Rifampicin Combination Therapy versus Targeted Antimicrobial Monotherapy in the Oral Antimicrobial Treatment Phase of Staphylococcal Prosthetic Joint Infection

The primary objective of this study is to determine whether targeted monotherapy with **clindamycin** for prosthetic joint infection (PJI) in the oral treatment phase is non-inferior to the traditional combination treatment of **rifampicin** and fluoroquinolones. This is clinically relevant as it may offer a simplified treatment regimen with potentially fewer side effects and improved patient compliance, while maintaining efficacy in managing PJI.

Secondary objectives include evaluating the quality of life using the EQ-5D-5L questionnaire at specified intervals, which provides a comprehensive measure of health status for clinical and economic appraisal. Additionally, the study aims to assess adverse events, including the number of serious adverse events (SAEs) during antimicrobial treatment and follow-up, the frequency of regimen switches, antibiotic side effects classified by the modified Hartwig and Siegel scale, the incidence of **Clostridioides difficile** infection during treatment, and the occurrence of rifampicin resistance in cases of microbiologically confirmed treatment failure.

The clinical trial focuses on adult patients diagnosed with **prosthetic joint infection** (PJI), specifically those involving the hip or knee and caused by Staphylococcus spp. The study population includes both male and female participants aged 18 years and older. Participants are required to have been hospitalized and treated with DAIR (Debridement, Antibiotics, and Implant Retention). The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of targeted monotherapy with **clindamycin** compared to traditional combination therapy with **rifampicin** and fluoroquinolones in the oral treatment phase of **prosthetic joint infection**. This is a phase 4 randomized, controlled, double-blind trial categorized as a low-intervention clinical trial. The trial is expected to run from March 2023 to March 2028, with the primary objective of determining non-inferiority in treatment success 15 months post-DAIR (Debridement, Antibiotics, and Implant Retention). The trial will involve adult patients diagnosed with hip or knee prosthetic joint infection caused by Staphylococcus spp. and treated with DAIR.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on the principal inclusion criteria. Following randomization, participants will receive either the monotherapy or combination therapy for a maximum treatment period of 12 weeks. Follow-up visits will be scheduled at week 6 post-surgical debridement and at 3 months to assess secondary endpoints, including quality of life, adverse events, and antibiotic resistance. The end-of-study visit will occur 15 months after DAIR to evaluate the primary endpoint of treatment success, defined by the absence of infection-related re-surgery, new antibiotic treatment, ongoing antibiotic use, or death.

Participant involvement is expected to last approximately 15 months, with conditions for early termination including withdrawal of consent, non-compliance with study procedures, or adverse events that necessitate discontinuation of the study medication. The trial will ensure rigorous monitoring to maintain the integrity of the double-blind design and adherence to ethical standards throughout the study duration.

The clinical trial involves the administration of several **experimental medications** and comparator treatments. **Levofloxacin** is provided in the form of 500 mg film-coated tablets, manufactured by FARMAPROJECTS S.A. The tablets are administered orally with a maximum daily dose of 1000 mg and a total dose not exceeding 84000 mg over a 12-week period. Participant compliance is monitored through regular assessments.

**Cotrimoxazol AL**, containing **sulfamethoxazole** 400 mg and **trimethoprim** 80 mg per tablet, is produced by ALIUD PHARMA GMBH. This oral tablet has a maximum daily dose of 1820 mg and a total dose limit of 10000000 mg over the same treatment period. Compliance is ensured through scheduled follow-ups.

**Clindamycin** is administered as 300 mg hard capsules, provided by MORNINGSIDE HEALTHCARE LTD. The oral route is used, with a maximum daily dose of 1800 mg and a total dose cap of 151200 mg. Monitoring of adherence is conducted throughout the trial.

**Minocycline** is available as 50 mg coated tablets from TEVA NEDERLAND B.V. The oral administration allows for a maximum daily dose of 200 mg, with a total dose not exceeding 10000000 mg. Participant adherence is tracked through periodic evaluations.

**Doxycycline** is dispensed as 100 mg tablets by AUROBINDO PHARMA B.V. The oral route is employed, with a maximum daily dose of 200 mg and a total dose limit of 1000000 mg. Compliance is monitored through regular check-ins.

**Moxifloxacin hydrochloride** is provided in 400 mg film-coated tablets by TILLOMED LABORATORIES LTD. The oral administration is limited to a maximum daily dose of 400 mg and a total dose of 35000 mg. Adherence is assessed through scheduled visits.

**Rifampicin** is administered as 300 mg hard capsules from GENERICS [UK] LIMITED. The oral route is used, with a maximum daily dose of 900 mg and a total dose cap of 75600 mg. Compliance is monitored through regular assessments.

**Ciprofloxacin hydrochloride monohydrate** is available as 500 mg film-coated tablets from RATIOPHARM GMBH. The oral administration allows for a maximum daily dose of 1000 mg, with a total dose not exceeding 84000 mg. Participant adherence is tracked through periodic evaluations.

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is defined as **treatment success** 15 months after DAIR (Debridement, Antibiotics, and Implant Retention), which equates to one year after the completion of antibiotic treatment. Treatment success is characterized by the absence of infection-related re-surgery of the initially affected prosthetic joint, no new antibiotic treatment for suspected or proven infection of the index joint, no ongoing use of antibiotics for the index joint at the end of follow-up, and no death.

Secondary endpoints include the assessment of quality of life using EQ-5D-5L questionnaires, which will be administered at the time of randomization, at week 6 after surgical debridement, and after 3 months. Additional secondary endpoints include the number of serious adverse events (SAEs) during antimicrobial treatment and follow-up, the number of switches to a different oral regimen, the number of antibiotic side effects classified by the modified Hartwig and Siegel scale, the number of patients developing Clostridioides difficile infection during treatment, and the occurrence of rifampicin resistance in bacteria in patients with a microbiologically confirmed failure of treatment.