Efficacy and Safety of Doxycycline Hyclate (D-PLEX) with Standard Care in Preventing Post-Abdominal Surgery Incisional Infections: A Phase III Randomized Study

The primary objective of this study is to evaluate the **anti-infective efficacy** of D-PLEX, administered concomitantly with the Standard of Care (SoC), in preventing surgical site infection (SSI) within 30 days post-operation. This is defined as the prevention of superficial and/or deep infection in the target incision, compared to a SoC treated control arm. Additionally, the study aims to assess the safety of D-PLEX when used alongside the SoC. The clinical relevance of this objective lies in its potential to reduce postoperative complications, improve patient outcomes, and decrease healthcare costs associated with post-surgical infections.

Secondary objectives include: - Measuring the **infection rate** by the proportion of subjects with at least one abdominal target incisional infection event within 30 days post-surgery, determined by a blinded and independent adjudication committee, in subjects with target incision length >20cm. - Evaluating the infection rate in the overall study population (incision ≥7cm), with all-cause mortality and re-interventions through the abdominal incision within 30 days post-surgery analyzed as treatment failure. - Determining the number (percent) of subjects with at least one ASEPSIS score >20 within 30 days post-surgery in the population with target incision length >20cm.

The clinical trial involves a total of **863 participants** who are undergoing an elective colorectal surgery involving resection, with or without a stoma formation, and includes at least one abdominal incision greater than 20 cm. The study population comprises both **male and non-pregnant female** subjects, aged 18 years and above, who are preoperatively hemodynamically stable. Participants are required to have a survival expectancy of at least 60 days post-randomization. The trial includes individuals who are willing and able to participate, having signed the informed consent form. The selection criteria ensure that participants are not only medically stable but also capable of adhering to the study requirements. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The study aims to assess the prevention of post-abdominal surgery incisional infection, focusing on the anti-infective efficacy and safety of D-PLEX administered alongside the Standard of Care over a 30-day postoperative period.

The clinical trial is a **Phase III**, prospective, multinational, multicenter study designed to evaluate the efficacy and safety of **D-PLEX**, a **doxycycline hyclate** formulation, in preventing post-abdominal surgery incisional infections. The trial employs a randomized, controlled, two-arm, double-blind design, comparing the administration of D-PLEX alongside the standard of care (SoC) against a control group receiving only the SoC. The primary objective is to assess the anti-infective efficacy of D-PLEX over a 30-day period post-operation by preventing surgical site infections (SSI), which include both superficial and deep infections at the target incision site. The trial is expected to conclude by December 31, 2024, with recruitment having commenced on April 27, 2021.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as undergoing elective colorectal surgery with a target incision greater than 20 cm, being hemodynamically stable, and providing informed consent. The study will include follow-up visits to monitor the incidence of incisional infections and assess safety outcomes. The end-of-study visit will occur 30 days post-surgery to evaluate the primary and secondary endpoints, including infection rates and any adverse events. The expected duration of participant involvement is approximately 30 days post-surgery, with conditions for early termination including withdrawal of consent or any significant adverse events that compromise participant safety.

Key inclusion criteria include subjects aged 18 years and older, undergoing elective colorectal surgery, and having a survival expectancy of at least 60 days post-randomization. The primary endpoint is the infection rate, measured by the proportion of subjects experiencing at least one abdominal target incisional infection event within 30 days post-surgery, adjudicated by a blinded and independent committee. Secondary endpoints include additional infection rates, all-cause mortality, and re-intervention rates. The trial aims to provide robust data on the efficacy and safety of D-PLEX in reducing the incidence of surgical site infections in the specified patient population.

The clinical trial involves the use of **D-PLEX**, an experimental medication formulated as a **powder for implantation paste**. The active substance in D-PLEX is **doxycycline hyclate**, a chemical compound belonging to the tetracycline-class of antimicrobial drugs. The medication is administered via **implantation** at the surgical site. The maximum daily dose and total dose of D-PLEX is 15 grams, with a treatment period limited to one day. The primary objective of the trial is to evaluate the anti-infective efficacy of D-PLEX when used in conjunction with the standard of care (SoC) to prevent surgical site infections following abdominal surgery.

In addition to D-PLEX, the study includes a control arm where participants receive only the standard-of-care therapy. This comparator treatment serves as a baseline to assess the efficacy and safety of D-PLEX. The standard-of-care therapy is administered according to established medical guidelines for the prevention of post-surgical infections. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol.

The efficacy of the clinical trial will be assessed by evaluating the **infection rate** as the primary endpoint. This will be measured by the proportion of subjects experiencing at least one abdominal target incisional infection event within 30 days post-abdominal surgery. The determination of infection events will be conducted by a blinded and independent adjudication committee. The primary endpoint focuses on subjects with a longer incision (>20 cm), with infections defined as Deep Incisional Surgical Site Infection (DSSI) and/or Superficial Incisional Surgical Site Infection (SSSI).

Secondary endpoints include the infection rate in the overall study population with incision lengths of ≥7 cm, all-cause mortality, and re-interventions through the abdominal incision within 30 days post-surgery, which will be analyzed as treatment failure. Additional endpoints for subjects with target incision lengths >20 cm include the incidence of SSSI and DSSI, all-cause mortality rates within 30 and 60 days post-randomization, and time to adjudicated SSI within 30 days post-surgery. The study will also assess the number of subjects re-admitted due to adjudicated SSI, the number of surgical re-interventions, and the presence of Doxycycline-resistant bacteria in bacteriology tests.

Further SSI-related endpoints involve the number of IV antibiotic treatment days, the average cumulative ASEPSIS assessment score for subjects with adjudicated SSI, and the number of subjects with an ASEPSIS score >20 within 30 days post-surgery. These efficacy parameters will be collected and analyzed according to the predefined schedule and methods outlined in the trial protocol.