Xofluza-Wearables Feasibility-Study

Study Overview
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Brief Summary
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The goal of this prospective, interventional, single-center study is to assess whether the early detection of Influenza with smartwatch 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.

Detailed Description
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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. Smartwatch 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 smartwatch devices to monitor biometrics including HR, HR variation (HRV) and proxies of body temperature. A smartwatch 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.

Official Title
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A Feasibility Study of Xofluza Treatment of Influenza in Pediatric Transplant Recipients, Waitlisted Subjects and Household Members After Early Infection Alerting Using Wearable Devices

Conditions
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Infection, Coronavirus, Infections, Influenza, Transplant, Infection Viral

Intervention / Treatment
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* Drug: Baloxavir Marboxil


Participation Criteria
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Eligibility Criteria
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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. All other inclusion criteria listed in 3.3.1. 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 < 40 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 < 40 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.

Ages Eligible for Study
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Minimum Age: 2 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Population 1: Transplant Recipients<br>Participants who are a CHOP kidney, heart, liver or lung single or multiple transplant recipients aged 5 years or older will receive a single dose of Baloxavir. | Drug: Baloxavir Marboxil<br>* Baloxavir marboxil will be administered as either a tablet or granules. Dose is based on body weight: 40 mg for a participants weighing 40-79 kg, or 80 mg for a patient weighing more than or equal to 80 kg<br>* Other names: Xofluza;|
| Experimental: Population 2: Waitlisted Patients for Transplant<br>Participants who are waitlisted CHOP kidney, heart, liver or lung single or multiple transplant recipients aged 5 years or older will receive a single dose of Baloxavir marboxil. | Drug: Baloxavir Marboxil<br>* Baloxavir marboxil will be administered as either a tablet or granules. Dose is based on body weight: 40 mg for a participants weighing 40-79 kg, or 80 mg for a patient weighing more than or equal to 80 kg<br>* Other names: Xofluza;|
| Experimental: Population 3: Household Members (Non-Transplant)<br>Non-Transplanted Household Members aged 5 years or older will receive a single dose of Baloxavir marboxil. | Drug: Baloxavir Marboxil<br>* Baloxavir marboxil will be administered as either a tablet or granules. Dose is based on body weight: 40 mg for a participants weighing 40-79 kg, or 80 mg for a patient weighing more than or equal to 80 kg<br>* Other names: Xofluza;|
| No Intervention: Population 4: Non-Baloxavir treatment subjects<br>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 | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time-to-Clinical-Response | For subjects infected with Influenza investigators will assess Time-to-Clinical-Response in a time frame up to 30 days post Baloxavir treatment in this study vs comparable data available from national control groups. Time to Clinical Response is based on: (a) temperature ranges as measured by (standard of care and/or smartwatch biometric data), oxygen saturation, respiratory status, HR, and hospitalization status; (b) return to healthy baseline data including from biometric data derived from the subjects' smartwatch; (c) time to symptom resolution in a time frame up to 30 days post Baloxavir treatment as assessed from a return to healthy baseline on the daily questionnaires). | 30 days post-Baloxavir treatment | 
| Incidence of complicated hospital stay(s) | Incidence of complicated hospital stay(s) for a time frame up to 30 days post Baloxavir treatment in this study versus comparable data available from the previously described national control groups. A complicated hospital stay is defined as a hospital admission that was either prolonged (greater than 7 days), requiring ICU level of care or death at day 30 as a result of influenza infection. | 30 days post-Baloxavir treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Respiratory Tract Infection Progression Following Treatment | Progression to lower respiratory tract infections in a time frame up to 30 days post Baloxavir treatment in this study versus comparable data available from national control groups. | 30 days post-Baloxavir treatment | 
| Length of hospital Stay Following Treatment | Length of hospital stay in a time frame up to 30 days post Baloxavir treatment in our study versus comparable data available from national control groups. | 30 days post-Baloxavir treatment | 
| Oxygen requirement Following Treatment | Oxygen requirement in a time frame up to 30 days post Baloxavir treatment in this study versus comparable data available from national control groups. | 30 days post-Baloxavir treatment | 
| Rate of Respiratory Failure Following Treatment | Rate of respiratory failure in a time frame up to 30 days post Baloxavir treatment in this study versus comparable data available from national control groups. | 30 days post-Baloxavir treatment | 
| 30-day Mortality Rate Following Treatment | 30-day mortality for post Baloxavir treatment in this study versus comparable data available from national control groups. | 30 days post-Baloxavir treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Transplant, Infections, Wearable Devices