Randomized Open-Label Non-Inferiority Study of Outpatient Oral Antibiotic Therapy Versus Hospitalization with Intravenous Antibiotics in Pediatric Acute Osteomyelitis

The primary objective of this study is to demonstrate the **non-inferiority** of an outpatient management strategy compared to a standard strategy involving hospitalization for the treatment of acute non-severe **osteomyelitis** in children aged 1-5 years. The focus is on achieving complete recovery without relapse at 6 months post-episode. This objective is clinically relevant as it aims to evaluate whether less invasive outpatient care can be as effective as traditional inpatient care, potentially reducing healthcare costs and improving patient quality of life by minimizing hospital stays.

The clinical trial focuses on children aged **1 to 4 years** diagnosed with **acute osteomyelitis**. The study population includes both male and female participants, with no specific gender preference. Participants are selected based on their first episode of acute osteomyelitis, confirmed by clinical evaluation and imaging techniques such as bone scintigraphy or MRI. The trial excludes children with severe conditions such as sepsis, subperiosteal abscess, associated arthritis, deep vein thrombosis, or scarlatiniform rash. Additionally, participants must have a C-reactive protein level of less than 50 mg/ml and a normal initial bone x-ray or only soft tissue thickening. The trial involves a vulnerable population, given the young age of the participants. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the **non-inferiority** of an outpatient management strategy compared to a standard strategy involving hospitalization for children aged 1 to 5 years with acute osteomyelitis. This study is a randomized, open-label, non-inferiority trial with Bayesian and medico-economic analyses. The trial is expected to run from May 31, 2021, to November 30, 2025. Participants will be randomly assigned to receive either oral antibiotic therapy or conventional hospitalization with intravenous antibiotic therapy. The primary endpoint is complete recovery without relapse at six months, defined by the absence of clinical signs of osteomyelitis and secondary septic complications, as well as no rehospitalization related to the initial infection.

Study visits will follow a structured sequence, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, clinical suspicion of acute osteomyelitis, and absence of severe symptoms or complications. Follow-up visits will be scheduled to monitor the participants' progress and adherence to the treatment protocol. The end-of-study visit will occur at six months post-treatment to assess the primary endpoint. The expected length of participant involvement is approximately six months, with conditions for early termination including the development of severe symptoms, non-compliance with the study protocol, or withdrawal of consent.

The trial involves the administration of antibiotics such as **cefazolin**, **cloxacillin**, **clavulanic acid**, and **amoxicillin**. These medications will be provided in various forms, including powder for solution for injection/infusion and powder for oral suspension, with specific dosing regimens tailored to the treatment group. The maximum treatment period for each medication ranges from three to five days, depending on the formulation and route of administration. Participants will be closely monitored for any adverse effects or complications throughout the study duration.

The clinical trial involves the administration of several **antibiotics** to evaluate their efficacy in the treatment of acute non-severe osteomyelitis in children. **Cefazolin** is utilized in this study as a **powder for solution for injection/infusion**. The active substance, cefazolin, is administered via injection with a maximum daily dose of 150 mg/kg and a total maximum dose of 450 mg/kg over a treatment period of up to 3 days. This formulation is not specifically designed for pediatric use.

**Cloxacillin** is another antibiotic used in the trial, provided as a **solution for injection/infusion**. The active substance, cloxacillin, is administered through injection with a maximum daily dose of 150 mg/kg and a total maximum dose of 450 mg/kg, also over a treatment period of up to 3 days. This formulation is similarly not pediatric-specific.

**Clavulanic acid** is included in the study as a **powder for oral suspension**. The active substance, clavulanic acid, is administered orally with a maximum daily dose of 10 mg/kg and a total maximum dose of 50 mg/kg over a treatment period of up to 5 days. This formulation is not specifically designed for pediatric use.

**Amoxicillin** is administered in two different forms within the trial. The first form is a **powder for oral suspension**, with the active substance, amoxicillin, given orally. The maximum daily dose is 80 mg/kg, with a total maximum dose of 400 mg/kg over a treatment period of up to 5 days. The second form is an **injection**, with the active substance administered via injection. The maximum daily dose for this form is 150 mg/kg, with a total maximum dose of 450 mg/kg over a treatment period of up to 3 days. Neither formulation is specifically designed for pediatric use.

Throughout the trial, participant compliance with the dosing schedules is monitored to ensure adherence to the prescribed treatment regimens. The study aims to compare the efficacy of these antibiotics in an outpatient management strategy against a standard strategy involving hospitalization, focusing on complete recovery without relapse at 6 months post-treatment.

Efficacy in this clinical trial will be assessed by evaluating the primary endpoint of complete recovery without relapse at 6 months. This is defined by the absence of clinical signs of **osteomyelitis** at 6 months, the absence of secondary septic complications such as septic arthritis or periosteal abscess before the end of antibiotic therapy, and the absence of relapse or rehospitalization for osteomyelitis related to the initial infection. The trial aims to demonstrate the non-inferiority of an outpatient management strategy compared to a standard strategy involving hospitalization. The study will involve children aged 1 to 4 years who are experiencing their first episode of acute osteomyelitis, confirmed by bone scintigraphy or MRI, and who meet specific inclusion criteria such as the absence of sepsis and a C-reactive protein (CRP) level of less than 50 mg/ml. The trial is designed as a randomized open-label non-inferiority study with Bayesian and medico-economic analyses, and it is expected to conclude by November 30, 2025.