Non-Inferiority Trial of Amoxicillin Versus Amoxicillin/Clavulanic Acid in Elderly Patients with Community-Acquired Pneumonia Hospitalized in Non-ICU Wards

The primary objective of this study is to evaluate the **non-inferiority** in terms of clinical efficacy of narrow-spectrum antimicrobial therapy (amoxicillin) compared to broad-spectrum therapy (amoxicillin/clavulanate) in patients aged 65 years or older, who are hospitalized in a non-intensive care unit (ICU) ward for community-acquired pneumonia (CAP). This assessment is conducted at Day 30 following hospital admission. The clinical relevance of this objective lies in determining whether a less broad-spectrum antibiotic can be as effective as a broad-spectrum one, potentially reducing the risk of antibiotic resistance and adverse effects associated with broader-spectrum antibiotics.

Secondary objectives include: - Rates of early clinical response at Day 3. - Clinical cure after the end of treatment. - Investigation of the total duration of antibiotic treatment during the Day 30 follow-up. - All-cause mortality at Day 30 post-admission. - Rate of polymerase chain reaction (PCR)-positive **Clostridium difficile** among patients with diarrhea. - In-hospital mortality. - ICU transfer during the Day 30 follow-up. - Recurrence of CAP and hospital readmissions up to Day 30 from admission. - Adverse events attributable to antibiotics up to Day 30 from admission. - Compliance with the antibiotic treatment.

The clinical trial involves **participants** aged 65 years or older who are hospitalized in a non-ICU ward for **community-acquired pneumonia** (CAP). The study population includes both male and female subjects, with no specific mention of the total number of participants, as this information was not provided by the sponsor. Participants are selected based on their hospitalization for CAP, characterized by at least two clinical signs such as cough, sputum production, dyspnea, tachypnea, or pleuritic pain, along with radiological evidence of a new infiltrate. The trial does not focus on a vulnerable population, and participants may have comorbidities defined by chronic diseases in immunocompetent individuals. Lifestyle considerations such as diet and physical activity are not specified. The trial aims to compare the clinical efficacy of narrow-spectrum (amoxicillin) versus broad-spectrum (amoxicillin/clavulanate) antimicrobial therapy by Day 30 since hospital admission.

The clinical trial is designed to evaluate the **non-inferiority** of narrow-spectrum antimicrobial therapy using **amoxicillin** compared to broad-spectrum therapy with amoxicillin/clavulanate in patients aged 65 years or older, hospitalized for community-acquired pneumonia (CAP) in a non-intensive care unit (ICU) setting. This is a randomized, controlled, open-label trial with an estimated duration from March 2024 to March 2027. The trial will involve a series of study visits, beginning with an inclusion visit where participants will be screened based on specific criteria, including age, clinical signs of pneumonia, and radiological evidence. Written informed consent will be obtained prior to participation.

Participants will be randomly assigned to receive either amoxicillin or amoxicillin/clavulanate, with the treatment administered intravenously or orally, depending on the formulation. The maximum treatment period is five days, with a maximum daily dose of 3 grams and a total dose not exceeding 15 grams. The primary endpoint is the clinical success rate at Day 30, defined by survival, resolution of infection symptoms, and no need for further antibacterial therapy. Secondary endpoints include early clinical response, clinical cure, and various safety and efficacy measures such as all-cause mortality, adverse events, and hospital readmissions.

Study visits will include follow-up assessments at Days 5 and 10 via phone calls, and a final evaluation at Day 30 to assess the primary and secondary endpoints. Participants are expected to be involved in the study for approximately 30 days. Conditions that may lead to early termination from the study include withdrawal of consent, significant protocol deviations, or adverse events that necessitate discontinuation of the study drug. The trial is categorized as low-intervention due to the minimal additional constraints compared to routine clinical practice, and no Data Safety Monitoring Board (DSMB) is required.

The clinical trial involves the administration of **AMOXICILLIN** in various formulations. One of the experimental medications is **AMOXICILLINE PANPHARMA 1 g**, presented as a powder for solution injectable. This pharmaceutical form is a **SOLUTION FOR INJECTION** and is administered via the **INTRAVENOUS** route. The maximum daily dose is 3 grams, with a total maximum dose of 15 grams over a treatment period of up to 5 days. The medication is produced by PANPHARMA and is not a pediatric formulation. Compliance with the dosing schedule is monitored throughout the trial.

Another experimental treatment is **AMOXICILLINE/ACIDE CLAVULANIQUE PANPHARMA 1 g/200 mg ADULTES**, also in the form of a powder for solution injectable. This combination medication, containing **AMOXICILLIN** and **CLAVULANIC ACID**, is administered via **INTRAVENOUS USE**. The dosing regimen is similar to the previous formulation, with a maximum daily dose of 3 grams and a total maximum dose of 15 grams over a 5-day period. This product is also manufactured by PANPHARMA and is intended for adult use only.

The trial also includes **AMOXICILLINE ARROW 500 mg**, available as a capsule. This formulation is administered **ORALLY**. The dosing schedule allows for a maximum daily intake of 3 grams, with a total maximum dose of 15 grams over the course of 5 days. This product is manufactured by ARROW GENERIQUES and is not designed for pediatric use.

Additionally, the study involves **AMOXICILLIN/ACIDE CLAVULANIQUE ZYDUS FRANCE 500 mg/62.5 mg**, provided as a film-coated tablet. This formulation, containing both **AMOXICILLIN** and **CLAVULANIC ACID**, is also administered **ORALLY**. The dosing parameters are consistent with the other formulations, with a maximum daily dose of 3 grams and a total maximum dose of 15 grams over a 5-day treatment period. This product is produced by ZYDUS FRANCE and is intended for adult patients.

Throughout the trial, participant compliance with the dosing schedules is closely monitored to ensure adherence to the treatment protocols. The trial aims to compare the efficacy of narrow-spectrum **AMOXICILLIN** therapy against broad-spectrum **AMOXICILLIN/CLAVULANATE** therapy in treating community-acquired pneumonia in patients aged 65 years or older.

Efficacy in this clinical trial will be assessed primarily through the **clinical success rate** at Day 30 since hospital admission. This endpoint is defined as survival after the completion of the antibiotic treatment course, resolution of signs and symptoms of the infection such as cough, purulent sputum production, dyspnea, or pleuritic chest pain present at baseline, with no new symptoms or complications attributable to community-acquired pneumonia (CAP), and no need for further antibacterial therapy.

Secondary endpoints include early clinical response, defined as survival with improvement in two or more symptoms of CAP without worsening of other symptoms, and clinical cure after the end of treatment, characterized by resolution of baseline symptoms and no change in antimicrobial regimen. Additional secondary endpoints encompass the number of days taking antibiotics, all-cause mortality at Day 30, the number of positive PCR-positive **Clostridium difficile** cases among patients with diarrhea, deaths during hospitalization, ICU transfers, hospital readmissions, CAP recurrence, adverse events attributable to antibiotics, and total days of antibiotic treatment and hospitalization during the 30-day follow-up period.