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

Trial Summary

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 the combination of Baloxavir and Oseltamivir safe for humans?

Oseltamivir (Tamiflu) has been used safely in over 11,000 people, including children and the elderly, with the main side effect being mild stomach upset, which can be reduced by taking it with food. No major safety concerns have been found that would limit its use for treating and preventing the flu. ^{1 2 3 4 5}

How is the drug combination of Baloxavir and Oseltamivir unique for treating severe flu?

The combination of Baloxavir and Oseltamivir is unique because it uses two different mechanisms to fight the flu virus: Baloxavir blocks the virus from multiplying by inhibiting a key enzyme, while Oseltamivir prevents the virus from spreading by stopping it from leaving infected cells. This dual approach may enhance the treatment's effectiveness, especially in severe cases. ^{6 7 8 9 10}

What is the purpose of this trial?

This phase II trial studies the effect of baloxavir in combination with oseltamivir in treating severe influenza infection in patients who have previously received a hematopoietic (blood) stem cell transplant or have a hematological malignancy. Baloxavir is an antiviral drug that inhibits the growth of influenza virus, reduces viral load and prevents further influenza infection. Osetamivir is an antiviral drug that blocks enzymes on the surfaces of influenza viruses, interfering with cell release of complete viral particles. Giving baloxavir in combination with oseltamivir may shorten or decrease the intensity of influenza infection compared to oseltamivir alone.

Research Team

Roy F. Chemaly, MD,MPH

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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]

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]

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]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Safety and pharmacology of oseltamivir in clinical use. [2020]

2. United States pubmed.ncbi.nlm.nih.gov

Transplacental transfer of oseltamivir and its metabolite using the human perfused placental cotyledon model. [2022]

3. England pubmed.ncbi.nlm.nih.gov

A multicentre, randomized, controlled trial of oseltamivir in the treatment of influenza in a high-risk Chinese population. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Stability of oseltamivir in various extemporaneous liquid preparations. [2013]

5. United States pubmed.ncbi.nlm.nih.gov

Oseltamivir carboxylate, the active metabolite of oseltamivir phosphate (Tamiflu), detected in sewage discharge and river water in Japan. [2021]

6. Netherlands 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. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and safety of coadministered oseltamivir and rimantadine in healthy volunteers: an open-label, multiple-dose, randomized, crossover study. [2013]

8. England pubmed.ncbi.nlm.nih.gov

Rates and predictors of switching to tenofovir alafenamide-containing ART in a nationwide cohort. [2022]

9. New Zealand pubmed.ncbi.nlm.nih.gov

Baloxavir: First Global Approval. [2020]

10. France 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. [2022]