Phase III Randomized Controlled Trial of Intravenous Dexamethasone for Severe Influenza‑Induced Acute Hypoxemic Respiratory Failure

The primary objective is to evaluate the efficacy of dexamethasone versus placebo in patients with severe influenza-induced acute hypoxemic respiratory failure using a hierarchical composite endpoint comprising all‑cause mortality, ventilator‑free days, and ICU‑free days from day 0 to day 28. Secondary objectives assess additional clinical and safety outcomes, including:

• Comparison of in‑hospital mortality at day 28.
• Comparison of the incidence of organ dysfunction at day 28.
• Comparison of days alive without life‑support at day 28.
• Comparison of the duration of supplemental oxygen, non‑invasive ventilation, and high‑flow oxygen therapy at day 28.
• Comparison of length of stay in hospital and intensive care unit.
• Comparison of viral clearance between treatment groups.
• Comparison of quality of life at day 90.
• Comparison of 90‑day mortality.
• Comparison of safety endpoints, specifically the occurrence of adverse events between day 0 and day 28.

The trial enrolled adult patients (age ≥ 18 years) of both sexes who were admitted to intensive or intermediate care units within two days of hospitalization for less than five days and who met criteria for influenza-induced acute hypoxemic respiratory failure. Participants were required to have a PCR‑confirmed influenza infection documented within five days, radiographic evidence of pulmonary infiltrates, and at least one respiratory symptom such as cough, purulent sputum, chest pain, or dyspnoea, together with a need for supplemental oxygen (≥3 L/min), non‑invasive ventilation, high‑flow oxygen therapy, or invasive mechanical ventilation. Inclusion also required written or emergency consent and ongoing medical insurance. Both female and male patients were eligible, and the population included individuals classified as vulnerable. No specific lifestyle factors (e.g., diet or physical activity) were stipulated in the available information. The sponsor did not provide the total number of participants enrolled in the study.

The study is a phase III randomized, double-blind, placebo-controlled trial comparing intravenous dexamethasone 6 mg with 0.9 % sodium chloride in adults diagnosed with influenza‑induced acute hypoxemic respiratory failure who are admitted to intensive or intermediate care within two days of ICU admission and five days of hospital admission. After written or emergency consent, participants undergo a screening visit (day ‑1 to 0) to confirm eligibility, including PCR‑positive influenza and requirement for ≥3 L/min supplemental oxygen or any form of ventilatory support. Eligible subjects are randomized 1:1 and receive the assigned study medication daily for up to ten days or until discharge. Follow‑up assessments are scheduled on days 4, 8, 14, and 28 to document vital status, ventilator‑free days, ICU‑free days, organ‑support interventions, nasopharyngeal viral load, and adverse events; the day‑28 visit captures the primary composite endpoint. A final quality‑of‑life questionnaire is completed on day 90, marking the end of participant involvement, which therefore spans approximately three months from screening. Early termination may be triggered by withdrawal of consent, occurrence of a predefined safety event, or loss to follow‑up. Recruitment is planned from September 2026 through December 2029.

The investigational product, DEXAMETHASONE VIATRIS 20 mg/5 ml, is supplied as a solution for injection in a single‑use ampoule. The active ingredient is dexamethasone phosphate. Each dose consists of 6 mg administered intravenously as a single infusion on day 0 of the study. The infusion is to be performed over a period consistent with standard clinical practice, and the exact administration time, volume, and rate are recorded in the case‑report form to ensure protocol adherence and to monitor participant compliance.

The control arm receives a placebo consisting of CHLORURE DE SODIUM 0.9 % solution for infusion, a solution for infusion containing sodium chloride. The placebo is administered at a dose of 13.5 mg, also intravenously, in a single infusion on day 0, mirroring the schedule of the active comparator. Infusion parameters and timing are documented in the same manner as for the investigational product to maintain blinding and to verify compliance with the dosing schedule.

Efficacy will be evaluated using a hierarchical composite endpoint assessed up to day 28. The composite is scored sequentially: (1) in‑hospital all‑cause death at day 28 (yes/no); (2) if alive, the number of ventilator‑free days from day 0 to day 28; (3) if mechanical ventilation was never required, the number of ICU‑free days from day 0 to day 28. Each participant in the dexamethasone group will be pair‑wise compared with a participant in the placebo group, and the outcome will be classified as a win, loss, or tie based on the composite score.

Secondary efficacy parameters include in‑hospital death at day 28; occurrence of organ dysfunction (need for ECMO, invasive mechanical ventilation, renal replacement therapy, or vasopressors); number of days alive without life‑support interventions at day 28; duration of supplemental oxygen, non‑invasive ventilation, and high‑flow oxygen at day 28; length of stay in hospital and ICU; and 90‑day mortality. Nasopharyngeal viral load will be quantified at baseline, day 4, and day 8 using standard laboratory PCR assays. Health‑related quality of life will be measured with the SF‑36 questionnaire at day 90.

Data collection will follow a predefined schedule: vital status and ventilator/ICU utilization recorded daily through day 28; organ‑support interventions documented continuously; viral specimens obtained at the specified time points; and the SF‑36 administered at the 90‑day follow‑up visit. All endpoints will be analyzed according to the prespecified hierarchical and statistical plan, with pairwise comparisons for the primary composite and appropriate descriptive and inferential methods for secondary outcomes.