Phase III Randomized, Double-Blind Study of Dexamethasone and Oseltamivir Versus Placebo in Patients with Severe Influenza

The primary objective of this randomized, double-blind, multicenter, phase III clinical trial is to compare the percentage of patients hospitalized with **severe influenza** according to treatment arm (oseltamivir-dexamethasone vs oseltamivir-placebo) with status 3 or higher on the Hospital Recovery Scale on day 7 after the start of treatment. This is clinically relevant as it aims to assess the efficacy of dexamethasone in improving patient outcomes in severe influenza cases, potentially reducing the need for supplemental oxygen, ICU admission, or invasive mechanical ventilation, and ultimately decreasing mortality.

Secondary objectives include:

• Comparing the time to clinical stability using the NEWS2 scale and the frequency of serious adverse effects between groups.
• Evaluating the metabolic impact of dexamethasone on hyperglycemia and comparing average hospital stay according to treatment group.
• Assessing the occurrence of clinical failure, defined as progression to ICU admission, intubation, or death, and comparing mortality at days 10, 30, and 90 post-randomization.
• Evaluating the impact of treatment on dependency and frailty, the evolution of the nasal microbiome, the kinetics of the influenza virus in nasopharyngeal swabs, and the impact on inflammatory markers.

The clinical trial focuses on patients diagnosed with **Severe Influenza**, specifically targeting individuals aged 18 years and older. Both male and female participants are included, with no vulnerable populations selected. The study population comprises hospitalized patients who have been diagnosed with influenza A or B virus infection, confirmed by antigen or RT-PCR testing. Participants are required to have an estimated hospital stay of more than 24 hours and must be undergoing treatment with oseltamivir. Women of childbearing age are required to use contraceptive methods until 30 days after completing the treatment. The sponsor has not provided information regarding the total number of participants. The selection criteria ensure that participants are in a stable health condition, excluding those with significant comorbidities that could interfere with the study outcomes. Lifestyle factors such as diet and physical activity are not specified as part of the selection process.

The clinical trial is a **randomized**, **double-blind**, multicenter, phase III study designed to evaluate the efficacy and safety of **dexamethasone** compared to placebo in patients with severe **influenza**. The trial aims to compare the percentage of patients hospitalized with influenza according to treatment arm (oseltamivir-dexamethasone vs. oseltamivir-placebo) with status 3 or higher on the Hospital Recovery Scale on day 7 after the start of treatment. The trial is expected to commence recruitment on October 1, 2024, and conclude by October 1, 2028.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), confirmed diagnosis of influenza A or B, and hospitalization status. Following randomization, participants will receive either the active treatment or placebo for a maximum treatment period of 7 to 10 days, depending on the assigned group. Follow-up visits will be conducted to assess primary and secondary endpoints, including clinical stability, hospital stay duration, ICU admissions, and the need for mechanical ventilation. The end-of-study visit will evaluate the overall health status and any adverse events experienced by the participants.

The expected length of participant involvement is approximately 30 days post-treatment, with follow-up assessments at 30 and 90 days to monitor long-term outcomes. Conditions that may lead to early termination from the study include withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety. The trial will adhere to rigorous scientific and ethical standards to ensure the validity and reliability of the results.

The clinical trial involves the administration of **oseltamivir**, an antiviral medication, as part of the treatment regimen. Oseltamivir is provided in an oral pharmaceutical form, with a maximum daily dose of 150 mg and a total maximum dose of 1500 mg over a treatment period of up to 10 days. The administration route is oral, and the medication is intended to be taken twice daily. Compliance with the dosing schedule is monitored through regular assessments and patient self-reporting.

**Dexamethasone**, a corticosteroid, is also utilized in the study. It is administered orally with a maximum daily dose of 6 mg and a total maximum dose of 43 mg over a 7-day treatment period. The oral route of administration is maintained throughout the study, and dosing compliance is similarly monitored through patient logs and periodic evaluations by the study team.

The study includes a **placebo** group, utilizing microcrystalline cellulose as the placebo substance. This placebo is administered in an oral powder form, with a maximum daily dose of 1 gram and a total maximum dose of 7 grams over a 7-day period. The placebo is designed to match the appearance and administration route of the active treatments to maintain the double-blind nature of the trial. Participant adherence to the placebo regimen is tracked using the same methods as for the active treatments.

The efficacy of the clinical trial evaluating the combination of **dexamethasone** and oseltamivir in patients with severe influenza will be assessed using both primary and secondary endpoints. The primary endpoint is the percentage of patients with a status of 3 or higher on the Hospital Recovery Scale (HRS) on day 7 after the start of treatment. This scale categorizes patients based on their hospitalization status, ranging from hospitalization with supplemental oxygen to death.

Secondary endpoints include several parameters: the time to clinical stability, defined by a NEWS-2 score of less than 2 for more than 24 hours or hospital discharge; the duration of hospital stay; ICU admissions; the need for non-invasive or invasive mechanical ventilation; and mortality from any cause. Additional assessments involve clinical failure, dependency index measured by the Barthel index, and frailty index measured by the Rockhood scale. The impact of steroid treatment on the nasal microbiome will be evaluated by analyzing alpha diversity and differential taxa on day 10 post-randomization. Viral kinetics will be assessed by quantifying viral load at baseline, day 2, 5, and 10. Inflammation markers, including leukocytes, lymphocytes, CRP, and IL-1 and IL-6, will be measured at baseline and on days 2, 5, 7, and 10.