Non-inferiority of an oral combination therapy versus intravenous antibiotic therapy for the treatment of infective endocarditis: The ROSIE trial

The primary objective is to prospectively evaluate whether a standardized local protocol for partial oral consolidation therapy in patients with infective endocarditis is non-inferior, utilizing a single-arm, performance goal design. The secondary objectives include:

• Assessment of the practical implementation of the protocol, including adherence, deviations, and barriers to uptake.
• Evaluation of plasma antibiotic concentrations and target level attainment of oral antibiotics, including their correlation with treatment outcomes.
• Description of the impact of treatment strategies on hospital length of stay, cost savings, and patient-reported outcomes such as treatment adherence, satisfaction, and quality of life.

The sponsor did not provide information regarding the total number of participants. The study population consists of adults aged between 18 and 64 years, including both male and female individuals. Participants are diagnosed with infective endocarditis involving either a native or prosthetic valve based on established clinical, microbiological, pathological, or imaging criteria. Inclusion requires that the causative organism be identified as Streptococcus species, Enterococcus faecalis, Staphylococcus aureus, a coagulase-negative staphylococcus, or a gram-negative microorganism. Eligible subjects must be admitted during the induction phase of treatment, specifically within the first 10 days of intravenous therapy. The use of highly effective contraception is required for participants of childbearing potential.

This study utilizes a single arm, performance goal design to prospectively evaluate a standardized local protocol for partial oral consolidation therapy in patients diagnosed with infective endocarditis. The research methodology aims to determine if this approach is non-inferior to current standards. The trial is expected to occur between January 2026 and January 2031. The study process begins with a screening phase to confirm eligibility based on diagnostic criteria, age, and causative organism identification. Following successful screening, participants undergo an induction phase consisting of intravenous treatment for less than 10 days before transitioning to the oral therapy protocol. Monitoring includes pharmacokinetic and pharmacodynamic assessments through two specific blood sampling time points during the treatment course. The primary endpoint is measured via composite clinical success at 6 months, which evaluates the absence of mortality, unplanned cardiac surgery, embolic events, and recurrent bacteremia. Additional assessments include patient-reported satisfaction, complications, hospital stay duration, and total antibiotic therapy length. Participant involvement concludes following the completion of the specified treatment and follow-up evaluations.

The experimental treatment arm involves several oral medications for the consolidation therapy of infective endocarditis. Amoxicillin trihydrate and clavulanic acid are administered as 875 mg/125 mg film-coated tablets via oral use at a dose of 2625 mg. Amoxicillin is provided as an oral solution at a dose of 4000 mg. Sulfamethoxazole and trimethoprim are administered as 160 mg/800 mg tablets via oral administration at a dose of 2880 mg. Moxifloxacin is administered as 400 mg film-coated tablets through oral administration. Clindamycin hydrochloride is administered as 300 mg hard capsules via oral route at a dose of 1800 mg. Rifampicin is administered as 300 mg hard capsules via oral administration at a dose of 900 mg. Levofloxacin is administered as 500 mg film-coated tablets via oral route at a dose of 1000 mg.

Comparator treatments include several injectable medications. Gentamicin is administered as a 1 mg/ml solution for infusion via IV infusion at a dose of 3 mg/kg. Cefazolin sodium is administered as a 1 g solution for injection via IV infusion at a dose of 6 g. Flucloxacillin is administered as a 1 g solution for injection via intravenous route at a dose of 12 g. Amoxicillin is administered as a 1 g solution for injection/infusion via intravenous route at a dose of 12 g. Ceftriaxone sodium is administered as a 1 g solution for injection/infusion via intravenous route at a dose of 4 g. Benzylpenicillin sodium is administered as a 1,000,000 IU solution for injection via IV infusion at a dose of 24,000,000 IU.

The primary efficacy endpoint is a composite clinical success at 6 months. This composite measure is defined by the absence of all-cause mortality, unplanned cardiac surgery, embolic events, and recurrent bacteremia in patients with infective endocarditis.

Secondary efficacy parameters include:

• Patient-reported satisfaction at the completion of oral treatment.
• Complications occurring throughout the entire treatment course, including antibiotic-related adverse events, treatment interruption or modification, and non-adherence.
• PK/PD target attainment of oral antibiotics, evaluated per agent based on predefined pharmacokinetic/pharmacodynamic thresholds at two time points during treatment.
• Length of hospital stay and associated costs, calculated from admission to discharge.
• Total duration of antibiotic therapy, measured from treatment initiation to the final administered dose for the same endocarditis episode.