Xofluza-Wearables Feasibility-Study

The goal of this prospective, interventional, single-center study is to assess whether the early detection of Influenza with smart wearable device algorithms and alerting, rapid testing, and subsequent Baloxavir treatment demonstrate better post-infection outcomes versus publicly available- and Centers for Disease Control (CDC)-derived national statistics for equivalent household populations as well as pediatric kidney, heart, liver, lung transplant recipients and waitlisted patients.

Influenza infections are a significant concern for the clinical management of transplant recipients, a highly vulnerable immunocompromised patient group. Early Influenza detection has major benefits for the successful treatment in that crucial early infection time window and allows for more timely mitigation measures to be employed. Xofluza® (Baloxavir Marboxil), FDA approved in 2018 for the treatment of acute Influenza, has been shown to have improved outcome characteristics versus Tamiflu® (Oseltamivir), as well as compliance (a single pill given once, versus 10 pills taken over 5 days for Oseltamivir). The timing of the influenza diagnoses and intervention greatly impacts the outcomes in both antiviral medications though. Smart wearable devices have demonstrated clear utility to detect early infection using physiological signatures such as sub-symptomatic increases in heart rate (HR) and body temperature. Detection of Influenza and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) have been shown to be robustly detectable several days prior to clinical symptoms onset in large well-powered smartwatch studies.

This is a sub-study of the existing Institutional Review Board (IRB) # 20-017872 protocol: "Early Detection of SARS-CoV-2 \& other Infections using Wearable Devices in Pediatric Transplant Patients and Household Members". This is a prospective, interventional, single-center study at The Children's Hospital of Philadelphia comprising kidney, heart, liver and lung transplant recipients, waitlisted patients, and their household members. Subjects will wear smart wearable devices to monitor biometrics including HR, HR variation (HRV) and proxies of body temperature. A smart wearable device alert generated from a validated early infection detection algorithm and alerting platform, precipitates subjects to use an at-home collection kit for SARS-CoV-2, Influenza A/B and respiratory syncytial virus (RSV) A/B which is then sent to a central clinical lab for polymerase chain reaction (PCR)-based diagnoses. If the transplant recipient is positive for Influenza A/B the local clinical care team will be informed to determine if Baloxavir and/or any other medication is warranted. Genentech will make the Baloxavir medication available via the CHOP transplant pharmacist through the recipients' regular pharmacy. If the non-transplanted household members are positive for Influenza or exposed to Influenza positive infected subject(s) their treatment will be determined by their own primary-care. All CHOP transplant recipients will have their medical records reviewed for relevant covariates and confounders after Baloxavir treatment. Study subjects will complete short daily REDCap symptom forms for the pre-, peri- and post-infection periods.

Eligibility Criteria:
Inclusion Criteria

Population 1: Potential Baloxavir treatment group (CHOP transplant subjects 5 years \& up)

* Willing CHOP male or female kidney, heart, liver or lung single or multiple transplant recipients aged 5 years or older as per FDA guidelines.
* Willing to regularly wear a smartwatch and take an at-home positive respiratory virus (RV) panel which will include a diagnoses of Influenza A or B.
* Have an antigen positive diagnoses of Influenza A or B (a PCR-based positive clinical diagnoses of Influenza A or B may be requested in "alarm positive plus antigen positive but asymptomatic" cases).
* Can be included if their treating physician prescribe prophylactic treatment of Baloxavir if the subject has been exposed to Influenza.
* If Baloxavir is prescribed the study subject should be treated within 48 hours of symptom onset (regardless of the alarming time).

Population 2: Potential Baloxavir treatment group (CHOP waitlisted subjects 5 years \& up)

• Willing waitlisted CHOP kidney, heart, liver or lung single or multiple transplant recipients aged 5 years or older, which are anticipated to have a transplant in the next 12 months.

Population 3: Potential Baloxavir treatment group (non-transplanted household members)

* Non-transplanted household member of a CHOP transplant recipient or waitlisted patient
* Be at least 5 years of age.
* Willing to regularly wear a smartwatch and take an at-home positive respiratory virus (RV) panel for diagnoses of Influenza A or B.
* Have a Antigen-based positive diagnoses of Influenza A or B

Population 4: Non-Baloxavir treatment subjects

* CHOP transplant recipients and all other non-transplanted household members who are 2-4 years of age.
* Subjects 5 years and up who are Influenza positive but whom do not receive Baloxavir treatment

Exclusion Criteria

Population 1:

* Any allergy to Baloxavir (although they can remain in the study as an influenza case or control without Baloxavir treatment, or if they have been treated with a different medication for influenza) or a recommendation from the study physicians'/transplant pharmacist(s) not to take Baloxavir.
* Subjects weighing \< 20 kg
* If the subject is unable or unwilling to consent.
* If the subject is younger than 5 years of age.
* If the subject requires mechanical ventilation at time of enrollment.
* If the subject is pregnant or breast feeding at the time of early infection alerting.
* If the subject is taking a prohibited medication. These include Influenza antiviral drugs with the exception of oseltamivir and baloxavir (such as peramivir, laninamivir, zanamivir, rimantadine, umifenovir or amantadine).
* Unwilling or unable to comply with the study requirements.

Population 2: All exclusion criteria listed for Population 1

Population 3:

* Subjects weighing \< 20 kg
* A household transplant recipient is not participating in the study
* Any allergy to Baloxavir (although they will remain in the study as an influenza case/control without treatment)
* A recommendation from the study physicians'/transplant pharmacist not to take Baloxavir
* If the subject is unable or unwilling to consent.
* If the subject is younger than 5 years of age.
* If the subject is pregnant at screening.
* If the subject is taking a prohibited medication. These include Influenza antiviral drugs with the exception of oseltamivir and baloxavir (such as peramivir, laninamivir, zanamivir, rimantadine, umifenovir or amantadine).
* Unwilling or unable to comply with the study requirements.