Clinical trial NCT06161454: Xofluza-Wearables Feasibility-Study
Official title: A Feasibility Study of Xofluza Treatment of Influenza in Pediatric Transplant Recipients, Waitlisted Subjects and Household Members After Early Infection Alerting Using Wearable Devices
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Infection, Coronavirus
Infections
Influenza
Transplant
Infection Viral
Keywords: Transplant
Infections
Wearable Devices
smart wearable device
Xofluza
Influenza
Lead sponsor: Children's Hospital of Philadelphia
Sponsor class: OTHER
Collaborators: name: Genentech, Inc.
First posted: 2023-12-08
Enrollment: 540
Sex: ALL
Minimum age (years): 2
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Primary outcomes:
measure: Time-to-Clinical-Response
timeFrame: 30 days post-Baloxavir treatment
measure: Incidence of complicated hospital stay(s)
timeFrame: 30 days post-Baloxavir treatment
Secondary outcomes:
measure: Incidence of Respiratory Tract Infection Progression Following Treatment
timeFrame: 30 days post-Baloxavir treatment
measure: Length of hospital Stay Following Treatment
timeFrame: 30 days post-Baloxavir treatment
measure: Oxygen requirement Following Treatment
timeFrame: 30 days post-Baloxavir treatment
measure: Rate of Respiratory Failure Following Treatment
timeFrame: 30 days post-Baloxavir treatment
measure: 30-day Mortality Rate Following Treatment
timeFrame: 30 days post-Baloxavir treatment
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
Study officials:
affiliation: Children's Hospital of Philadelphia
name: Matthew O Connor, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Baxter D. Evaluating the case for trivalent or quadrivalent influenza vaccines. Hum Vaccin Immunother. 2016 Oct 2;12(10):2712-2717. doi: 10.1080/21645515.2015.1091130. Epub 2016 Jul 19.
citation: Vanderlinden E, Naesens L. Emerging antiviral strategies to interfere with influenza virus entry. Med Res Rev. 2014 Mar;34(2):301-39. doi: 10.1002/med.21289. Epub 2013 Jun 25.
citation: Tsang TK, Lau LLH, Cauchemez S, Cowling BJ. Household Transmission of Influenza Virus. Trends Microbiol. 2016 Feb;24(2):123-133. doi: 10.1016/j.tim.2015.10.012. Epub 2015 Nov 21.
citation: Paules C, Subbarao K. Influenza. Lancet. 2017 Aug 12;390(10095):697-708. doi: 10.1016/S0140-6736(17)30129-0. Epub 2017 Mar 13.
citation: Lee N, Ison MG. Diagnosis, management and outcomes of adults hospitalized with influenza. Antivir Ther. 2012;17(1 Pt B):143-57. doi: 10.3851/IMP2059. Epub 2012 Feb 3.
citation: Kumar D, Michaels MG, Morris MI, Green M, Avery RK, Liu C, Danziger-Isakov L, Stosor V, Estabrook M, Gantt S, Marr KA, Martin S, Silveira FP, Razonable RR, Allen UD, Levi ME, Lyon GM, Bell LE, Huprikar S, Patel G, Gregg KS, Pursell K, Helmersen D, Julian KG, Shiley K, Bono B, Dharnidharka VR, Alavi G, Kalpoe JS, Shoham S, Reid GE, Humar A; American Society of Transplantation H1N1 Collaborative Study Group. Outcomes from pandemic influenza A H1N1 infection in recipients of solid-organ transplants: a multicentre cohort study. Lancet Infect Dis. 2010 Aug;10(8):521-6. doi: 10.1016/S1473-3099(10)70133-X. Epub 2010 Jul 9.
citation: Kumar D, Ferreira VH, Blumberg E, Silveira F, Cordero E, Perez-Romero P, Aydillo T, Danziger-Isakov L, Limaye AP, Carratala J, Munoz P, Montejo M, Lopez-Medrano F, Farinas MC, Gavalda J, Moreno A, Levi M, Fortun J, Torre-Cisneros J, Englund JA, Natori Y, Husain S, Reid G, Sharma TS, Humar A. A 5-Year Prospective Multicenter Evaluation of Influenza Infection in Transplant Recipients. Clin Infect Dis. 2018 Oct 15;67(9):1322-1329. doi: 10.1093/cid/ciy294.
citation: Noshi T, Kitano M, Taniguchi K, Yamamoto A, Omoto S, Baba K, Hashimoto T, Ishida K, Kushima Y, Hattori K, Kawai M, Yoshida R, Kobayashi M, Yoshinaga T, Sato A, Okamatsu M, Sakoda Y, Kida H, Shishido T, Naito A. In vitro characterization of baloxavir acid, a first-in-class cap-dependent endonuclease inhibitor of the influenza virus polymerase PA subunit. Antiviral Res. 2018 Dec;160:109-117. doi: 10.1016/j.antiviral.2018.10.008. Epub 2018 Oct 11.
citation: O'Hanlon R, Shaw ML. Baloxavir marboxil: the new influenza drug on the market. Curr Opin Virol. 2019 Apr;35:14-18. doi: 10.1016/j.coviro.2019.01.006. Epub 2019 Mar 8.
citation: Watanabe A, Ishida T, Hirotsu N, Kawaguchi K, Ishibashi T, Shishido T, Sato C, Portsmouth S, Tsuchiya K, Uehara T. Baloxavir marboxil in Japanese patients with seasonal influenza: Dose response and virus type/subtype outcomes from a randomized phase 2 study. Antiviral Res. 2019 Mar;163:75-81. doi: 10.1016/j.antiviral.2019.01.012. Epub 2019 Jan 23.
citation: Hayden FG, Sugaya N, Hirotsu N, Lee N, de Jong MD, Hurt AC, Ishida T, Sekino H, Yamada K, Portsmouth S, Kawaguchi K, Shishido T, Arai M, Tsuchiya K, Uehara T, Watanabe A; Baloxavir Marboxil Investigators Group. Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents. N Engl J Med. 2018 Sep 6;379(10):913-923. doi: 10.1056/NEJMoa1716197.
citation: Ison MG, Portsmouth S, Yoshida Y, Shishido T, Mitchener M, Tsuchiya K, Uehara T, Hayden FG. Early treatment with baloxavir marboxil in high-risk adolescent and adult outpatients with uncomplicated influenza (CAPSTONE-2): a randomised, placebo-controlled, phase 3 trial. Lancet Infect Dis. 2020 Oct;20(10):1204-1214. doi: 10.1016/S1473-3099(20)30004-9. Epub 2020 Jun 8.
citation: Baker J, Block SL, Matharu B, Burleigh Macutkiewicz L, Wildum S, Dimonaco S, Collinson N, Clinch B, Piedra PA. Baloxavir Marboxil Single-dose Treatment in Influenza-infected Children: A Randomized, Double-blind, Active Controlled Phase 3 Safety and Efficacy Trial (miniSTONE-2). Pediatr Infect Dis J. 2020 Aug;39(8):700-705. doi: 10.1097/INF.0000000000002747.
citation: Ikematsu H, Hayden FG, Kawaguchi K, Kinoshita M, de Jong MD, Lee N, Takashima S, Noshi T, Tsuchiya K, Uehara T. Baloxavir Marboxil for Prophylaxis against Influenza in Household Contacts. N Engl J Med. 2020 Jul 23;383(4):309-320. doi: 10.1056/NEJMoa1915341. Epub 2020 Jul 8.
citation: Umemura T, Mutoh Y, Kawamura T, Saito M, Mizuno T, Ota A, Kozaki K, Yamada T, Ikeda Y, Ichihara T. Efficacy of baloxavir marboxil on household transmission of influenza infection. J Pharm Health Care Sci. 2020 Oct 1;6:21. doi: 10.1186/s40780-020-00178-4. eCollection 2020.
citation: Shirley M. Baloxavir Marboxil: A Review in Acute Uncomplicated Influenza. Drugs. 2020 Jul;80(11):1109-1118. doi: 10.1007/s40265-020-01350-8.
citation: Neuberger E, Wallick C, Chawla D, Castro RC. Baloxavir vs oseltamivir: reduced utilization and costs in influenza. Am J Manag Care. 2022 Mar 1;28(3):e88-e95. doi: 10.37765/ajmc.2022.88786.
citation: Alavi A, Bogu GK, Wang M, Rangan ES, Brooks AW, Wang Q, Higgs E, Celli A, Mishra T, Metwally AA, Cha K, Knowles P, Alavi AA, Bhasin R, Panchamukhi S, Celis D, Aditya T, Honkala A, Rolnik B, Hunting E, Dagan-Rosenfeld O, Chauhan A, Li JW, Bejikian C, Krishnan V, McGuire L, Li X, Bahmani A, Snyder MP. Real-time alerting system for COVID-19 and other stress events using wearable data. Nat Med. 2022 Jan;28(1):175-184. doi: 10.1038/s41591-021-01593-2. Epub 2021 Nov 29.
citation: Keating BJ, Mukhtar EH, Elftmann ED, Eweje FR, Gao H, Ibrahim LI, Kathawate RG, Lee AC, Li EH, Moore KA, Nair N, Chaluvadi V, Reason J, Zanoni F, Honkala AT, Al-Ali AK, Abdullah Alrubaish F, Ahmad Al-Mozaini M, Al-Muhanna FA, Al-Romaih K, Goldfarb SB, Kellogg R, Kiryluk K, Kizilbash SJ, Kohut TJ, Kumar J, O'Connor MJ, Rand EB, Redfield RR, Rolnik B, Rossano J, Sanchez PG, Alavi A, Bahmani A, Bogu GK, Brooks AW, Metwally AA, Mishra T, Marks SD, Montgomery RA, Fishman JA, Amaral S, Jacobson PA, Wang M, Snyder MP. Early detection of SARS-CoV-2 and other infections in solid organ transplant recipients and household members using wearable devices. Transpl Int. 2021 Jun;34(6):1019-1031. doi: 10.1111/tri.13860. Epub 2021 May 5.
citation: Mishra T, Wang M, Metwally AA, Bogu GK, Brooks AW, Bahmani A, Alavi A, Celli A, Higgs E, Dagan-Rosenfeld O, Fay B, Kirkpatrick S, Kellogg R, Gibson M, Wang T, Hunting EM, Mamic P, Ganz AB, Rolnik B, Li X, Snyder MP. Pre-symptomatic detection of COVID-19 from smartwatch data. Nat Biomed Eng. 2020 Dec;4(12):1208-1220. doi: 10.1038/s41551-020-00640-6. Epub 2020 Nov 18.
citation: Grzesiak E, Bent B, McClain MT, Woods CW, Tsalik EL, Nicholson BP, Veldman T, Burke TW, Gardener Z, Bergstrom E, Turner RB, Chiu C, Doraiswamy PM, Hero A, Henao R, Ginsburg GS, Dunn J. Assessment of the Feasibility of Using Noninvasive Wearable Biometric Monitoring Sensors to Detect Influenza and the Common Cold Before Symptom Onset. JAMA Netw Open. 2021 Sep 1;4(9):e2128534. doi: 10.1001/jamanetworkopen.2021.28534.
citation: Vilchez RA, McCurry K, Dauber J, Lacono A, Griffith B, Fung J, Kusne S. Influenza virus infection in adult solid organ transplant recipients. Am J Transplant. 2002 Mar;2(3):287-91. doi: 10.1034/j.1600-6143.2002.20315.x.
citation: Marois C, Nedelec T, Pelle J, Rozes A, Durrleman S, Dufouil C, Demoule A. Comparison of Clinical Profiles and Mortality Outcomes Between Influenza and COVID-19 Patients Invasively Ventilated in the ICU: A Retrospective Study From All Paris Public Hospitals From 2016 to 2021. Crit Care Explor. 2022 Jul 25;4(7):e0737. doi: 10.1097/CCE.0000000000000737. eCollection 2022 Jul.
citation: Helantera I, Gissler M, Rimhanen-Finne R, Ikonen N, Kanerva M, Lempinen M, Finne P. Epidemiology of laboratory-confirmed influenza among kidney transplant recipients compared to the general population-A nationwide cohort study. Am J Transplant. 2021 May;21(5):1848-1856. doi: 10.1111/ajt.16421. Epub 2021 Feb 19.
citation: Mombelli M, Kampouri E, Manuel O. Influenza in solid organ transplant recipients: epidemiology, management, and outcomes. Expert Rev Anti Infect Ther. 2020 Feb;18(2):103-112. doi: 10.1080/14787210.2020.1713098. Epub 2020 Jan 18.
citation: Kuchipudi SV, Behring D, Nissly R, Chothe SK, Gontu A, Ravichandran A, Butler T. Mitigating the Impact of Emerging Animal Infectious Disease Threats: First Emerging Animal Infectious Diseases Conference (EAIDC) Report. Viruses. 2022 Apr 30;14(5):947. doi: 10.3390/v14050947.