Randomized, Double-Blind Study of Bacteriophage Therapy with PP1493 and PP1815 in Staphylococcus aureus-Induced Prosthetic Joint Infection

The primary objective of this study is to estimate the rate of clinical control of infection due to **Staphylococcus aureus** in patients with knee or hip prosthetic joint infection (PJI) treated with two different therapeutic regimens: DAIR (Debridement, Antibiotics, and Implant Retention) combined with curative antibiotics therapy and either bacteriophages or a solution of NaCl 0.9%. This estimation is crucial for determining the sample size for future comparative studies, particularly in patients presenting PJI later than one month after arthroplasty, with the indication of DAIR and Suppressive Antibiotics Therapy (SAT).

Secondary objectives include:

• Assessing the safety of the two therapeutic regimens throughout the study.
• Describing the initial activity of phages on patients' **Staphylococcus aureus** strains and the clinical outcomes, such as infection control or relapse.
• Characterizing superinfected patients in terms of clinical infection control.
• Profiling the **Staphylococcus aureus** strain in cases of treatment failure.
• Describing the duration of hospitalization and the quality of life for patients at each visit.
• Evaluating the rehabilitation process.
• Estimating the rate of clinical control of infection after rescue treatment and assessing the safety of such treatment in patients with relapse due to **Staphylococcus aureus**.

The clinical trial involves participants diagnosed with **knee or hip prosthetic joint infection (PJI)** due to **Staphylococcus aureus**, with an indication for DAIR and Suppressive Antibiotics Therapy (SAT). 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 two years and must be affiliated with a national social security system or private health insurance. The trial does not include a vulnerable population. Participants must have a monomicrobial infection with **Staphylococcus aureus** occurring more than one month after prosthesis implantation, with clinical signs of infection. The trial population was selected based on specific inclusion criteria, including the absence of superinfection by another pathogen and susceptibility of the strain to at least one of the phages. Lifestyle considerations such as diet and physical activity are not specified. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is a **randomized**, **double-blind**, controlled study designed to evaluate the efficacy of phage therapy in patients with knee or hip prosthetic joint infection (PJI) due to **Staphylococcus aureus**. The trial involves two therapeutic regimens: DAIR (Debridement, Antibiotics, and Implant Retention) combined with curative antibiotics therapy and either bacteriophages or a solution of sodium chloride (NaCl) 0.9%. The primary objective is to estimate the rate of clinical control of infection, which will inform the sample size for future comparative studies. The trial is expected to run from June 2022 to August 2025, with participant involvement lasting up to 18 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, infection status, and life expectancy. Following randomization, participants will receive the assigned treatment and attend follow-up visits to monitor safety and efficacy. These visits will include physical examinations, biological tests, and assessments of infection control. The end-of-study visit will evaluate the overall clinical outcome and collect final data on safety and efficacy.

The expected length of participant involvement is up to 18 months, with conditions for early termination including adverse events, withdrawal of consent, or failure to adhere to study protocols. The trial will assess primary endpoints such as the absence of clinical signs of infection and the need for additional surgical procedures. Secondary endpoints will include safety parameters, the activity of bacteriophages, and quality of life assessments. The study aims to provide valuable insights into the potential of phage therapy as a treatment for PJI due to **Staphylococcus aureus**.

The clinical trial involves the administration of **PP1493**, 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 PP1493, is administered via injection or infusion. The maximum daily dose is set at 10,000,000,000 plaque-forming units per milliliter (PFU/ml), with a total maximum dose of 40,000,000,000 PFU/ml over a treatment period of up to 18 days. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen.

Another experimental treatment in the study is **PP1815**, also provided as a **solution for injection**. Like PP1493, PP1815 is produced by Pherecydes Pharma SA and is classified as a structurally diverse substance. The administration route is either injection or infusion, with a maximum daily dose of 10,000,000,000 PFU/ml and a total maximum dose of 40,000,000,000 PFU/ml over a maximum treatment period of 18 days. Compliance with the dosing schedule is closely monitored to maintain the integrity of the trial.

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, classified as a chemical. The maximum daily and total dose is 30 milliliters, administered via injection or infusion over a single day. This comparator is used to evaluate the efficacy of the experimental treatments in controlling infections due to Staphylococcus aureus in patients with prosthetic joint infections.

The efficacy of the clinical trial will be assessed through both primary and secondary endpoints. The primary endpoint focuses on the **clinical control of infection** due to *Staphylococcus aureus* in patients with hip or knee prosthetic joint infection. This will be defined by the absence of clinical signs of evolving infection, such as no fever (temperature less than 38°C), no recurrence or worsening pain, no local post-surgical recurrence or worsening of local articular swelling, and no unusual scar aspects like erythema or abnormal flow. Additionally, no new surgical procedures should be requested, and no *Staphylococcus aureus* should be detected.

Secondary endpoints include safety parameters such as adverse events, physical examinations, and biological tests (hematology and biochemistry) throughout the study. The initial activity of phages (PP1493 and/or PP1815) will be evaluated in relation to clinical outcomes, including infection control or relapse. The clinical control of infection will also be assessed for superinfected patients. In case of failure, joint fluid aspiration will be performed for microbiological testing and identification of the *Staphylococcus aureus* strain. Other secondary measures include the duration of hospitalization, quality of life assessed by the EQ-5D-5L questionnaire at each visit (except D14±1 and D28±2), and joint function evaluation using the KOOS 12-Knee Survey for knees and the HOOS 12-Hip Survey for hips. The potential appearance of abnormal loosening or an abnormal periprosthetic border will also be checked. In cases requiring rescue treatment, clinical infection control after the first ultra-guided injection, safety parameters, pharmacokinetics, and bacteriological and immunological tests will be evaluated.