Baloxavir + Oseltamivir for Severe Flu

Overseen By Roy F. Chemaly, MD,MPH

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Influenza antivirals, Herbal therapies

Disqualifiers: Mechanical ventilation, Age under 12, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 10 days

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of two antiviral drugs, baloxavir (Xofluza) and oseltamivir (Tamiflu), used together to treat severe flu infections. The goal is to determine if combining these drugs reduces the severity or shortens the duration of the flu compared to oseltamivir alone. The trial seeks participants who have undergone a blood stem cell transplant or have blood-related cancers and are currently experiencing a severe flu infection. Participants should have confirmed flu and either a serious lower or high-risk upper respiratory infection. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

You may need to stop taking certain medications. The trial does not allow the use of other influenza antiviral drugs besides oseltamivir and baloxavir, and herbal therapies are also prohibited.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that baloxavir is generally safe and easy to tolerate. Studies have found that baloxavir causes fewer stomach issues, such as nausea and vomiting, compared to oseltamivir. It also appears to reduce fever more quickly. One study found that baloxavir works well in children, suggesting it is safe for many age groups.

Oseltamivir is a common flu treatment with well-established safety. When combined with baloxavir, the treatment might offer additional benefits without significant added risk. No major safety concerns have been reported when these drugs are used together. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about combining baloxavir marboxil and oseltamivir for severe flu because this duo might offer a one-two punch against the virus. While oseltamivir is already a standard treatment that helps stop the flu virus from spreading in your body, adding baloxavir marboxil could enhance the effect by preventing the virus from replicating in the first place. This combination could potentially shorten the duration of symptoms and reduce complications more effectively than oseltamivir alone. With flu seasons becoming increasingly unpredictable, having a more powerful treatment option could make a significant difference in patient outcomes.

What evidence suggests that this trial's treatments could be effective for severe flu?

Research has shown that baloxavir marboxil reduces the flu virus in the body more quickly than oseltamivir. This trial will compare two treatment approaches: one group will receive a combination of baloxavir marboxil and oseltamivir, while another group will receive oseltamivir alone. Baloxavir marboxil, when combined with oseltamivir, may enhance treatment effectiveness for severe flu, particularly in individuals with weakened immune systems. Additionally, baloxavir is associated with fewer side effects than oseltamivir alone, making it a promising option for treating severe flu. ^{1 3 6 7 8}

Who Is on the Research Team?

Roy F. Chemaly, MD,MPH

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with severe flu who've had a blood stem cell transplant or have blood cancer. They must show signs of lower respiratory tract infection (LRTI) or be at high risk due to weakened immunity. Participants need confirmed influenza and can't be on certain antiviral drugs, unable to take oral meds, pregnant, under 12 years old, unable to consent, or require mechanical breathing support.

Inclusion Criteria

I have a lung infection confirmed by imaging, bronchoscopy, or biopsy.

I have a severe lung infection or a serious upper respiratory infection.

I have a high-risk upper respiratory infection without lung involvement, with a weak immune system or very low white blood cell counts.

Exclusion Criteria

Patient requires mechanical ventilation at time of enrollment

I am able to give my consent for treatment.

I am not taking certain flu drugs or herbal treatments.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive oseltamivir orally twice daily for up to 10 days and baloxavir marboxil every 72 hours for a total of 3 doses

10 days

Daily visits for medication administration

Follow-up

Participants are monitored for changes in influenza viral loads and other health outcomes

30 days

Follow-up visits on days 0, 1, 3, 7, 14, and 30

What Are the Treatments Tested in This Trial?

Interventions

• Baloxavir Marboxil
• Oseltamivir

Trial Overview The study tests if combining two antiviral drugs—Baloxavir and Oseltamivir—is more effective in treating severe flu in immunocompromised patients than using Oseltamivir alone. Baloxavir reduces viral growth while Oseltamivir blocks virus spread from infected cells.

How Is the Trial Designed?

Group I: Arm I (oseltamivir, baloxavir marboxil) Experimental Treatment 2 Interventions

Patients receive oseltamivir PO 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.

Group II: Arm II (oseltamivir) Active Control 1 Intervention

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

Baloxavir Marboxil is already approved in United States, Japan, European Union for the following indications:

Approved in United States as Xofluza for:

• Acute uncomplicated influenza within 2 days of illness onset in people aged ≥5 years who are otherwise healthy, or in people aged ≥12 years who are at high risk of developing influenza-related complications

Approved in Japan as Xofluza for:

• Influenza A and B virus infections

Approved in European Union as Xofluza for:

• Treatment of uncomplicated influenza in adults and adolescents aged 12 years and older weighing at least 40 kg

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Published Research Related to This Trial

More than half (55.8%) of the 5,012 patients on TDF-containing therapy switched to the newer tenofovir alafenamide (TAF) within two years of its introduction, especially among those with risk factors for TDF toxicity, such as osteoporosis or impaired renal function.

Factors influencing the switch to TAF included being male, over 50 years old, and having risk factors for TDF toxicity, while patients on certain regimens or with lower CD4 counts were less likely to switch.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rates and predictors of switching to tenofovir alafenamide-containing ART in a nationwide cohort. Surial, B., Cavassini, M., Calmy, A., et al.[2022]

Baloxavir marboxil (Xofluza™) is an oral medication that effectively inhibits the influenza virus by blocking the initiation of mRNA synthesis, which is crucial for the virus's replication.

The drug received its first global approval in Japan in February 2018 for treating influenza A or B infections, and further Phase III trials are ongoing in the USA, EU, and other regions to support its use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Baloxavir: First Global Approval. Heo, YA.[2020]

Oseltamivir phosphate and its active metabolite, oseltamivir carboxylate, can transfer across the placenta, with median fetal transfer rates of 8.5% and 6.6%, respectively, indicating potential exposure to the fetus during pregnancy.

The study suggests that the clinical relevance of this placental transfer warrants further reporting and investigation of oseltamivir treatment outcomes in pregnant patients, as the data on its safety and efficacy during pregnancy is currently limited.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transplacental transfer of oseltamivir and its metabolite using the human perfused placental cotyledon model. Berveiller, P., Mir, O., Vinot, C., et al.[2022]

In a study involving 1053 participants over 96 weeks, both dolutegravir-based regimens (with tenofovir alafenamide or tenofovir disoproxil fumarate) showed non-inferior efficacy compared to the efavirenz-based regimen, with 79% and 78% of participants achieving undetectable HIV-1 levels, respectively.

Participants receiving the tenofovir alafenamide regimen experienced fewer changes in bone density and greater weight gain (average of 7.1 kg) compared to the other regimens, indicating a potentially safer metabolic profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dolutegravir with emtricitabine and tenofovir alafenamide or tenofovir disoproxil fumarate versus efavirenz, emtricitabine, and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection (ADVANCE): week 96 results from a randomised, phase 3, non-inferiority trial. Venter, WDF., Sokhela, S., Simmons, B., et al.[2021]

A study involving healthy volunteers showed that combining oseltamivir and rimantadine for 5 days did not affect the pharmacokinetics of either drug, meaning their absorption and elimination from the body remained unchanged.

The combination treatment was well-tolerated with no serious adverse events reported, indicating it is a safe option for potential enhanced antiviral activity without significant side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and safety of coadministered oseltamivir and rimantadine in healthy volunteers: an open-label, multiple-dose, randomized, crossover study. Cirrincione-Dall, G., Brennan, BJ., Ballester-Sanchis, RM., et al.[2013]

Oseltamivir has been evaluated in over 11,000 subjects across various demographics, including children and high-risk adults, and has shown a favorable safety profile with no significant drug-drug interactions or effects on heart function, even at high doses.

The most common side effect of oseltamivir is transient gastrointestinal disturbance, which can be minimized by taking the medication after a light snack, and overall, no serious safety concerns have been identified that would limit its use in treating and preventing influenza.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and pharmacology of oseltamivir in clinical use. Dutkowski, R., Thakrar, B., Froehlich, E., et al.[2020]

In a study of 118 high-risk patients with chronic respiratory or cardiac diseases, oseltamivir significantly reduced the duration of influenza symptoms by 36.8% and severity by 43.1% compared to symptomatic treatment.

Oseltamivir also lowered the incidence of complications (11% vs. 45%) and antibiotic use (37% vs. 69%), demonstrating its efficacy in preventing secondary issues without increasing overall medical costs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A multicentre, randomized, controlled trial of oseltamivir in the treatment of influenza in a high-risk Chinese population. Lin, JT., Yu, XZ., Cui, DJ., et al.[2022]

Oseltamivir, the active ingredient in Tamiflu, remains stable in compounded suspensions for at least 90 days, regardless of the storage temperature (2-8°C and 25°C).

The stability of oseltamivir was consistent across different suspension vehicles, including PCCA-Plus, PCCA Acacia, and 1% methylcellulose, showing no significant difference compared to the commercial liquid form of Tamiflu.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stability of oseltamivir in various extemporaneous liquid preparations. Ford, SM., Kloesel, LG., Grabenstein, JD.[2013]

Oseltamivir carboxylate (OC), the active form of Tamiflu, was found in sewage treatment plant effluent and river water during the 2008-2009 flu season in Japan, indicating its presence in the environment during influenza outbreaks.

The study demonstrated that advanced sewage treatment methods, specifically ozonation, significantly reduce the concentration of OC in effluent, suggesting a safer approach to managing the environmental impact of Tamiflu during flu epidemics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oseltamivir carboxylate, the active metabolite of oseltamivir phosphate (Tamiflu), detected in sewage discharge and river water in Japan. Ghosh, GC., Nakada, N., Yamashita, N., et al.[2021]

Baloxavir, a new treatment for severe influenza, works by inhibiting a key enzyme needed for the virus to replicate, and it has been recently approved for use.

In a case study of two hematopoietic cell transplant recipients treated with a combination of baloxavir and oseltamivir, their differing responses highlight the need for further investigation into how this combination therapy affects patients with severe influenza.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of baloxavir and oseltamivir for treatment of severe influenza infection in hematopoietic cell transplant recipients: a novel treatment strategy for a high-risk population. Angelidakis, G., Khawaja, F., Mulanovich, VE., et al.[2022]

Citations

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Comparison of the Effectiveness of Baloxavir and ... In conclusion, this real‐world database study found that patients with influenza B treated with baloxavir had a reduced incidence of severe ...

2. journals.plos.org journals.plos.org/plosone/article?id=10.1371/journal.pone.0326777

Clinical efficacy and Safety of Baloxavir Marboxil compared ... Baloxavir marboxil appears more effective than oseltamivir in reducing viral load and is associated with fewer adverse events in children with influenza.

3. nejm.org nejm.org/doi/full/10.1056/NEJMe2503242

Baloxavir Treatment to Reduce Influenza Virus Transmission In addition, upper respiratory tract virus levels were significantly lower with baloxavir than with oseltamivir or placebo as early as 24 hours ...

4. frontiersin.org frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2024.1428095/full

Real-world effectiveness and safety of Baloxavir Marboxil ... Baloxavir Marboxil was superior to Oseltamivir in alleviating influenza symptoms in outpatients with uncomplicated influenza.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11070769/

A Post Hoc Analysis of the BLOCKSTONE Trial - PMC BXM treatment of index cases appeared to result in a greater reduction in secondary household transmission than OTV treatment.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11993522/

Clinical and Virologic Outcomes of Baloxavir Compared ... In this study, baloxavir showed the potential for shortening of symptom duration compared with oseltamivir, which suggests baloxavir as an important treatment ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11317237/

Safety and effectiveness of baloxavir marboxil and ... The incidence of nausea and vomiting is lower with baloxavir compared to oseltamivir, and the duration for complete fever reduction is shorter with baloxavir ...

8. journals.lww.com journals.lww.com/pidj/fulltext/2025/07000/a_phase_3_safety_and_efficacy_study_of_baloxavir.7.aspx

A Phase 3 Safety and Efficacy Study of Baloxavir Marboxil... Baloxavir marboxil (baloxavir) inhibits influenza virus cap-dependent endonuclease and has demonstrated safety and efficacy in children 1–<12 years of age.