Non-Inferiority Study of Rifampin-Free Versus Rifampin-Containing Regimens in Staphylococcal Prosthetic Valve Endocarditis Treatment

The primary objective of this study is to demonstrate that a **rifampin**-free regimen is non-inferior to the rifampin-containing regimen in terms of all-cause mortality in patients with staphylococcal prosthetic valve endocarditis within 6 months after randomization. This is clinically relevant as it may offer an alternative treatment strategy that could potentially reduce the side effects associated with rifampin, thereby improving patient outcomes and quality of life.

Secondary objectives include comparing the following outcomes between treatment groups within 6 months: microbiological failure, relapse, clinically evident embolic events, valvular surgery post-randomization, clinical failure, time to clinical failure, adverse events related to antibiotic endocarditis treatment, bleeding complications, length of hospital stay, and duration of curative antibiotic treatment for endocarditis. Additionally, the study aims to compare all-cause mortality at discharge and at 3 months, as well as readmissions, valvular surgery, all-cause mortality, and relapse at 12 months. Furthermore, it seeks to analyze the characteristics of relapse in staphylococcal prosthetic valve endocarditis regardless of randomization arm and assess the economic efficiency of a rifampin-free regimen compared to a rifampin-containing regimen from a collective perspective over a one-year time horizon.

The clinical trial focuses on participants diagnosed with **staphylococcal endocarditis**, specifically targeting those with prosthetic valve endocarditis. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a confirmed diagnosis of infective endocarditis due to Staphylococcus species, with susceptibility to rifampin, and must have at least one positive blood culture followed by a negative culture after a minimum of 72 hours of incubation. The trial does not involve a vulnerable population. Participants must have initiated antistaphylococcal treatment for endocarditis less than 14 days prior to enrollment. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified. Key inclusion criteria include being insured under a health insurance scheme and providing informed, written consent. The selection process for the trial population is based on these criteria, ensuring a focus on individuals with the specified medical condition and treatment history.

The clinical trial is designed to evaluate the efficacy of a **rifampin**-free regimen compared to a **rifampin**-containing regimen in the treatment of **staphylococcal endocarditis**. This is a multicenter, randomized, controlled, non-inferiority study with a primary endpoint of all-cause mortality at six months post-randomization. The trial is structured as a double-blind study to ensure unbiased results. The estimated duration of the trial is from August 18, 2025, to August 30, 2030, with participant involvement expected to last up to six months. The trial includes several key phases, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of **staphylococcal endocarditis**, and informed consent. Participants will be randomly assigned to either the test or comparator group, receiving either the **rifampin**-free or **rifampin**-containing regimen. Follow-up visits will occur at regular intervals to monitor treatment efficacy and safety, with assessments including blood cultures and clinical evaluations. The end-of-study visit will conclude the participant's involvement, with a final assessment of outcomes. Conditions for early termination from the study include withdrawal of consent, adverse events, or protocol non-compliance. The trial aims to provide robust data on the comparative effectiveness of the two regimens, with secondary endpoints including microbiological failure, relapse rates, and adverse events. The study's design ensures comprehensive data collection to support the primary objective of demonstrating non-inferiority in terms of mortality rates.

The clinical trial involves the administration of several experimental and non-experimental treatments to evaluate their efficacy in the treatment of **staphylococcal prosthetic valve endocarditis**. The primary experimental medication is **Zinforo**, containing the active substance **ceftaroline fosamil**. It is provided as a 600 mg powder for concentrate for solution for infusion. The pharmaceutical form is a solution for infusion, administered via parenteral use. The maximum daily dose is 1800 mg/kg, with a total maximum dose of 75600 mg/kg over a treatment period of up to 6 months. This medication is used off-label for the indication being studied.

**Cefazoline Viatris** is used as a comparator treatment. It contains **cefazolin sodium** and is available as a 1 g powder for solution injectable (IM-IV). The pharmaceutical form is a solution for injection, administered parenterally. The maximum daily dose is 100 mg/kg, with a total maximum dose of 4200 mg/kg over a 6-month period. This treatment is also used off-label for dosage purposes.

Another comparator treatment is **Vancomycine Sandoz**, containing **vancomycin hydrochloride**. It is provided as a 500 mg powder for solution to dilute for infusion or for oral solution. The pharmaceutical form is a solution for infusion, administered orally. The maximum daily dose is 30 mg/kg, with a total maximum dose of 840 mg/kg over a 4-month period, used off-label for dosage purposes.

**Rifadine IV** is included as a comparator, containing **rifampicin**. It is available as a 600 mg powder and solvent for solution for infusion. The pharmaceutical form is a solution for infusion, administered via intravenous infusion. The maximum daily dose is 900 mg, with a total maximum dose of 37800 mg over a 6-month period. This treatment is not used off-label.

A **placebo** is utilized as an auxiliary treatment. It is provided in tablet form and is considered as "no treatment." The placebo is administered orally, with no active substance and no maximum dose, over a 6-month period.

**Cotrimoxazole Teva** is another auxiliary treatment, containing **sulfamethoxazole** and **trimethoprim**. It is available as an 800 mg/160 mg tablet. The pharmaceutical form is a tablet, administered orally. The maximum daily dose is 5760 mg/kg, with a total maximum dose of 161280 mg/kg over a 4-month period, used off-label for indication purposes.

**Daptomycine Medac** is included as an auxiliary treatment, containing **daptomycin**. It is provided as a 350 mg powder for solution injectable/for infusion. The pharmaceutical form is a solution for injection/infusion, administered parenterally. The maximum daily dose is 10 mg/kg, with a total maximum dose of 420 mg/kg over a 6-month period, used off-label for dosage purposes.

**Levofloxacine Arrow Lab** is another auxiliary treatment, containing **levofloxacin**. It is available as a 500 mg film-coated tablet. The pharmaceutical form is a film-coated tablet, administered orally. The maximum daily dose is 500 mg/kg, with a total maximum dose of 14000 mg/kg over a 4-month period, used off-label for indication purposes.

**Rimactan** and **Rifadine** are auxiliary treatments, both containing **rifampicin**. Rimactan is available as a 300 mg hard capsule, and Rifadine is also available as a 300 mg hard capsule. Both are administered orally, with a maximum daily dose of 900 mg and a total maximum dose of 37800 mg over a 6-month period. These treatments are not used off-label.

The efficacy of the clinical trial will be assessed primarily through the evaluation of the **all-cause mortality rate** at 6 months post-randomization. This primary endpoint is designed to determine the non-inferiority of a rifampin-free regimen compared to a rifampin-containing regimen in the treatment of staphylococcal prosthetic valve endocarditis. Secondary endpoints will include a range of clinical and microbiological outcomes measured within 6 and 12 months after randomization. These include the proportions of patients experiencing microbiological failure, relapse, clinically evident embolic events, valvular surgery, and clinical failure, as well as the time to clinical failure, adverse events, bleeding complications, hospital length of stay, and duration of antibiotic treatment.

Additional secondary endpoints will assess all-cause mortality rates at discharge and at 3 months, readmission rates, and further valvular surgeries within 12 months. Microbiological analyses will be conducted to evaluate relapse, reinfection, and associated clinical and biological factors. The trial will also calculate the incremental cost-effectiveness ratio, comparing the cost per quality-adjusted life year (QALY) gained between the two treatment arms. These efficacy parameters will be collected and analyzed at specified time points to ensure comprehensive assessment of the treatment regimens' effectiveness.