Evaluation of Inhaled Levofloxacin Versus Intravenous Piperacillin/Tazobactam in the Management of Community-Acquired Pneumonia

The primary objective of the study titled "Local Antibiotic Delivery for Community Acquired Pneumonia (LANDCAP 2)" is to evaluate whether treatment with **inhaled levofloxacin** 240 mg twice daily, without systemic antibiotics for 4-5 days, is non-inferior to intravenous **piperacillin/tazobactam**. This is measured by the number of days patients are alive and out of the hospital within 14 days. This objective is clinically relevant as it aims to determine the efficacy of a less invasive treatment option for community-acquired pneumonia, potentially reducing hospital stays and healthcare costs.

Secondary objectives include:

• Reducing the proportion of patients experiencing antibiotic side-effects.
• Preserving diversity in the gut microbiome following treatment.
• Examining whether inhaled levofloxacin is non-inferior on 30-day all-cause mortality.
• Assessing non-inferiority of inhaled levofloxacin as measured by readmission, intensive care transfers, or death within 30 days.
• Evaluating non-inferiority on biochemical and vital parameters such as blood pressure, temperature, and peripheral oxygen saturation.
• Investigating non-inferiority on patient-reported outcomes.

The clinical trial focuses on patients diagnosed with **community-acquired pneumonia**. The study population includes both male and female participants aged 18 years and older. Participants are required to be in general good health, aside from their pneumonia diagnosis, and must have been admitted to the hospital within 24 hours of enrollment. The trial does not involve a vulnerable population. Participants were selected based on specific criteria, including the presence of a radiologically confirmed new-onset chest infiltrate consistent with pneumonia, accompanied by symptoms such as fever, cough, sputum production, dyspnea, and/or chest pain. Additionally, a C-reactive protein level greater than 50 or a central body temperature exceeding 38.0°C is required. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The sponsor has not provided information regarding the total number of participants involved in the study.

The clinical trial is designed to evaluate the efficacy of **levofloxacin** administered via inhalation compared to intravenous **piperacillin/tazobactam** in the treatment of community-acquired pneumonia. This is a Phase 4, randomized, double-blind, controlled trial. The primary objective is to determine if inhaled levofloxacin is non-inferior to intravenous piperacillin/tazobactam, as measured by the number of days participants are alive and out of the hospital within 14 days. The trial is expected to commence on January 1, 2025, and conclude by January 1, 2028.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as hospital admission within 24 hours, new-onset chest infiltrate consistent with pneumonia, and a C-reactive protein level greater than 50. Following the screening, eligible participants will be randomized to receive either inhaled levofloxacin or intravenous piperacillin/tazobactam for a maximum treatment period of 5 days. The study includes follow-up visits to monitor primary and secondary endpoints, such as days alive and out of the hospital at 30 days, antibiotic-related side effects, and changes in gut microbiome diversity.

The end-of-study visit will assess the overall outcomes, including all-cause mortality at 30 days and patient-reported outcomes related to symptoms such as dyspnea, cough, and fatigue. Participant involvement is expected to last up to 30 days, with conditions for early termination including adverse reactions or the need to switch to guideline-based therapy. The trial will ensure rigorous monitoring and data collection to maintain the integrity and reliability of the results.

The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. **SALINE** is utilized as a placebo in this study. It is provided in the form of a **solution for injection** and is administered intravenously. The maximum daily dose is 20 ml, with a total maximum dose of 100 ml over a treatment period of up to 5 days. This isotonic saline solution serves as a control to evaluate the efficacy of the experimental treatments.

**SODIUM CHLORIDE** is another non-experimental treatment used in the trial, also serving as a placebo. It is delivered as a **nebuliser solution** via inhalation. The maximum daily dose is 5 ml, with a total maximum dose of 25 ml over a 5-day treatment period. This saline solution is used to mimic the administration of the active experimental medication without providing therapeutic effects.

The experimental medication **Quinsair 240 mg nebuliser solution** contains the active substance **LEVOFLOXACIN**. It is administered via inhalation as a nebuliser solution. The maximum daily dose is 480 mg, with a total maximum dose of 2400 mg over a 5-day treatment period. This medication is being tested for its efficacy in treating community-acquired pneumonia, with the objective of determining its non-inferiority compared to systemic antibiotics.

**Piperacillin/Tazobactam "Stada"** is used as a comparator treatment in the trial. It is provided as a **solution for infusion** and administered via intravenous infusion. The active substances are **PIPERACILLIN** and **TAZOBACTAM**. The maximum daily dose is 16 g, with a total maximum dose of 80 g over a 5-day treatment period. This combination antibiotic serves as the standard-of-care therapy against which the experimental treatment is compared.

Efficacy in the clinical trial titled "Local Antibiotic Delivery for Community Acquired Pneumonia (LANDCAP 2)" will be assessed using both primary and secondary endpoints. The primary endpoint is the number of days alive and out of hospital within 14 days. Secondary endpoints include the number of days alive and out of hospital at 30 days, days alive and out of hospital and without antibiotics at 30 days, and the proportion of patients experiencing antibiotic-related side effects. Additional secondary endpoints involve differences in gut microbiome diversity and composition in stool and oral samples on day 5 and day 60, all-cause mortality at 30 days, and the proportion of patients readmitted, admitted to ICU, or deceased at 30 days.

Further secondary endpoints include C-reactive protein (CRP) levels on day 5, both continuous and binary, mean arterial pressure (MAP) ≤ 65, respiratory frequency > 25, pulse > 100, or the need for supplemental oxygen on day 5, and procalcitonin (PCT) levels on day 5, both continuous and binary. Temperature ≥ 38.0 on day 5 and patient-reported outcome measurements, such as changes in Visual Analogue Scales for dyspnoea, cough, and fatigue from day 1 to day 5, will also be evaluated. These parameters will be measured and collected at specified time points to ensure comprehensive analysis of the treatment's efficacy.