Comparison of Rifabutin and Rifampicin in the Management of Staphylococcal Prosthetic Joint Infection Using DAIR Strategy: A Multicenter Randomized Non-Inferiority Trial

The primary objective of this study is to demonstrate that in the **DAIR strategy** for prosthetic joint infection due to staphylococci (S. aureus and CoNS), which are susceptible or resistant to methicillin, oral **rifabutin** is non-inferior to oral **rifampicin**. This is clinically relevant as it may provide an alternative treatment option for patients with staphylococcal prosthetic joint infections, potentially improving patient outcomes and expanding therapeutic choices.

Secondary objectives include evaluating the following:

• Tolerance I: Occurrence of serious adverse events (SAEs), including death (i.e., all cause).
• Tolerance II: Occurrence of any adverse event that could be related to rifampicin or rifabutin.
• Tolerance III: Proportion of patients from each arm who will complete the 12-week duration of rifampicin/rifabutin treatment, including early termination of the planned 12 weeks' period of antibiotics.
• Adherence to antibiotics regimen.
• Quality of life, as evaluated by EQ 5D 3L questionnaire.
• Functional prognosis using Oxford Hip and Knee Scores (Oxford questionnaire) evolution according to the location of prosthetic joint infection.
• Long-term efficacy of rifampicin and rifabutin treatment, assessed two years after the surgical intervention.

The clinical trial involves **adults** diagnosed with a staphylococcal prosthetic joint infection, specifically those treated with the debridement, antibiotics, and implant retention (DAIR) strategy. The study population includes both male and female participants aged 18 years and older. Participants are required to have a microbiologically documented infection with **Staphylococcus aureus** or coagulase-negative Staphylococcus, susceptible to rifampicin and at least one other suitable antibiotic. The trial does not include a vulnerable population. Participants must have received at least two days of appropriate empirical antibiotic therapy and must be eligible for French social insurance. Women of childbearing potential are required to use effective contraception. The sponsor has not provided the total number of participants for this trial.

The clinical trial is designed to evaluate the efficacy of **rifabutin** compared to **rifampicin** in the treatment of staphylococcal prosthetic joint infection using the debridement, antibiotics, and implant retention (DAIR) strategy. This is a multicenter, randomized, open-label, non-inferiority trial. The trial aims to demonstrate that oral rifabutin is non-inferior to oral rifampicin in treating infections caused by staphylococci, including both methicillin-susceptible and methicillin-resistant strains. The trial is expected to last until November 2026, with recruitment having started in November 2021.

Participants will be randomly assigned to receive either rifabutin or rifampicin, administered orally in hard capsule form. The maximum treatment period is 12 weeks. The primary endpoint is treatment failure after one year, defined by the need for further surgical procedures, prosthetic joint infection-related death, or the use of unplanned suppressive antibiotic therapy. Secondary endpoints include the occurrence of serious adverse events, liver cytolysis, acute kidney failure, digestive symptoms, and other health-related quality of life measures.

The study involves several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment progress and adverse events, and an end-of-study visit to assess the primary and secondary outcomes. Participants are expected to be involved in the study for up to 24 months, with the primary treatment phase lasting 12 weeks. Conditions that may lead to early termination from the study include the occurrence of severe adverse events, non-compliance with the study protocol, or withdrawal of consent by the participant.

Inclusion criteria require participants to be adults aged 18 years or older with a microbiologically documented staphylococcal prosthetic joint infection, treated by the DAIR strategy, and susceptible to rifampicin and at least one other suitable antibiotic. Participants must have completed at least two days of appropriate empirical antibiotic therapy and provide informed consent. Exclusion criteria are not specified in the provided data. The trial will measure adherence to medication through a daily pill count and assess quality of life using the EQ5D5L questionnaire at specified intervals.

The clinical trial involves the use of two experimental medications, **Rifampicin** and **Rifabutin**, both administered in the form of hard capsules. **Rifampicin**, marketed under the name RIFADINE 300 mg, is provided in a capsule form with a dosage of 300 mg per capsule. The administration route is oral, with a maximum daily dose of 10 mg/kg, not exceeding a total of 840 mg per day. The treatment period is set for a maximum of 12 weeks. The active substance, **Rifampicin**, is of chemical origin and is produced by SANOFI WINTHROP INDUSTRIE. The medication is authorized for use in France and is classified under the ATC code J04AB02.

**Rifabutin**, marketed as ANSATIPINE 150 mg, is also provided in a hard capsule form with a dosage of 150 mg per capsule. The administration route is oral, with a maximum daily dose of 300 mg, not exceeding a total of 25,200 mg over the treatment period. The treatment duration is similarly set for a maximum of 12 weeks. The active substance, **Rifabutin**, is of chemical origin and is produced by SERB. This medication is also authorized for use in France and is classified under the ATC code J04AB04.

In this trial, **Rifabutin** serves as the test medication, while **Rifampicin** is used as the comparator. Both medications are part of a multicenter randomized, open-label, non-inferiority trial aimed at evaluating their efficacy in the treatment of staphylococcal prosthetic joint infection using the DAIR strategy. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the prescribed treatment regimen.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is defined as treatment failure after one year of follow-up. This includes the need for any further surgical procedure such as implant removal, exchange, or amputation, prosthetic joint infection (PJI) related death, or the use of suppressive antibiotic therapy not planned before randomization.

Secondary endpoints will evaluate various aspects of patient outcomes and treatment effects. These include the proportion of patients free from serious adverse events (SAEs), the number and rate of patients experiencing specific adverse events such as liver cytolysis, acute kidney failure, digestive symptoms, uveitis, and neurological disorders. Additionally, the early termination rate, adherence rate to medication, and quality of life will be measured. Quality of life will be assessed using the EQ5D5L auto-questionnaire at specified intervals: week 6, month 6, month 12, and month 24. The Oxford Hip and Knee Scores will also be evaluated at these timepoints to monitor changes over time. Long-term efficacy will be assessed by monitoring treatment failure, as defined for the primary outcome, occurring between 12 and 24 months after initial surgery.

Data collection will involve patient-reported outcomes, clinical assessments, and laboratory tests. The adherence rate will be determined by the number of days on which all doses were missed, recorded in a daily notebook by the patients. This comprehensive approach ensures a robust evaluation of the efficacy of oral **rifabutin** compared to oral **rifampicin** in the treatment of staphylococcal prosthetic joint infection using the DAIR strategy.