Non-Inferiority Trial of Cotrimoxazole Versus Standard Care in Ventilator-Associated Pneumonia Management in ICU Patients

The primary objective of this study is to demonstrate that **cotrimoxazole** is non-inferior to the best standard of care for the treatment of **ventilator-associated pneumonia** (VAP) in the intensive care unit (ICU). This is clinically relevant as it may provide an alternative treatment option that is equally effective, potentially offering benefits in terms of cost, availability, or side effect profile.

The secondary objectives are to demonstrate the superiority of cotrimoxazole over the best standard of care in terms of several clinical outcomes: mortality at day 28 and day 90, mechanical ventilation-free days through day 28, rate of cure between days 7 and 10, VAP recurrence, ICU length of stay, hospital length of stay, and overall antibiotic consumption. Additionally, the study aims to assess the safety of cotrimoxazole compared to the best standard of care at day 28, specifically regarding allergy to antibiotics. Furthermore, the ecological impact of the treatment will be evaluated by examining the acquisition of multidrug-resistant (MDR) bacteria in the ICU and the rate of **Clostridioides difficile** infection.

The clinical trial involves participants diagnosed with **ventilator-associated pneumonia** (VAP) in an **intensive care** setting. The study population includes both male and female adults aged 18 years and older, who are under mechanical ventilation for a minimum of five days. Participants are required to have microbiologically confirmed VAP, preferably diagnosed through a distal lung sample. The trial population is selected based on the susceptibility of Enterobacteriaceae to cotrimoxazole, and for those with polymicrobial VAP, all bacteria must be susceptible to the treatment. Participants must have been treated with an appropriate empiric antibiotic therapy for at least 24 to 72 hours. The study includes a vulnerable population, and the stability of haemodynamic and respiratory parameters is a consideration. The sponsor has not provided the total number of participants involved in the trial.

The clinical trial is designed to evaluate the efficacy of **co-trimoxazole** as a de-escalation treatment for **ventilator-associated pneumonia** (VAP) in an intensive care unit setting. This is a multicentric, randomized, controlled, non-inferiority trial. The primary objective is to demonstrate that co-trimoxazole is non-inferior to the best standard of care for treating VAP in the intensive care unit. The trial is expected to run from September 2023 to December 2026, with participant involvement lasting up to 28 days post-inclusion.

Participants will be randomly assigned to receive either co-trimoxazole or a comparator antibiotic regimen. The trial will be conducted in a double-blind manner to ensure unbiased results. The inclusion criteria require participants to be adults (age ≥ 18 years) who have been under mechanical ventilation for at least five days and have microbiologically confirmed VAP. The VAP must be caused by Enterobacteriaceae susceptible to co-trimoxazole, and participants must have been treated with an appropriate empiric antibiotic therapy for at least 24 to 72 hours prior to inclusion.

The sequence of study visits includes an initial screening visit to confirm eligibility, followed by regular follow-up visits to monitor the participant's clinical status, vital signs, and any adverse events. The primary endpoint is the vital status at day 28, while secondary endpoints include the number of mechanical ventilation-free days, clinical cure rates, and safety assessments. The end-of-study visit will occur at day 28, or earlier if the participant is discharged from the ICU or hospital.

Participants may be withdrawn from the study early if they experience significant adverse events, if their condition worsens, or if they withdraw consent. The trial will also assess the ecological impact, including the rate of multidrug-resistant bacterial colonization and the incidence of **Clostridioides difficile** infection. The trial's findings will contribute to optimizing treatment strategies for VAP in critically ill patients.

The clinical trial involves the administration of **IMIPENEM MONOHYDRATE**, a chemical compound provided in the form of a powder for solution for infusion. The maximum daily dose is 4 grams, with a total maximum dose of 24 grams over a treatment period of up to 6 days. The medication is administered via **intravenous infusion**.

**MEROPENEM** is another experimental medication used in this trial. It is also a chemical compound, available as a powder for solution for injection or infusion. The maximum daily dose is 6 grams, with a total maximum dose of 36 grams over a 6-day period. Administration is conducted through intravenous infusion.

**OFLOXACIN** is provided as a solution for infusion, with a maximum daily dose of 800 milligrams and a total maximum dose of 4.8 grams over the course of 6 days. This medication is administered via intravenous infusion.

**CEFEPIME** is administered as a powder for solution for injection or infusion. The maximum daily dose is 6 grams, with a total maximum dose of 36 grams over a 6-day treatment period. The route of administration is intravenous infusion.

**TEMOCILLIN** is available as a powder for solution for injection or infusion, with a maximum daily dose of 6 grams and a total maximum dose of 36 grams over 6 days. It is administered through intravenous infusion.

**LEVOFLOXACIN** is provided as a solution for injection, with a maximum daily dose of 1 gram and a total maximum dose of 6 grams over a 6-day period. The administration route is intravenous infusion.

**CIPROFLOXACIN** is administered as a powder for injection, with a maximum daily dose of 1.2 grams and a total maximum dose of 7.2 grams over 6 days. The route of administration is intravenous infusion.

**AMOXICILLIN** is available as a powder for solution for injection or infusion, with a maximum daily dose of 8 grams and a total maximum dose of 48 grams over a 6-day period. It is administered via intravenous infusion.

**AZTREONAM** is provided as a powder for solution for injection, with a maximum daily dose of 8 grams and a total maximum dose of 48 grams over 6 days. The administration route is intravenous infusion.

**CO-TRIMOXAZOLE** serves as the test medication in this trial. It is a chemical compound available as a solution for injection, with a maximum daily dose of 5.76 grams and a total maximum dose of 34.56 grams over a 6-day period. The route of administration is intravenous infusion.

**ERTAPENEM** is administered as a powder for concentrate for solution for infusion, with a maximum daily dose of 2 grams and a total maximum dose of 12 grams over 6 days. The administration is conducted via intravenous infusion.

**AMOXICILLIN SODIUM** is available as a powder for solution for injection or infusion, with a maximum daily dose of 8.8 grams and a total maximum dose of 52.8 grams over a 6-day period. It is administered through intravenous infusion.

**CEFTRIAXONE** is provided as a powder for solution for infusion, with a maximum daily dose of 3 grams and a total maximum dose of 18 grams over 6 days. The route of administration is intravenous infusion.

**PIPERACILLIN SODIUM** is administered as a powder for solution for injection or infusion, with a maximum daily dose of 20 grams and a total maximum dose of 120 grams over a 6-day period. The administration route is intravenous infusion.

**PIPERACILLIN** is available as a powder for solution for infusion, with a maximum daily dose of 16 grams and a total maximum dose of 96 grams over 6 days. It is administered via intravenous infusion.

**CEFOTAXIME** is provided as a powder for solution for injection or infusion, with a maximum daily dose of 8 grams and a total maximum dose of 48 grams over a 6-day period. The administration is conducted through intravenous infusion.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the **vital status at day 28**. Secondary endpoints include the number of mechanical ventilation-free days from inclusion to day 28 or death, clinical, biological, and radiological cure evaluated 7 to 10 days after the diagnosis of Ventilator-Associated Pneumonia (VAP), and the occurrence of a new episode of VAP with the same Enterobacteriaceae. Additional secondary endpoints are the length of stay in the intensive care unit (ICU) and hospital, the number of antibiotic-free days from inclusion to day 28 or death, safety measured by the rate of allergy due to antimicrobial drugs, and the ecological impact assessed by the evolution of the rate of multidrug-resistant (MDR) bacterial colonization from systematic screening at enrolment until ICU discharge. The diagnostic of Clostridioides difficile infection between inclusion and day 28 and the vital status at day 90 are also included as secondary endpoints.

The clinical, biological, and radiological cure will be defined as the combination of resolution of signs and symptoms present at enrolment, biological improvement, and improvement or lack of progression of radiological signs, as adjudicated by an independent committee using the PROBE methodology. The trial is designed to demonstrate that cotrimoxazole is non-inferior to the best standard of care for the treatment of VAP in the ICU setting. The trial will follow a multicentric, non-inferiority, randomized controlled design, with assessments conducted at specified time points to ensure comprehensive evaluation of the treatment's efficacy.