Prognostic Impact of Early Low Plasma Oseltamivir Carboxylate Concentration in Critically Ill Adults with Severe Influenza in Intensive Care

The primary objective of this study is to determine the **prognostic impact** of early plasma underdosing of **oseltamivir carboxylate** (OC) on early morbidity and mortality in patients hospitalized in the intensive care unit (ICU) for severe influenza infection. This is clinically relevant as it aims to assess the potential consequences of inadequate OC plasma levels on patient outcomes, which could inform treatment strategies and improve management of severe influenza cases in critical care settings.

Secondary objectives include:

• Determining the diagnostic performance of the paracetamol absorption test for early diagnosis of plasma OC underdosing.
• Determining the prevalence of early plasma OC underdosing.
• Identifying factors associated with early plasma OC underdosing.
• Determining the relationship between early OC concentration and viral clearance.
• Determining the relationship between early OC concentration and the acquisition of a variant carrying the oseltamivir resistance mutation (H275Y) in patients with influenza A(H1N1)pdm2009 infection.
• Studying oseltamivir plasma pharmacokinetics and determining the prevalence of OC overdosage.
• Determining the prognostic impact of early plasma OC underdosing on mortality at 28 and 90 days in patients hospitalized in the ICU for severe influenza infection.

The clinical trial involves **adult patients** admitted to the ICU for the management of severe influenza infection, specifically those requiring orotracheal intubation for invasive mechanical ventilation. The study population includes both male and female participants over the age of 18, with no upper age limit specified. Participants are selected based on confirmed severe influenza infection necessitating intensive care, with conditions such as influenza ARDS, cardiorespiratory decompensation of influenza origin, or influenza myocarditis. The trial does not specify the total number of participants, as the sponsor has not provided this information. Participants must have initiated oseltamivir treatment through a gastric tube within 24 hours prior to inclusion, with a maximum of two doses administered. The trial includes a vulnerable population, and participants must be affiliated with a social security scheme or be beneficiaries. Written consent is required from the patient or, if unavailable, from a trusted support person or informed family member. Lifestyle considerations such as diet and physical activity are not detailed in the available data.

The clinical trial is designed to evaluate the **prognostic impact** of early plasma underdosing of **oseltamivir carboxylate** in critically ill patients with severe influenza infection. This study is a prospective cohort trial, which will be conducted in a randomized, double-blind, and controlled manner. The trial is expected to commence on December 18, 2023, and conclude by March 21, 2026. Participants will be involved in the study for a maximum treatment period of 10 days, with the primary endpoint being the number of days alive without invasive mechanical ventilation at day 28.

The sequence of study visits begins with an inclusion (screening) visit, where eligibility criteria are assessed. Participants must be over 18 years of age, have a confirmed severe influenza infection requiring intensive care, and have initiated oseltamivir treatment within 24 hours prior to the visit. Follow-up visits will occur at specified intervals to monitor the plasma concentration of oseltamivir carboxylate and assess clinical outcomes. The end-of-study visit will evaluate the primary and secondary endpoints, including mortality at day 28 and day 90, viral clearance, and the prevalence of oseltamivir resistance mutations.

Participants may be terminated early from the study if they experience adverse events that compromise their safety, withdraw consent, or if the investigator deems it necessary for medical reasons. The study will also assess the diagnostic performance of the paracetamol absorption test at 48 hours for detecting plasma oseltamivir underdosing. The trial aims to provide valuable insights into the management of severe influenza in critically ill patients, with a focus on optimizing oseltamivir dosing strategies.

The clinical trial involves the administration of two **experimental medications**. The first medication is **DOLIPRANE 1000 mg**, which is formulated as a **poudre pour solution buvable en sachet-dose**. This medication contains the active substance **paracetamol** and is administered as an **oral solution**. The maximum daily dose is 1000 mg, and the treatment period is limited to one day. The administration routes include oral, nasogastric tube, or percutaneous endoscopic gastrostomy tube use. The medication is manufactured by Opella Healthcare France SAS and is not a pediatric formulation.

The second medication used in the trial is **Tamiflu 75 mg hard capsules**, containing the active substance **oseltamivir**. This medication is provided in the form of hard capsules and is administered orally. The maximum daily dose is 150 mg, with a total maximum dose of 1500 mg over a treatment period of up to ten days. Similar to the first medication, the administration routes include oral, nasogastric tube, or percutaneous endoscopic gastrostomy tube use. The manufacturer of this medication is Roche Registration GmbH, and it is also not a pediatric formulation.

Both medications are classified as chemical substances and are used as test products in the trial. The trial does not involve any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the prescribed treatment regimen.

Efficacy in this clinical trial will be assessed through a combination of primary and secondary endpoints. The primary endpoint is defined as the number of days alive without invasive mechanical ventilation at day 28 (D28). This endpoint will provide a direct measure of the treatment's impact on patient survival and respiratory function in critically ill patients with severe influenza.

Secondary endpoints include several parameters to evaluate the broader impact of the treatment. These include the diagnostic performance of the paracetamol absorption test at 48 hours (H48) for detecting plasma **oseltamivir** underdosing, with metrics such as sensitivity, specificity, and predictive values. The prevalence of patients with low plasma oseltamivir carboxylate (OC) concentration will also be assessed. Plasma OC underdosage at H48 will be analyzed using univariate and multivariate logistic regression models, considering clinical and biological data as prognostic factors.

Additional secondary endpoints involve viral clearance, determined from nasopharyngeal viral load measurements on day 1 (D1) and day 5 (D5), and its association with plasma OC concentration at H48. The prevalence of the H275Y oseltamivir resistance mutation will be investigated using PCR and high-throughput sequencing. Pharmacokinetic measurements, including Cmax and residual OC and oseltamivir phosphate (OP) levels, will be taken on days 2, 3, and 5. Mortality rates at D28 and D90 will be compared between patients with and without OC underdosing at 48 hours of treatment initiation.