Evaluation of Antimicrobial Stewardship Using Amoxicillin and Clavulanic Acid for Ventilator-Associated Pneumonia in Intensive Care Patients

The primary objective of this study is to evaluate whether an **antimicrobial stewardship** strategy for **Ventilator Associated Pneumonia (VAP)**, based on daily assessment of clinical cure and subsequent antimicrobial discontinuation, is non-inferior in terms of all-cause mortality, treatment failure, or the occurrence of a new episode of VAP. This is clinically relevant as it aims to optimize antibiotic use, potentially reducing unnecessary exposure to antibiotics and associated adverse effects, while maintaining patient safety and treatment efficacy.

Secondary objectives include: - Investigating the non-inferiority of this strategy in terms of the occurrence of treatment failure and new episodes of VAP. - Assessing whether the strategy increases the number of antibiotic-free days and reduces the global DOOR (Desirability Of Outcome Ranking) and RADAR (Response Adjusted for Duration of Antibiotic Risk analysis) scores by day 28. - Evaluating reductions in the duration of invasive mechanical ventilation, length of stay in the intensive care unit, and rate of VAP recurrence by day 28. - Examining the reduction in complications related to antibiotic therapy, such as gastrointestinal symptoms, acute kidney injury, and skin reactions. - Studying the impact on the rate of acquisition of multidrug-resistant bacteria and subsequent infections. - Assessing improvements in survival at days 28 and 90, adherence to the antimicrobial stewardship strategy, and the medico-economic impact of the intervention.

The clinical trial focuses on **Ventilator Associated Pneumonia** in an **intensive care** setting. The study population includes both male and female adults aged 18 years and older. Participants are selected based on a microbiologically confirmed first episode of VAP, with initial appropriate antibiotic therapy administered. The trial involves a vulnerable population, as it includes patients under mechanical ventilation for more than 48 hours. The sponsor has not provided the total number of participants. Key lifestyle considerations such as diet and physical activity are not specified. Participants must have a definitive diagnosis of VAP, characterized by new pulmonary infiltrates, worsening oxygenation, and specific clinical and microbiological criteria. Written informed consent is required from the patient or a legal representative, with emergency procedures in place if necessary.

The clinical trial is designed to evaluate the efficacy of an **antimicrobial stewardship** strategy for patients with **ventilator-associated pneumonia** (VAP) in an intensive care setting. This is a Phase III, randomized, double-blind, controlled trial. The trial aims to determine if a daily assessment of clinical cure and subsequent discontinuation of antimicrobials, when appropriate, is non-inferior to standard care in terms of all-cause mortality, treatment failure, or the occurrence of a new episode of VAP. The trial is expected to run from September 2022 to January 2026, with participant involvement lasting up to 28 days post-initiation of antibiotic therapy.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), a microbiologically confirmed first episode of VAP, and appropriate initial antibiotic therapy. Written informed consent is required, either from the patient or a legal representative. The inclusion visit will also ensure a definitive diagnosis of VAP, in line with international guidelines, through clinical and microbiological criteria.

Following the inclusion visit, participants will be monitored through regular follow-up visits to assess clinical outcomes, including signs of pneumonia and any new episodes of VAP. The primary endpoint is a composite measure of non-inferiority, including all-cause mortality at day 28, treatment failure within 72 hours post-antibiotic therapy, and new VAP episodes from 72 hours post-treatment to day 28. Secondary endpoints include rates of mortality, treatment failure, new VAP episodes, antibiotic-free days, and other clinical outcomes at day 28.

The end-of-study visit will occur at day 28, where final assessments will be conducted to evaluate the primary and secondary endpoints. Participants may be withdrawn from the study early if they experience significant adverse events, fail to adhere to the study protocol, or withdraw consent. The trial will utilize **amoxicillin** and **clavulanic acid** as the investigational products, administered intravenously, with a maximum treatment period of 7 days. The study is not classified as low intervention, and the trial phase is categorized as Phase III.

The clinical trial involves the administration of **AMOXICILLIN/CLAVULANIC ACID PANPHARMA 2 g/200 mg ADULTES**, a **powder for solution injectable**. This experimental medication is formulated as a **solution for injection** and is administered **intravenously**. The active substances in this formulation are **amoxicillin** and **clavulanic acid**, both of which are of chemical origin. The maximum daily dose is 4 grams, with a total maximum dose of 28 grams over a treatment period not exceeding 7 days. The medication is not a pediatric formulation and is intended for adult use only. The product is manufactured by PANPHARMA and is identified by the marketing authorization number 34009 382 208 5 8.

In addition to the experimental treatment, the study may involve the use of standard-of-care therapy as a comparator treatment. The trial aims to assess the efficacy of antimicrobial stewardship for ventilator-associated pneumonia (VAP) by evaluating clinical cure and the potential for antimicrobial discontinuation. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment protocol. The trial does not involve the use of a placebo, and all treatments are administered under controlled clinical conditions.

Efficacy in the clinical trial titled "ASPIC - Antimicrobial Stewardship for Ventilator Associated Pneumonia in Intensive Care" will be assessed using a composite primary endpoint. This endpoint includes non-inferiority criteria such as all-cause mortality measured at day 28 after the initiation of antibiotic therapy, treatment failure defined by signs of pneumonia within 72 hours after the end of antibiotic therapy at the test of cure visit, and the occurrence of a new episode of microbiologically confirmed **Ventilator-Associated Pneumonia (VAP)** from 72 hours after the end of antibiotic treatment to day 28 after initiation of VAP antibiotic treatment.

Secondary endpoints will further evaluate efficacy through various parameters, including the rate of all-cause mortality, rate of treatment failure, rate of new episodes of VAP, and the number of antibiotic-free alive days from the initiation of VAP antibiotic therapy to day 28. Additional assessments will include a global score constructed with the DOOR and RADAR, duration of invasive mechanical ventilation at day 28, length of ICU stay at day 28, rate of VAP recurrence, rate of antibiotic-related side effects, rate of acquisition of multidrug-resistant (MDR) bacteria at day 28, rate of death at days 28 and 90, rate of non-interruption of antibiotic therapy despite a positive clinical cure in the intervention group, and total cumulative costs of antibiotics at day 28 along with the incremental cost-effectiveness ratio.