK, Fang VJ, et al. Association of oseltamivir treatment with virus 
shedding, illness, and household transmission of influenza viruses. J Infect Dis. 
2015;212(3):391-396. doi:10.1093/infdis/jiv058 
25. Ng S, Cowling BJ, Fang VJ, et al. Effects of oseltamivir treatment on duration of clinical 
illness and viral shedding and household transmission of influenza virus. Clin Infect Dis. 
2010;50(5):707-714. doi:10.1086/650458 
26. Hayden FG, Sugaya N, Hirotsu N, et al. Baloxavir marboxil for uncomplicated influenza in 
adults and adolescents. N Engl J Med. 2018;379(10):913-923. 
doi:10.1056/NEJMoa1716197 
27. Genentech. Phase III Study Showed XOFLUZA (Baloxavir Marboxil) is Effective at 
Preventing Influenza Infection. https://www.gene.com/media/press-releases/14793/2019-06-
03/phase-iii-study-showed-xofluza-baloxavir. Published June 3, 2019. Accessed July 23, 
2019.  
28. Petrie JG, Ohmit SE, Cowling BJ, et al. Influenza transmission in a cohort of household with 
children: 2010-2011. PLoS One. 2013;8(9):e753339. doi:10.1371/journal.pone.0075339 
29. Cauchemez S, Ferguson NM, Fox A, et al. Determinants of influenza transmission in South 
East Asia: insights from a household cohort study in Vietnam. PLoS Pathog. 
2014;10(8):e1004310. doi:10.1371/journal.ppat.1004310 
30. Yom-Tov E, Johansson-Cox I, Lampos V, Hayward AC. Estimating the secondary attack 
rate and serial interval of influenza-like illnesses using social media. Influenza Other Respir 
Viruses. 2015;9(4):191-199. doi:10.111.irv.12321 
31. Carcione D, Giele CM, Goggin LS, et al. Secondary attack rate of pandemic influenza 
A(H1N1) 2009 in Western Australian households, 29 May-7 August 2009. Euro Surveill. 
2011;16(3):pii:19765. doi:10/2807/ese.16.03.19765-en  
32. Viboud C, Boëlle P, Cauchemez S, Valleron A, Flahault A, Carrat F. Risk factors of influenza 
transmission in households. Br J Gen Pract. 2004;54(506):684-689. 
doi:10.1016/j.ics.2004.01.013 
33. Takashita E, Ichikawa M, Morita H, et al. Human-to-human transmission of influenza 
A(H3N2) virus with reduced susceptibility to baloxavir, Japan, February 2019. Emerg Infect 
Dis. 2019;25(11). doi:10/3201/eid2511.190757 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


30 
 
 
 
 

SAP_001.pdf: 
 
 
 
SFS Statistical Analysis Plan 
Household Intervention Study 
Last Revised 10/8/19  
 
 
 
Applicable to the following UW IRB Study Protocols:  
Seattle Flu Study (SFS) (6181) 
Household Intervention Study (8200) 
 
Funding:  
Brotman-Baty Institute, University of Washington   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Table of Contents 
A. STUDY OBJECTIVES AND SUMMARY 
3 
B. FINAL ANALYSIS PLAN 
B1. ANALYSIS DATASETS  
B2. BASELINE TABLES AND STUDY CONDUCT 
Description of the main tables and statistical analyses 
Study Accrual 
Baseline Demographic Characteristics 
Baseline Behavioral Characteristics 
Baseline Influenza and Respiratory Illness Symptoms 
Drug adherence 
Retention 
Follow-up 
B3. SAFETY ANALYSIS 
B4. ENDPOINT ANALYSIS 
Primary Analysis 
Secondary Analyses 
Additional analyses with Influenza virus infection as the Endpoint 
Additional analyses with other respiratory infections as Endpoints 
Sensitivity Analyses 
4 
4 
5 
5 
5 
5 
5 
5 
5 
5 
5 
5 
5 
5 
5 
5 
5 
5 
 
C1. INTERIM ANALYSIS PLAN 
Original plan 
5 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A. Study Objectives and Summary 


 
 
Purpose: To evaluate the efficacy of a home-based approach to influenza testing in households 
in order to shorten the time to diagnosis, antiviral delivery, and antiviral initiation and reduce 
influenza transmission within the household.  
 
Design: This study is an open cohort intervention study with prospective exposure assessment. 
It is a pilot study of a home-based approach to influenza infection, utilizing self-test kits and 
rapid home delivery of baloxavir (BXM). All members of all households must be asymptomatic at 
enrollment. 
 
Population: Households with at least 3 individuals residing there at least 4 days a week, 
including at least 2 household members that are eligible to take BXM, will be monitored 
throughout the influenza season for the onset of a cough.  
 
Expected study size: This study will be conducted in up to 1,000 households in the Seattle, 
WA area.  
 
Study duration: One influenza season, beginning November 1, 2019 and ending May 1, 2020.  
 
Primary aim: Evaluate whether this home-based strategy leads to a large percentage of 
influenza-positive individuals initiating antiviral therapy within 48 hours of symptom onset.  
 
Secondary aim: Determine the social and technical infrastructure that would be required to 
rapidly detect and interrupt influenza transmission at the household level and to determine 
whether a home-based self-test and antiviral delivery strategy would be feasible in the context 
of a pandemic. 
 
Primary Objectives: 
P1) To measure the proportion of individuals who are initiated on antiviral therapy within 
48 hours of symptom onset using home-based self-test to diagnose influenza and home 
delivery of antivirals. 
 
Secondary Objectives: 
S1) Proportion of individuals who test positive for influenza using the home-based test 
within 48 hours of symptom onset  
S2) Proportion of individuals who are delivered antivirals within 48 hours of symptom 
onset 
S3) Symptom duration and severity among cases and household contacts 
S4) Viral titer and duration of viral RNA detection among influenza-positive cases  
S5) Cost effectiveness, assessed using health resource utilization and school and work 
absenteeism 
S6) Emergence of antiviral resistance, assessed by genetic sequencing of influenza 
strains 
 
B. Final Analysis Plan 
This section describes the main statistical analyses that will be conducted on enrolled 
households at DSMB meetings and at the end of the study. 


 
 
B1. Analysis Datasets 
The Primary Dataset will consist of all individuals from enrolled households who enroll in the 
study, comprised of symptomatic (drug-eligible) individuals. 
 
All eligible and enrolled households will be included in the study unless they meet one or more 
of the following exclusion criteria: 
1. Previous documentation of an influenza infection prior to or during the annual influenza 
season in any household member prior to enrollment  
 
At the participant level, enrolled individuals meeting any of the following criteria will be excluded 
from analysis (note: their household may still be eligible, as another eligible member of their 
household may still enroll): 
1. The individual’s informed consent is determined to be not valid 
2. The individual has been double enrolled in the study. In this case, the individual’s data 
will be used once.  
3. No symptom questionnaire is collected.  
 
B2. Variable definitions 
[See Tables 1a-c for details] 
 
B3. Baseline Tables and Study Conduct 
Description of the main tables and statistical analyses 
This section describes the main tables and statistical analyses. Metrics will be updated monthly 
and presented to the DSMB at each meeting.  
Baseline sociodemographic and health characteristics 
Table 1a will display baseline sociodemographic, health, and household-related characteristics 
of individuals enrolled in the study. Sociodemographic variables will include: age, sex, race, 
currently employed, highest level of educational attainment. Health variables will include: health 
insurance type, comorbidities, pregnant, lactating, any use of tobacco and/or e-cigarettes, and 
influenza vaccination history (for both this season and the previous season). Household-level 
variables will include: type of household, number of people sharing living space, number and 
ages of children in the household. Data will be presented both (1) overall and (2) by households 
with a case v. households with no cases. No formal statistical testing will be performed.  
Follow-up behavioral and clinical characteristics 
Table 1b will display follow-up behavioral and symptom characteristics of individuals enrolled in 
the study, based on the weekly symptom diary. Behavioral variables will include: daily activities 
affected by illness (includes school and work outcomes), number of days absent from school or 
work, office culture around (paid) sick time off, sought clinical care, behavioral/ hygiene change 
since received test result, recovery status from illness, and reason for not receiving vaccine. 
Symptom characteristics will include: positive test result, number of household members with 
influenza diagnosis in the past week, weekly temperature measurement, number of days sick, 
time since symptom onset, time between symptom onset and worst symptom presentation, 
symptoms and symptom severity (for each day with symptoms). Summary statistics appropriate 


 
 
for the measurement scale will be used to describe the distribution of these variables. Data will 
be presented both (1) overall and (2) by households with a case v. households with no cases. 
No formal statistical testing will be performed.   
 
Household-specific characteristics 
Table 1c will describe characteristics of the households included in the study. Measures 
included in this table will include: location (based on address). Summary statistics appropriate 
for the measurement scale will be used to describe the distribution of these variables. Data will 
be presented both (1) overall and (2) by households with a case v. households with no cases. 
No formal statistical testing will be performed.   
B4. Safety Analysis 
Serious adverse events (SAEs) 
A list of serious adverse events will be presented by shelter and by treatment v. intervention 
period. As defined in the study protocol, serious adverse events include death, a life-threatening 
reaction to the study drug (or placebo) or other study procedure, hospitalization, or significant or 
persistent disability or impairment. The incidence of SAE’s (events/person-days of follow-up) will 
be presented both (1) overall and (2) by case v. non-cases. We will test for a difference in SAE 
rate between the two study periods (intervention v. control) using an exact Poisson test in R. 
Baloxavir-resistant influenza transmission 
Evidence of a strong intervention effect causing incidence of baloxavir-resistant influenza strains 
will be evaluated using linear mixed effects logistic regression. The unit of analysis will be 
influenza-positive tests, and the outcome will be binary: baloxavir-resistant or not baloxavir-
resistant.  
 
B5. Power sample size 
 
Table 1. Sample size calculations: Number of clusters needed per arm for two-group 
cluster-randomized trial - Household intervention study  
Effect size (% reduction in flu incidence) 
Power 
0.30 
0.40 
0.50 
0.80 
57 
84 
129 
0.90 
76 
112 
172 
All calculations above assume an ICC of 0.29, anticipated average (or actual) cluster size of 4, 
and a 15% transmission rate for flu.  
 
Based on these calculations, an arm size of 250 households should be sufficient to detect a 
30% reduction in flu incidence at 90% power.   
B6. Endpoint Analyses  
Primary Analysis 


 
 
Question: Does this home-based self-test diagnostic tool and rapid treatment 
intervention lead to a large percentage of influenza-positive individuals initiating antiviral 
therapy within 48 hours of symptom onset?  
 
Endpoint: Cumulative incidence of influenza virus infection  
 
Measure of Association: 
Cumulative Incidence (Attack Rate, Incidence Proportion) 
 
Cumulative Incidence =  
Number of participants that successfully initiate antiviral therapy within 48 
hours of symptom onset (among participants who have a cough and self-test 
positive for influenza) during the October 2019-May 2020 influenza season 
 
Number of influenza-free participants at risk at t₀ (baseline) 
 
Relevant DAG 
 
 
Exposure: 
Exposed (Treatment) = Participants who develop cough and self-test positive 
Unexposed (No treatment) = Participants who develop cough but self-test negative 
 
Outcome: 
Success = Participant initiated on antiviral therapy within 48 hours of symptom onset 
Failure = Participant is not initiated on antiviral therapy (more than 48 hours after symptom 
onset or participant never initiates antiviral therapy) 
 
Table 1. Estimated secondary attack rates for planned 2019-2020 study aim on household 
transmission dynamics. 
The study is being conducted in the Seattle, WA area over one influenza season. The goal is to 
enroll at least 250 (up to 1,000) households. Of these, 25% are estimated to have an individual 
in the household diagnosed with influenza based on estimates from previous household 
studies.23, 28-29 
A table for influenza attack rates by household size is provided below. 
  
Household 
attack rate 
Total 
households 
enrolled 
Primary 
cases 
Secondary 
cases (mean 
household size 
5) 
Secondary 
cases (mean 
household size 4) 
Secondary 
cases (mean 
household size 3) 
25% 
250 
63 45-96 
34-72 
23-48 


 
 
20% 
250 
50 36-76 
27-57 
18-38 
10% 
250 
25 18-38 
14-29 
9-19 
Mean household size includes case. 
Secondary attack rate 18-38%, secondary cases presented as a range based on these high 
and low bounds.30-32 
  
Incidence Density 
Using time-specific variables such as date of enrollment, weekly symptom diaries and 
questionnaires, Incidence Density (ID) will be calculated, defined with the following formula: 
 
Incidence Density =  
Number of participants that successfully initiate antiviral therapy within 48 
hours of symptom onset (among participants who have a cough and self-test 
positive for influenza)  
 
Total person-days 
 
Model 
The proportion of individuals that 1) test positive and 2) receive and initiate treatment within 48 
hours of symptom onset using home-based self-test and delivery methods will be analyzed with 
a binomial regression GLMM with a log link. The outcome follows a binomial distribution, with 
the number of successes in a series of n independent Bernoulli trials, where each trial has 
probability of success p. Successes here are defined as an individual successfully initiated on 
antiviral therapy within 48 hours of symptom onset using home-based self-test to diagnose 
influenza and home delivery of antivirals. The model is defined below:  
 
Incidence proportions of influenza will be presented in tables.  
 
A formal statistical comparisons between study periods (control vs. intervention) will be 
performed using a Wald test of the hypothesis 
H₀: RR=1 
!ₐ"#$$%& 


 
 
where each individual β value represents the change in log-odds of receiving and initiating 
treatment within 48 hours, that are associated with a particular demographic or clinical risk 
factor. A one-sided test with ɑ = .05 will be used. A table of the estimated Risk Ratios for a one 
unit increase in each covariate, given the other covariate values will be presented, along with 
the corresponding 95% confidence intervals, and p-values. 
 
Data cleaning and analysis 
All analyses will be performed in R version 3.6.1 using the package ‘lme4.’  
 
Secondary Analyses: 
 
Question: How well does the self-test perform in comparison to the gold standard 
molecular test? 
 
Sensitivity, specificity, PPV and NPV of the self-test will be calculated and compared to the gold 
standard molecular test. Table 2 (below) presents relevant formulas. 
 
 
 


 
 
Question: What is the association between influenza infection and: (1) influenza strain 
(by genetic sequencing) and (2) viral kinetics (maximum titer, duration viral RNA 
detection)? 
 
Sensitivity analysis  
Sensitivity analyses will be performed to explore the uniformity of any treatment effects found in 
the overall analysis. 
 
Question: Does influenza incidence change when we look at varying testing timepoints 
(e.g. testing within 24, 48, and 72 hours of symptom onset)?  
 
Details: 
A sensitivity analysis will be performed to assess the effect of delayed testing on the 
intervention effect. The model will be re-run with three subsets of the data: those that were 
treated within 24, 48, and 72 hours of symptom onset. This will then be further analyzed with a 
time*age interaction. For example, we might expect that a 13-year-old might have more 
detectable RNA virus than an older adult at the same time point.  
 
 
Data cleaning and software 
All analyses will be performed in R version 3.6.1 using packages ‘lme4’ and 
‘swCRTdesign’.  
C. Interim Analysis Plan 
Original Plan 
The DSMB will meet every month to review study progress and other issues as outlined below. 
In the proposed 6 month study, it is expected that the DSMB will meet X times. 
  
Study progress and validity 
At each monthly visit the DSMB will review data on enrollment, adherence of both households 
and household members, and all protocol violations. The DSMB will also compare the (pooled) 
observed influenza incidence rate to the (pooled) expected influenza rate to determine if the 
influenza incidence rate among study participants is at least as great as the incidence rate 
assumed in the study design, since incidence varies by influenza season. The DSMB will 
recommend any changes to the study design they believe are needed to ensure study validity.  
  
Expected event rate: 150/1000 pdy in the control period and 120/1000 pdy in the 
intervention period; 135/1000 pdy overall. 
  
Efficacy monitoring  
 
Baloxavir-resistant influenza strain transmission 
Additional testing and sequencing of non-influenza respiratory pathogens will also occur. 
Baloxavir resistance will be analyzed via interim analyses and monitored for the duration of the 
study. In the unlikely event that the incidence of the transmission of baloxavir-resistant strains of 
flu exceeds 20% of study participants, the study will be halted.  
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tables and Figures 


 
 
 
 


 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
References 
https://jamanetwork.com/journals/jama/article-abstract/193547