D-PLEX 310: Safety and Efficacy of D-PLEX in the Prevention of Post Abdominal Surgery Incisional Infection

Study Overview
=================
Brief Summary
-----------------
Subjects who are planned to undergo an abdominal (colon) surgery and who will meet the study entry criteria will be randomly divided into 2 groups: for half D-PLEX will be administered concomitantly with the standard of care (SOC). The other half will receive the Standard of Care treatment. Following the surgery subjects will be followed up for additional 5 visits, at least half are in line with the routine practice of surgery Follow-Ups. Visits will include patient safety and wound assessments.

Detailed Description
-----------------
D-PLEX is a new formulation of extended controlled release of Doxycycline in the applied area for about 30 days. This study is aimed to assess the safety and efficacy of D-PLEX in prevention of post abdominal surgery incisional infection. Eligible and willing subjects will be randomly divided, in a single-blinded manor into 2 study arms D-PLEX with SOC or SOC alone. D-PLEX will be applied during the surgery at the final stage of incision closure. All patients will be followed up for additional 5 visits over 2 months, for safety and incisional wound assessment. This will include blood tests for hematology, chemistry and PK (for some only) as well as physicians assessment of the incisional wound.

Official Title
-----------------
Phase II, Multicentre, Randomized, Controlled, Two Arm, Single Blind Study to Assess Safety and Efficacy of D-PLEX Administered Concomitantly With SOC, Compared to SOC, in Prevention of Post Abdominal Surgery Incisional Infection.

Conditions
-----------------
Abdominal Surgery, Colon Surgery, Post-Op Infection

Intervention / Treatment
-----------------
* Drug: D_PLEX
* Other: Standard of Care (SoC)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects undergoing elective abdominal colon surgery involving resection and anastomosis or a stoma. Male or non-pregnant female Female of childbearing potential should have a negative serum pregnancy test prior to index procedure and agree to use a highly effective method of contraception consistently and correctly for the duration of the study. Subjects who sign a written informed consent Subjects who are willing and able to participate and meet all study requirements. Survival expectancy of at least 60 days post randomization. Exclusion Criteria: Subjects scheduled for abdominal surgery which is classified as emergency. Subjects with any preoperative active infection that is currently being treated with antibiotics. Subjects receiving any antibiotic therapy in the past 4 weeks prior to enrolment besides prophylaxis or antibiotic for the treatment of the disease that consists the indication for surgery. Patients undergoing concomitant additional procedures besides colon resection surgery, e.g. Hyper-thermic Intraperitoneal Chemotherapy, liver resection etc. Female sterilization surgery (i.e. salpingo-oophorectomy, hysterectomy etc.), or involvement of a small bowel procedure or Cholecystectomy may be allowed, pending an advanced consultation and approval from the sponsor. Subject received chemotherapy within the last 4 weeks of surgery, or radiation for colorectal cancer to the abdomen area, prior to the planned abdominal surgery (neo- adjuvant treatment). Subjects that received oral or IV doxycycline during the past 4 weeks prior to screening. Subjects with known sensitivity to doxycycline and/or to the tetracycline family of drugs or to the D-PLEX's excipients. Subjects with known allergies to more than 3 substances (an allergy questionnaire will be filled in during the screening process). Subjects with a history of allergic/hypersensitivity reaction to any substance having required hospitalization and/or treatment with intravenous steroids/intramuscular epinephrine or in the opinion of the investigator the patient is at high risk of developing severe allergic/hypersensitivity reactions. Subjects with uncontrolled Asthma (GINA III-IV). Subjects with End Stage Renal Disease [Chronic Kidney Disease (CKD) stage 5]. Subjects with chronic urticaria. Subjects diagnosed with severe neurological/cardiac events within the past 1 year prior to randomization. Subjects that undergone any abdominal surgery and current planned surgery involves re-opening the scar of prior abdominal surgery. Any subject with active malignancy or with malignancy that has not been in complete remission for at least 5 years. Excluding: subjects with potentially resectable non-metastatic colorectal cancer which consists the indication for surgery. In addition, patients Patients who have had carcinoma in situ of the cervix, squamous cell carcinoma of the skin and basal cell carcinoma of the skin Non-violent cancer that does not require treatment 4 weeks prior to, and throughout the entire study duration will be eligible. Subjects with other concurrent severe and/or uncontrolled medical condition that could compromise participation in the study (e.g. non-GI active infection, uncontrolled diabetes, uncontrolled hypertension, congestive heart failure, unstable angina, ventricular arrhythmias, active ischemic heart disease, uncompensated cirrhosis, active upper gastrointestinal (GI) tract ulceration). Psychiatric, addictive, or any other disorder that compromises ability to provide informed consent for participation in this study. Chronic alcoholic or drug abuse subjects. Pregnant or breast-feeding women or women of childbearing age who refuse or prohibited of using an effective contraceptive method of birth control (such as double barrier, oral or parenteral hormonal, intrauterine device and spermicide) throughout study participation including safety follow-up period. Subjects that received any investigational drug within 30 days or 5½ half-lives of enrollment to the study (whichever is longer). Subjects participating in any other interventional studies. In the opinion of investigator, subject is not eligible to participate in the study and/or to comply with protocol requirements (e.g. due to a cognitive or medical condition).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Males and females, >18 years old, undergoing scheduled abdominal colon surgery involving resection and anastomosis or a stoma, who meet the inclusion criteria and none of the exclusion criteria and provide signed informed consent will be enrolled in the study. Subjects will be randomized to either the investigational arm (SOC + D-PLEX) or to the control arm (SOC only) in a 1:1 ratio. Subjects will be blinded to the study arm.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Standard of Care (SoC)<br>SOC prophylactic treatment pre-operation will be as per Israeli Ministry of Health and international guidelines: 1st or 2nd generation of Cephalosporine family, plus Metronidazole. | Other: Standard of Care (SoC)<br>* Prophylactic, pre-operation: 1st or 2nd generation of Cephalosporine family, plus Metronidazole. Post-operation: this is each participating center standard practice for this type of procedure<br>|
| Experimental: D-PLEX + SoC<br>D-PLEX is provided to suitable and willing study subjects as an adjunct to the SoC treatment | Drug: D_PLEX<br>* D_PLEX is reconstituted into paste and administered in a single application following closure of the fascia, on the fascia suture line, and on the soft tissues of the abdominal wall along the whole length of the surgical wound (including muscle, fat and dermis).<br>Other: Standard of Care (SoC)<br>* Prophylactic, pre-operation: 1st or 2nd generation of Cephalosporine family, plus Metronidazole. Post-operation: this is each participating center standard practice for this type of procedure<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Infection rate as measured by the proportion of subjects with abdominal incisional infection event | Infection rate as measured by the proportion of subjects with abdominal incisional infection event, as determined by a blinded and independent adjudication committee, within 30 days post abdominal surgery. | By day 30 post surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average ASEPSIS assessment score (Additional treatment, Serous discharge, Erythema, Purulent exudate, Separation of deep tissue, Isolation of bacteria, Stay duration as inpatient) during 30 days post-surgery. | ASEPSIS is acronym of wound assessment and treatment parameters (described in the title), which provides numerically score during an inspection of the surgical site. The final score is being interpreted to severity of wound appearance and the clinical consequences of the infection. Each parameter will be evaluated and numerically scored. Some (Serous discharge & Erythema) will be marked between 0 - 5 and others (Purulent exudate & Separation of deep tissue) are marked between 0 - 10 - based on the proportion of the wound they affect when 0 is none and either 5 or 10 are for over 80% of the wound. Other parameters (Additional antibiotic treatment, a requirement for pus drainage, solation of bacteria & Stay duration as an inpatient) are scored Yes or No. No equals 0. Yes is calculated as either 5 points (for some parameters) or 10 for others. The final score can in the range of 0 - 70. 0 - 10 for wound which heals satisfactorily and over 40 for a severe wound infection. | At post surgery study visits : day 1, day 5, day 14 & day 30 | 
| Incidence of Deep Surgical Site Infection during 30 days post-surgery | Number of deep surgical site infections events during the 30 days post surgery, as confirmed by an independent adjudication committee. | At study visits: day 1, day 5, day 14 and day 30 post surgery | 
| Incidence of Superficial Surgical Site Infection during 30 days post-surgery | Number of superficial surgical site infections events during the 30 days post surgery, as confirmed by an independent adjudication committee. | At study visits: day 1, day 5, day 14 and day 30 post surgery | 
| Mortality rate within 60 days post abdominal surgery | Death from any reason | During 60 days of study participation | 
| Susceptibility to Doxycycline | Susceptibility to Doxycycline for any organisms recovered from an abdominal surgery incisional Infection site will be done using a central lab. When an infection is suspected in the incisional wound, a sample will be taken and sent for a bacteriology test in a central lab. Any organism which will grow (if), will be further tested for Doxycycline susceptibility. | At study visits: day 1, day 5, day 14 and day 30 post surgery | 
| Number of overall hospitalization days post surgery | Number of hospitalization days after surgery and until discharge. Will include prolongation of primary hospitalization compared to the average of the rest of the recruited patients and re-admission due to infection | During 60 days of study participation | 
| Number of re-admissions due to surgical site infection | Out of the entire hospitalization period, how many days were attributed due to a surgical site infection | During 60 days of study participation | 
| Number of antibiotic treatment days post surgery | Number of days antibiotic treatment is administered (any route) to treat an incisional infection. | During 60 days of study participation | 
| Time to surgical site infection | Number of days between surgery and a confirmed incisional surgery infection | At study visits: day 1, day 5, day 14 and day 30 post surgery | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Surgical site infection, Abdominal surgery, Colon and small bowl surgery