Phase II Multicenter Randomized Double-Blind Study on Phage Therapy Efficacy and Safety in Staphylococcus aureus-Induced Prosthetic Joint Infections

The primary objective of this study is to evaluate the **safety** and **efficacy** of phage therapy combined with Debridement, Antibiotics, and Implant Retention (DAIR) compared to placebo combined with DAIR in patients with hip or knee prosthetic joint infection due to **Staphylococcus aureus** over a period of up to 3 months. This is clinically relevant as it aims to determine whether phage therapy can be a viable treatment option for such infections, potentially improving patient outcomes and reducing the need for more invasive procedures.

Secondary objectives include:

• Assessing the specific effect of phage therapy on **S. aureus** infection compared to placebo over 3 and 12 months.
• Evaluating the safety of phage therapy compared to placebo over 12 months.
• Assessing the efficacy of phage therapy compared to placebo over 12 months.
• Describing the immunological response, **S. aureus** bacterial load, and cytology in specified areas over defined periods.
• Describing hospitalization duration, quality of life, joint function rehabilitation, and the evolution of X-ray images over 3 and 12 months.

The clinical trial involves a total of **34 participants** diagnosed with **hip or knee prosthetic joint infection due to Staphylococcus aureus**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a life expectancy of at least one year, as determined by the principal investigator. The trial population was selected based on specific inclusion criteria, including the presence of a monobacterial infection due to S. aureus and the absence of a preoperative diagnosis of superinfection by another pathogen. Participants must be affiliated with a national social security system or private health insurance. Lifestyle considerations include the commitment to use effective birth control methods for females of childbearing potential and sexually active males with partners of childbearing potential. The trial also includes a vulnerable population, ensuring comprehensive representation within the study. The selection process ensures that participants meet the necessary health and lifestyle criteria to assess the safety and efficacy of the treatment under investigation.

The clinical trial is a **randomized, double-blind, controlled** study designed to evaluate the safety and efficacy of phage therapy in patients with hip or knee prosthetic joint infection due to **Staphylococcus aureus**. The trial will compare phage therapy combined with DAIR (Debridement, Antibiotics, and Implant Retention) against a placebo combined with DAIR over a period of up to three months. The study is expected to commence recruitment in February 2025 and conclude by December 2026. Participants will be involved in the trial for a maximum of three months, with the possibility of early termination if serious adverse events occur or if the participant withdraws consent.

Study visits will follow a structured sequence, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, medical history, and infection status. Following successful screening, participants will be randomized to receive either the investigational product or placebo. Subsequent follow-up visits will be scheduled to monitor the incidence of adverse events, assess clinical cure rates, and evaluate safety parameters including vital signs, ECG, and laboratory tests. The end-of-study visit will occur at the three-month mark, or earlier if the participant experiences a relapse or completes the treatment protocol.

Participants will be required to attend regular follow-up visits to ensure comprehensive monitoring of their health status and response to treatment. The primary endpoints include the incidence of serious adverse events and the percentage of patients achieving clinical cure within the three-month period. Secondary endpoints will assess long-term outcomes, including relapse rates and quality of life up to 12 months. The trial will employ intra-articular injection as the route of administration for the investigational products, which include PP1815 and PP1493, both solutions for injection, and a sodium chloride solution for infusion as a comparator. The trial is categorized as a Phase II proof of concept study, focusing on therapeutic exploratory and confirmatory objectives.

The clinical trial involves the administration of **PP1815**, an experimental medication formulated as a **solution for injection**. This investigational product is developed by PHERECYDES PHARMA SA and is characterized as a structurally diverse substance. The active substance, also named PP1815, is administered via **intra-articular injection**. The dosing regimen includes a maximum daily dose of 10,000,000,000 PFU (plaque forming units) and a total maximum dose of 30,000,000,000 PFU over a treatment period of up to 3 days. Participant compliance with the dosing schedule is monitored throughout the trial.

Another investigational product used in the study is **PP1493**, also a **solution for injection**. Like PP1815, PP1493 is produced by PHERECYDES PHARMA SA and is classified as a structurally diverse substance. The administration route is **intra-articular injection**, with a dosing schedule identical to that of PP1815, allowing for a maximum daily dose of 10,000,000,000 PFU and a total maximum dose of 30,000,000,000 PFU over a 3-day period. Compliance with the administration protocol is closely monitored.

The study also includes the use of **CHLORURE DE SODIUM FRESENIUS 0.9%**, a **solution for infusion** serving as a comparator treatment. This product, manufactured by FRESENIUS KABI FRANCE S.A.S., contains **sodium chloride** as the active substance, which is of chemical origin. The solution is administered via **intra-articular injection** with a maximum daily volume of 30 ml and a total maximum volume of 90 ml over the course of 3 days. The administration of this comparator is conducted under controlled conditions to ensure adherence to the study protocol.

The efficacy of the investigational treatment in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include the **incidence of serious adverse events** and the **percentage of patients achieving clinical cure** up to 3 months. Secondary endpoints will further evaluate the percentage of patients with clinical cure from **Staphylococcus aureus** infection up to 3 and 12 months, as well as the percentage of patients experiencing relapse due to another germ within the same timeframes. Additional secondary endpoints include the incidence of all adverse events, assessment of safety parameters such as vital signs, ECG/Echocardiography, hematology, hemostasis, and biochemistry, and the percentage of patients achieving clinical cure of prosthetic joint infection (PJI) up to 12 months.

Other secondary measures involve the titration of anti-S. aureus phage antibodies, quantitative or semi-quantitative analysis of bacterial load, quantification and identification of polynuclear cells, and the number and duration of hospitalizations up to 3 and 12 months. Quality-of-life assessments and imaging studies, such as X-rays, will also be conducted to monitor potential prosthesis loosening. These efficacy parameters will be collected and analyzed at specified intervals throughout the study duration, ensuring a comprehensive evaluation of the treatment's impact on patients with hip or knee prosthetic joint infections.