Evaluation of Rifampicin Efficacy and Safety in Cutibacterium acnes Prosthetic Joint Infections with Amoxicillin, Moxifloxacin, Clindamycin, and Doxycycline

The primary objective of this study is to evaluate the **safety** and **efficacy** of **rifampicin** during the treatment of **Cutibacterium acnes** prosthetic joint infections. This is clinically relevant as it aims to determine the potential benefits and risks associated with the use of rifampicin in managing these infections, which can significantly impact patient outcomes and treatment protocols.

Secondary objectives include:

• To study rifampicin efficacy according to its companion antibiotic.
• To assess the clinical cure of monomicrobial C. acnes prosthetic joint infections 12 months after antibiotic cessation, comparing dual antibiotic treatment including rifampicin with single antibiotic treatment without rifampicin.

The clinical trial focuses on individuals diagnosed with **Cutibacterium acnes** prosthetic joint infection, specifically targeting those with late total knee arthroplasty, hip arthroplasty, or shoulder arthroplasty infections. The study population includes both male and female participants aged 18 years and older. Participants are required to have a monomicrobial, rifampicin-susceptible infection, and the infection must be confirmed through detection of C. acnes on two distinct per-operative samples. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants' general health status and lifestyle considerations such as diet and physical activity are not specified. Key inclusion criteria include the ability to treat the infection with amoxicillin or moxifloxacin based on antimicrobial susceptibility tests and medical history. The selection process for the trial population is not detailed in the available data.

The clinical trial is designed to evaluate the **safety** and **efficacy** of **rifampicin** in the treatment of **Cutibacterium acnes** prosthetic joint infections. This study is structured as a randomized, double-blind, controlled trial, with an estimated duration extending from June 2023 to July 2027. Participants will be randomly assigned to receive either rifampicin or a comparator antibiotic, such as **amoxicillin** or **moxifloxacin**, with the treatment administered orally. The trial will include a series of study visits to monitor the participants' progress and gather data on the primary and secondary endpoints.

The sequence of study visits begins with an inclusion (screening) visit, where eligibility criteria are assessed. Participants must be 18 years or older and have a monomicrobial, rifampicin-susceptible **C. acnes** infection associated with a prosthetic joint, confirmed by two distinct per-operative samples. Following the screening, participants will undergo a baseline visit to initiate treatment. Subsequent follow-up visits will occur at regular intervals to monitor the rate of infection management failure and adverse events linked to rifampicin, classified according to the CTCAE 5.0. The end-of-study visit will conclude the trial, assessing the long-term outcomes of the treatment over a 24-month follow-up period.

The expected length of participant involvement is approximately 12 months, with the possibility of early termination if specific conditions arise, such as significant adverse events or lack of efficacy. The primary endpoints include the rate of **C. acnes** prosthetic joint infections management failure and the rate of adverse events associated with rifampicin. Secondary endpoints will evaluate the probable failure of infection management and the comparative efficacy of the antibiotics used in the trial. The trial aims to provide comprehensive data on the role of rifampicin in managing **C. acnes** prosthetic joint infections, contributing to improved treatment protocols.

The clinical trial involves the administration of several **antibiotics** to evaluate their impact on the treatment of **Cutibacterium acnes** prosthetic joint infections. The experimental medications include **amoxicillin**, **moxifloxacin**, **clindamycin**, **doxycycline**, and **rifampicin**. Each medication is administered orally, with specific dosage forms and dosing regimens.

**Amoxicillin** is provided in the form of a coated tablet. The maximum daily dose is 3 grams, with a total maximum dose of 252 grams over a treatment period of up to 12 weeks. The administration is oral, and the medication is classified as an antibiotic.

**Moxifloxacin** is administered as a tablet, with a maximum daily dose of 400 milligrams and a total maximum dose of 33.60 grams over the same treatment period. This medication is also taken orally and serves as an antibiotic in the study.

**Clindamycin** is provided in a hard capsule form. The maximum daily dose is 2.40 grams, with a total maximum dose of 201.60 grams over 12 weeks. The route of administration is oral, and it is classified as an antibiotic.

**Doxycycline** is administered in tablet form, with a maximum daily dose of 200 milligrams and a total maximum dose of 16.80 grams over the treatment period. It is taken orally and functions as an antibiotic in the trial.

**Rifampicin** is included in two formulations: Rifadine 300 mg capsules and Rimactan 300 mg capsules. Both are administered orally. Rifadine has a maximum daily dose of 600 milligrams and a total maximum dose of 1200 milligrams, while Rimactan has a maximum daily dose of 1200 milligrams and a total maximum dose of 100 grams over 12 weeks. Both formulations are classified as antibiotics.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen. The trial aims to assess the safety and efficacy of these medications in treating **Cutibacterium acnes** prosthetic joint infections.

The efficacy of rifampicin in the treatment of **Cutibacterium acnes** prosthetic joint infections will be assessed through a hierarchical sequential procedure. The primary endpoints for evaluating efficacy include the rate of management failure of **C. acnes** prosthetic joint infections, defined by relapse, new infection, or early failure. Additionally, the rate of adverse events linked to rifampicin will be classified according to the CTCAE 5.0, with adverse events described by frequency and grade throughout the treatment. The maximum grade over all cycles will be used as the summary measure for each patient.

Secondary endpoints will further assess the rate of probable failure in cases of specific clinical signs, such as fistula or inflammatory synovial fluid without microbiological positive results, and the rate of management failure during the 24 months of follow-up. The efficacy will also be evaluated based on the management failure rate during the 12 months of follow-up, according to the two usable companions in the trial, amoxicillin and moxifloxacin. These endpoints will be measured and analyzed to determine the overall efficacy of rifampicin in the specified treatment context.