Baloxavir and Oseltamivir for the Treatment of Severe Influenza Infection in Immunocompromised Patients

PRIMARY OBJECTIVE:

I. To compare the efficacy of baloxavir marboxil (baloxavir) in combination with oseltamivir to oseltamivir monotherapy as measured by changes in influenza viral loads at day 1 from baseline for treatment of severe influenza infections in immunocompromised hosts (such as hematopoietic cell transplant \[HCT\] recipients and hematological malignancy \[HM\] patients) and compare the main clinical outcome, complicated hospital stay between the intervention arm and control arm.

SECONDARY OBJECTIVES:

I. To compare the efficacy of baloxavir in combination with oseltamivir to oseltamivir monotherapy as measured by changes in influenza viral loads at day 3, 7, 14 and 30 from baseline.

II. To measure the incidence of baloxavir and oseltamivir resistance, development of lower respiratory tract infections (LRTI), oxygen requirement, respiratory failure, changes in microbiome of the upper airway, length of hospital stay and all-cause mortality at day 30 while on baloxavir and/or oseltamivir in these immunocompromised hosts.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive oseltamivir orally (PO) twice daily (BID) for up to 10 days and baloxavir marboxil PO every 72 hours for a total of 3 doses in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive oseltamivir PO BID for up to 10 days in the absence of disease progression or unacceptable toxicity.

After completion of study, patients are followed up at 30 days.

• Baloxavir Marboxil (Drug), also known as BXM, Xofluza: Given PO
• Oseltamivir (Drug): Given PO

Primary outcomes

• Changes in viral loads [On day 0, 1, 3, 7, 14, and 30]: Will be measured via repeat nasopharyngeal swabs at each follow up on day 0, 1, 3, 7, 14 and 30 for influenza quantification.
• Incidence of complicated hospital stay [Up to 30 days]: Defined as a hospital admission that was either prolonged (greater than 7 days), requiring intensive care unit level of care or death at day 30 as a result of influenza infection.

Secondary outcomes

• Rate of resistance to antiviral agents [Up to 30 days]: Will compare variables between the interventional and control groups using Fischer's exact test or Wilcoxon rank sum test when appropriate.
• Progression to lower respiratory tract infections [Up to 30 days]: Will compare variables between the interventional and control groups using Fischer's exact test or Wilcoxon rank sum test when appropriate.
• Length of hospital stay [Up to 30 days]: Will compare variables between the interventional and control groups using Fischer's exact test or Wilcoxon rank sum test when appropriate.
• Oxygen requirement [Up to 30 days]: Will compare variables between the interventional and control groups using Fischer's exact test or Wilcoxon rank sum test when appropriate.
• Rate of respiratory failure [Up to 30 days]: Will compare variables between the interventional and control groups using Fischer's exact test or Wilcoxon rank sum test when appropriate.
• 30-day mortality [At 30 days]: Will compare variables between the interventional and control groups using Fischer's exact test or Wilcoxon rank sum test when appropriate.
• Changes in microbiome diversity [On day 0, 1, 3, 7, 14, and 30]: Analysis of alpha and beta diversity of microbiome will be assessed using Agile Toolkit for Incisive Microbial Analyses. Using Shannon index, we will quantify the alpha diversity of the microbiome. Changes in microbiome diversity will be made by comparing alpha diversity at each time point of sample collection (days 0, 1, 3, 7, 14 and 30).

Sex: All, ages: 12 Years to any

Inclusion criteria:

1. Hematopoeitic cell transplant recipients OR hematological malignancy patients
2. Diagnosed with influenza ⱡ
3. Evidence of LRTI* or high risk upper respiratory tract infection (URTI)**

ⱡ A positive multiplex PCR for influenza is required to confirm a diagnosis of influenza infection.

* LRTI will be defined as influenza cases that have evidence of disease below the level of the trachea on either imaging only (possible LRTI), imaging and microbiological evidence of lower airway disease with a bronchoscopy (probable LRTD) or pathological evidence of disease via biopsy (proven LRTI).

** High risk URI will be defined as those cases of influenza that do not have microbiological nor radiological evidence of LRTI, yet they have an immunodeficiency scoring index (ISI) of 3 or greater as defined by Shah D et al (19) for HCT recipients or severe neutropenia (ANC ≤500 cells/ml) and/or lymphopenia (ALC ≤200 cells/ml) for HM patients.

Exclusion criteria:

1. Patient requires mechanical ventilation at time of enrollment
2. Patient is younger than the age of 12 years old
3. The patient is unable to tolerate oral therapy
4. The patient is pregnant at screening ( Positive serum β-HCG (beta-human chorionic gonadotropin) test for women of child-bearing potential).
5. The patient is on a prohibited medication. These include Influenza antiviral drugs with the exception of oseltamivir and baloxavir (such as peramivir, laninamivir, zanamivir, rimantadine, umifenovir or amantadine) and herbal therapies.
6. The patient is unable to consent will be excluded

• Results publication: Vetter P, Cabecinhas ARG, Schibler M, Kaiser L, Cruz-Fauquex K, Chalandon Y, Masouridi-Levrat S, Neofytos D. Use of baloxavir as adjunctive antiviral therapy to neuraminidase inhibitors in severely immunocompromised individuals infected with influenza. Antimicrob Agents Chemother. 2026 May 6;70(5):e0165925. doi: 10.1128/aac.01659-25. Epub 2026 Mar 27. PMID 41891860

• Roy F Chemaly, MD,MPH, Principal investigator, M.D. Anderson Cancer Center