Evaluation of Oseltamivir and Drug Combinations in Hospitalized Patients with Acute Respiratory Tract Infection: A Randomized Adaptive Platform Trial

The primary objective of this study is to evaluate the effect of various interventions on a composite outcome of 90-day all-cause mortality and, among survivors, a daily ordinal scale of trajectory of illness and recovery over 28 days in hospitalized patients with acute **respiratory tract infection**. This is clinically relevant as it aims to improve patient outcomes by identifying effective treatments for reducing mortality and enhancing recovery trajectories in this patient population.

The secondary objectives include:

• Determining the effect of interventions on hospital length of stay (LOS) and 90-day mortality.
• Evaluating other endpoints as indicated for specific domains, where feasible or specified in a Domain-Specific Appendix (DSA) or Region-Specific Appendix (RSA).
• Assessing survival, health-related quality of life (HRQoL), and disability after 180 days.

The clinical trial involves **hospitalized patients** with **acute respiratory tract infection**. The study population includes both male and female participants aged 28 days and older. The trial does not focus on a vulnerable population. Participants were selected based on their hospitalization status and the presence of an acute respiratory tract infection. The sponsor has not provided information regarding the total number of participants. The trial does not specify any particular lifestyle considerations such as diet or physical activity. Key inclusion criteria include being hospitalized, having an acute respiratory tract infection, and meeting domain-specific eligibility criteria, with eligibility for at least two interventions within a domain. The study aims to evaluate the effect of various interventions on a composite of 90-day all-cause mortality and, among survivors, a daily ordinal scale of illness trajectory and recovery over 28 days.

The clinical trial is designed to evaluate the effectiveness of various interventions for hospitalized patients with acute **respiratory tract infection**. This trial employs a **randomized**, **double-blind**, and **controlled** methodology to ensure the reliability and validity of the results. The trial is structured as a multifactorial adaptive platform, allowing for the assessment of multiple interventions simultaneously. The primary objective is to assess the impact of these interventions on a composite endpoint of 90-day all-cause mortality and a daily ordinal scale of illness and recovery trajectory over 28 days. The trial is expected to conclude by March 2026, with recruitment having commenced in April 2016.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as hospitalization, age of 28 days or older, and the presence of an acute respiratory tract infection. Following randomization, participants will attend follow-up visits to monitor their health status and response to the interventions. The end-of-study visit will occur at the conclusion of the participant's involvement, which may last up to 90 days post-randomization, depending on their recovery trajectory and the specific intervention received.

The expected length of participant involvement is determined by the intervention and the individual's recovery, with a maximum duration of 90 days. Conditions that may lead to early termination from the study include withdrawal of consent, adverse events, or failure to adhere to the study protocol. The trial's design ensures that data collection and analysis are conducted rigorously, with primary and secondary endpoints clearly defined to measure outcomes such as hospital length-of-stay and mortality rates. This comprehensive approach aims to provide valuable insights into the management of respiratory tract infections in hospitalized patients.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, routes, and frequencies of administration. **Oseltamivir** is administered as a hard capsule with a maximum daily dose of 150 mg, taken orally for up to 10 days. It functions as a neuraminidase inhibitor.

**Erythromycin lactobionate** is provided as a powder for solution for infusion, with a maximum daily dose of 12 g, administered via intravenous injection or infusion over a period of 14 days. It is classified as a macrolide antibiotic.

**Erythromycin** is available in tablet form, with a maximum daily dose of 4 g, taken orally for up to 14 days. It is also categorized as a macrolide antibiotic.

**Roxithromycin** is administered as a tablet with a maximum daily dose of 300 mg, taken orally for up to 14 days, and is classified as a macrolide antibiotic.

**Azithromycin** is provided in two forms: as a tablet with a maximum daily dose of 500 mg, taken orally for up to 14 days, and as a powder for solution for infusion, administered intravenously with the same daily dose and duration. Both forms are classified as macrolide antibiotics.

**Clarithromycin** is available in two forms: as a powder for concentrate for solution for infusion with a maximum daily dose of 1 g, administered intravenously for up to 14 days, and as a tablet with the same daily dose, taken orally for the same duration. It is classified as a macrolide antibiotic.

**Ceftriaxone** is administered as a powder for solution for injection or infusion, with a maximum daily dose of 4 g, delivered intravenously for up to 14 days. It is classified as a cephalosporin antibiotic.

**Baloxavir marboxil** is provided as a film-coated tablet with a maximum daily dose of 80 mg, taken orally for up to 2 days. It functions as an antiviral medication.

**Imatinib** is administered as a film-coated tablet with a maximum daily dose of 800 mg, taken orally for up to 14 days. It is classified as a protein kinase inhibitor.

**Moxifloxacin** is provided as a solution for infusion with a maximum daily dose of 400 mg, administered intravenously for up to 14 days. It is classified as a fluoroquinolone antibiotic.

**Baricitinib** is administered as a film-coated tablet with a maximum daily dose of 4 mg, taken orally for up to 10 days. It functions as an immunosuppressant.

**Levofloxacin** is provided as a solution for infusion with a maximum daily dose of 1 g, administered intravenously for up to 14 days. It is classified as a fluoroquinolone antibiotic.

**Hydrocortisone** is administered as a powder for solution for injection or infusion, with a maximum daily dose of 200 mg, delivered intravenously for up to 7 days. It functions as a corticosteroid.

**Amoxicillin and beta-lactamase inhibitor** is provided as a powder for solution for injection or infusion, with a maximum daily dose of 4 g, administered intravenously for up to 14 days. It is classified as a beta-lactam antibiotic.

**Dexamethasone** is available in two forms: as a tablet with a maximum daily dose of 6 mg, taken orally for up to 10 days, and as a solution for injection or infusion, administered intravenously with the same daily dose and duration. It functions as a corticosteroid.

**Tocilizumab** is provided as a concentrate for solution for infusion with a maximum daily dose of 8 mg, administered intravenously for up to 1 day. It functions as an interleukin inhibitor.

**Piperacillin and beta-lactamase inhibitor** is administered as a powder for solution for infusion, with a maximum daily dose of 16 g, delivered intravenously for up to 14 days. It is classified as a beta-lactam antibiotic.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial does not include any non-experimental treatments such as standard-of-care therapy or placebo. The focus is on evaluating the effects of these experimental medications on the specified clinical outcomes.

The efficacy of the clinical trial will be assessed using a primary endpoint known as the Survival and Recovery Trajectory. This endpoint is a composite measure that includes 90-day all-cause mortality and, for survivors, a daily ordinal scale that tracks the trajectory of illness and recovery over 28 days. The ordinal scale is hierarchical and consists of five categories: hospitalized on ECMO or invasive mechanical ventilation, hospitalized on non-invasive ventilation or high-flow oxygen, hospitalized on low-intensity oxygen, hospitalized with no oxygen, and discharged from the index hospitalization.

Secondary endpoints include hospital length-of-stay and mortality censored at 90 days. Additionally, domain-specific secondary outcomes will be evaluated during the index hospitalization, censored 90 days after enrollment. The trial aims to evaluate the effect of various interventions on these endpoints for hospitalized patients with acute respiratory tract infections, including those with community-acquired pneumonia and COVID-19 infection.