Non-Inferiority Trial of Oral Antibiotics Versus Intravenous Antibiotics in Patients with Bacterial Brain Abscess: Moxifloxacin, Linezolid, Clindamycin, and Drug Combination

The primary objective of this study is to evaluate whether **oral antibiotics** are non-inferior to intravenous (IV) antibiotics in the treatment of bacterial **brain abscess**. This is assessed by the number of patients meeting a primary, objective endpoint at six months post-randomization, with a non-inferiority margin set at 10%. The clinical relevance of this objective lies in potentially offering a less invasive and more convenient treatment option for patients, which could improve adherence and reduce healthcare costs associated with IV administration.

Secondary objectives include determining the proportions of patients with a favorable outcome and all-cause mortalities during a one-year follow-up. Additionally, the study aims to assess the completion of the allocated treatment (oral or IV), evaluate safety, and measure quality of life through secondary endpoints. These objectives are crucial for understanding the broader impact of treatment modalities on patient health and well-being over an extended period.

The clinical trial involves a total of **80 participants** diagnosed with a **brain abscess**. The study population includes both male and female subjects, aged 18 years and older, who are not considered part of a vulnerable population. Participants were selected based on specific criteria, including a clinical presentation and brain imaging consistent with a brain abscess, the ability to absorb oral medications, and having received guideline-recommended intravenous antimicrobials for at least 14 consecutive days prior to randomization. The trial does not impose specific lifestyle considerations such as diet or physical activity. Participants are expected to continue treatment for at least another 14 days after randomization, with no progression in neurological deficits or new-onset neurological symptoms, excluding seizures, within 5 days before randomization.

The clinical trial is designed to evaluate the efficacy of oral antibiotics compared to intravenous (IV) antibiotics in the treatment of **brain abscess**. This is an open-label, randomized, non-inferiority trial with a primary objective to determine if oral antibiotics are non-inferior to IV antibiotics, with a non-inferiority margin set at 10%. The trial is expected to run from May 2021 to October 2028, with participants being involved for a maximum of 52 weeks. The study involves a comparison of treatment strategies, specifically an early switch to oral antimicrobials versus continued IV antimicrobial treatment, using licensed and marketed antimicrobials.

Participants will be randomly assigned to either the oral or IV treatment group. The trial includes several key phases: an initial screening visit, randomization, and subsequent follow-up visits. The inclusion visit will assess eligibility based on criteria such as age over 17 years, clinical presentation consistent with a brain abscess, and the ability to absorb oral medications. Participants must have received guideline-recommended IV antimicrobials for at least 14 consecutive days prior to randomization and are expected to continue treatment for at least another 14 days post-randomization. Follow-up visits will monitor the primary endpoint, which includes the 6-month risk of death, rupture of the brain abscess, unplanned aspiration or excision, relapse, or recurrence. Secondary endpoints will assess various outcomes such as all-cause mortality, treatment adherence, and quality of life scores at multiple intervals post-randomization.

The trial will conclude with an end-of-study visit to evaluate the overall treatment outcomes and any adverse events. Participants may be terminated early from the study if they experience progression in neurological deficits or new-onset neurological symptoms, excluding seizures, within 5 days before randomization. The study aims to provide valuable insights into the treatment of brain abscesses, potentially influencing future clinical practices.

The clinical trial involves the administration of several **antimicrobial** agents, each with specific pharmaceutical forms, dosages, and routes of administration. The experimental medication, **Meropenem**, is provided as a 2 g powder for solution for injection/infusion. It is administered intravenously with a maximum daily dose of 6 g and a total dose not exceeding 2184 g over a treatment period of up to 52 weeks. The active substance is **meropenem anhydrous**, and the product is manufactured by HIKMA FARMACÊUTICA (PORTUGAL), S.A.

**Cefotaxime** is another experimental treatment used in the study, available as a 1 g powder for solution for injection/infusion. This medication is also administered intravenously, with a maximum daily dose of 12 g and a total dose limit of 4368 g over the same treatment period. The active substance is **cefotaxime**, produced by MIP PHARMA GMBH.

**Moxifloxacin** is provided in the form of 400 mg film-coated tablets, administered orally. The maximum daily dose is 400 mg, with a total dose not exceeding 145600 mg over 52 weeks. The active substance is **moxifloxacin hydrochloride**, and the product is manufactured by TILLOMED LABORATORIES LTD.

**Linezolid** is available as 600 mg film-coated tablets, also administered orally. The maximum daily dose is 1200 mg, with a total dose limit of 438000 mg over the treatment period. The active substance is **linezolid**, produced by VIATRIS SANTE.

**Clindamycin** is provided in 600 mg hard capsules, administered orally. The maximum daily dose is 2400 mg, with a total dose not exceeding 876000 mg over 52 weeks. The active substance is **clindamycin**, manufactured by MORNINGSIDE HEALTHCARE LTD.

**Metronidazole** is available as 500 mg hard capsules, administered orally. The maximum daily dose is 1500 mg, with a total dose limit of 546000 mg over the treatment period. The active substance is **metronidazole**, produced by SANOFI-AVENTIS MONOPROSOPI A.E.B.E.

**Ceftriaxone** is provided as a 1 g powder and solvent for solution injectable (IM), administered intravenously. The maximum daily dose is 4 g, with a total dose not exceeding 1456 g over 52 weeks. The active substance is **ceftriaxone sodium**, manufactured by EUGIA PHARMA (MALTA) LTD.

**Amoxicillin** is used as a comparator treatment in the form of hard capsules, administered orally. The maximum daily dose is 4 g, with a total dose limit of 1460 g over the treatment period. The active substance is **amoxicillin**.

All medications are chemically derived and are not formulated for pediatric use. Participant compliance with dosing schedules is monitored throughout the trial to ensure adherence to the prescribed treatment regimens.

Efficacy in this clinical trial will be assessed by evaluating the non-inferiority of oral antibiotics compared to intravenous (IV) antibiotics for the treatment of bacterial brain abscess. The primary endpoint for efficacy assessment is the 6-month risk of death, rupture of brain abscess, unplanned aspiration or excision of brain abscess, relapse, or recurrence. Secondary endpoints include the occurrence of each component of the primary composite endpoint after 6 months, all-cause mortality at 3, 6, and 12 months, and unfavourable outcomes at the end of treatment as well as at 3, 6, and 12 months using a sliding dichotomy of the Extended Glasgow Outcome Scale (E-GOS) stratified by the level of comorbidity at the time of randomisation.

Additional secondary endpoints include completion and adherence to the assigned treatment strategy, line complications, durations of admission and antibiotic treatment, number of readmissions within 6 months, occurrence of **Clostridioides difficile** associated diarrhoea, oedema on cranial imaging at 3 months, severe adverse events, and quality of life scores and cognitive evaluations using SF-36, EQ-5D-5L, and MoCA at the time of randomisation, end of treatment, and at 3, 6, and 12 months. These efficacy parameters will be measured and collected at specified timepoints, including the end of treatment and at 3, 6, and 12 months post-randomisation, using validated scales and patient-reported outcomes where applicable.