Abdominal Surgery, Colon Surgery, Post-Op Infection, Surgical Site Infection
Conditions
Keywords
Surgical site infection, Abdominal surgery, Colon and small bowl surgery
Brief summary
Phase III, Prospective, Multinational, Multicenter, Randomized, Controlled, Two-arm, Double Blind Study to assess Efficacy and Safety of D-PLEX Administered Concomitantly with the Standard of Care (SoC), compared to a SoC treated control arm, in prevention of post abdominal surgery incisional infection.
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. The study population includes male and female, 18 years old and above at screening, undergoing an elective colorectal surgery involving resection, with or without a stoma, that includes at least 1 incision that is \> 10 cm (target incision). Eligible and willing subjects will be randomly allocated into 2 blinded 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 and chemistry well as physicians assessment of the incisional wound. The final number of subjects will be determined following a comparative interim analysis for an early efficacy or futility stop or unblinded sample size re-estimation: when about 750 subjects will complete their 30 days (1 month) follow-up and evaluated for primary endpoint
Interventions
DRUGD-PLEX
D-PLEX is a new formulation of extended release of Doxycycline. Each 5g D-PLEX vial contains 54.6mg Doxycycline free base (1.09%), which is equivalent to 63mg Doxycycline hyclate (1.26%). D-PLEX is supplied as a sterile powder to be reconstituted to paste in the operating room, using standard aseptic techniques and is intended for single administration. The non-active components of the extended release antibiotic formulation are β Tri-Calcium polymer and a lipid matrix. All formulation components are biodegradable.
DRUGStandard of Care (SoC)
prophylactic, pre-operation per institution guidelines
Sponsors
PolyPid Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
This is a double-blind clinical trial. The sponsor, the subjects, outcomes assessor and all staff involved in the collection and recording of the clinical and laboratory data, based on which the independent adjudication committee will perform their assessment, will be blind to treatment assignment. In addition, all aspects of data management and clean-up will be done in blinded datasets. The study site personnel, who perform the index surgery (Operation room staff), will be trained not to disclose the treatment arm to the blinded Investigator, to the subject, his/her family, to other health care providers not present during the surgery or to the study Sponsor representatives. Wound assessment throughout the study follow-up visits will be done by a blinded Investigator, that will not be involved in the surgery. An emergency card containing the Study Name, NIH number, Center Name/number, PI's name and contact details will be provided to the subjects.
Intervention 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. The final number of subjects will be determined following a comparative interim analysis for an early efficacy or futility stop or unblinded sample size re-estimation: when about 750 subjects will complete their 30 days (1 month) follow-up and evaluated for primary endpoint.
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
1. Subjects undergoing an elective colorectal surgery involving resection, with or without a stoma formation, that includes at least 1 abdominal incision that is \> 10cm (target incision). 2. Subjects are preoperative hemodynamically stable 3. Male or non-pregnant female. 4. Female of child-bearing potential should have a negative pregnancy test prior to index procedure. 5. Subjects' age 18 years old and above at screening. 6. Subjects who sign the written Informed Consent Form. 7. Subjects who are willing and able to participate and meet all study requirements. 8. Survival expectancy of at least 60 days post randomization
Exclusion criteria
1. Subjects with suspected/diagnosed intestinal perforation, intra-abdominal abscess, or any emergency/urgent colorectal surgery with acute intestinal obstruction (ex. toxic colitis, ileus/sub-ileus, megacolon, diverticulitis, volvulus, ect.) 2. Subjects who underwent an intra-abdominal surgery within the last 6 months prior to randomization. 3. Subjects with any preoperative active infection or who are receiving any antibiotic therapy in the past 1 week prior to randomization, excluding pre-operative prophylaxis. 4. Subjects undergoing concomitant major procedures in addition to the abdominal surgery, including concomitant repair of ventral hernia. Salpingo-oophorectomy and cholecystectomy are allowed. 5. Subjects who received any anti-cancer treatment within the last 4 weeks of surgery. 6. Subjects who received radiation for colorectal cancer to the abdomen area, prior to the planned abdominal surgery. 7. Subjects who received oral or IV Doxycycline or Tetracycline family antibiotics during the past 4 weeks prior to randomization. 8. Subjects with known allergy to Doxycycline and/or to the tetracycline family of drugs or to the D-PLEX's excipients. 9. Subjects with known allergies to more than 3 substances (an allergy questionnaire will be completed during the screening process). 10. Subjects with history of severe allergic reaction to any substance, having required treatment with intravenous steroids/intramuscular epinephrine, or who in the opinion of the PI is at high risk of developing severe allergic reactions. 11. Subjects with End Stage Renal Disease (ESRD/ CKD stage 5). 12. Subjects with severe hepatic impairment. 13. Subjects with chronic urticaria. 14. Subjects diagnosed with CVA within the past 6 months prior to randomization. 15. Subjects who underwent any abdominal surgery and current planned index surgery involves re-opening the scar of a prior abdominal surgery performed within the last 3 years. 16. Any subject with an active malignancy, other than resectable non-metastatic colorectal cancer, that is the reason for the index surgery, or carcinoma in situ (or other cancer "in situ = Stage 0"), or squamous cell carcinoma of the skin, or basal cell carcinoma of the skin, or a malignancy that has not been in complete clinical remission and without maintenance chemo or immunotherapy for at least 3 years. 17. Subjects with other concurrent severe and/or uncontrolled medical conditions. 18. Psychiatric or any other disorder that compromises ability to provide informed consent for participation in this study. 19. Chronic alcoholic or drug abuse subjects. 20. Pregnant or breast-feeding women or women of child-bearing age who refuse or are prohibited of using an effective contraceptive method of birth control throughout study participation, including the safety follow-up period. 21. Subjects who received any investigational drug within 30 days or 5 half-lives prior to randomization to the study (whichever is longer) and through the study. 22. Subjects participating in any other interventional study. 23. Subjects, who in the opinion of Investigator, are not eligible to participate in the study and/or to comply with the protocol requirements (e.g. due to a cognitive or medical condition).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To Assess the Anti-infective Efficacy of D-PLEX Over a Period of 30 Days Post Operation, by Preventing Surgical Site Infection (SSI), Defined as Superficial and Deep Infection, in the Target Incision(s), Compared to the SoC Treated Control. | By day 30 post surgery | Infection rate as measured by the proportion of subjects with at least one abdominal incisional infection event, as determined by a blinded and independent adjudication committee, within 30 days post-abdominal surgery. \[Abdominal incisional infection is composed of Deep Incisional Surgical Site Infection (DSSI) and Superficial Incisional Surgical Site Infection (SSSI)\]. The blinded and independent adjudication committee review will include all index surgery incisions, regardless of any re-intervention at the target site, for the determination of infection status. The committee will also assess re-interventions at the primary incision site through the abdominal incision (target) for the determination of re-intervention due to suspected SSI or due to poor wound healing, including wound dehiscence. Such events, as well as all-cause mortality within 30 days post-index surgery will be analyzed as treatment failure. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Infection Rate | 30 days post-surgery | infection rate as measured by the proportion of subjects with at least one abdominal incisional infection event, as determined by a blinded and independent adjudication committee, within 30 days post abdominal surgery. \[abdominal incisional infection is composed of Deep Incisional Surgical Site Infection (DSSI) and Superficial Incisional Surgical Site Infection (SSSI)\]. |
Countries
Bulgaria, Croatia, Czechia, Hungary, Israel, Moldova, Poland, Romania, Slovakia, United States
Contacts
STUDY_DIRECTORShmuel Sharoni, MD
PolyPid Ltd.
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| D-PLEX+SoC D-PLEX is provided to suitable and willing study subjects as an adjunct to the SoC treatment
D-PLEX: D-PLEX is a new formulation of extended release of Doxycycline. | 485 |
| Standard of Care The SoC for prophylactic antibiotic treatment is based on international guidelines
Standard of Care (SoC): prophylactic, pre-operation per institution guidelines | 489 |
| Total | 974 |
Baseline characteristics
| Characteristic | Total | D-PLEX+SoC | Standard of Care |
|---|---|---|---|
| Age, Continuous | 64.2 years STANDARD_DEVIATION 13.02 | 64.7 years STANDARD_DEVIATION 12.75 | 63.7 years STANDARD_DEVIATION 13.27 |
| BMI | 26.96 kg/m^2 STANDARD_DEVIATION 4.6 | 26.80 kg/m^2 STANDARD_DEVIATION 4.54 | 27.11 kg/m^2 STANDARD_DEVIATION 4.65 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 969 Participants | 483 Participants | 486 Participants |
| Region of Enrollment Bulgaria | 92 Participants | 47 Participants | 45 Participants |
| Region of Enrollment Croatia | 40 Participants | 26 Participants | 14 Participants |
| Region of Enrollment Czechia | 131 Participants | 64 Participants | 67 Participants |
| Region of Enrollment Hungary | 160 Participants | 84 Participants | 76 Participants |
| Region of Enrollment Israel | 138 Participants | 67 Participants | 71 Participants |
| Region of Enrollment Moldova | 177 Participants | 84 Participants | 93 Participants |
| Region of Enrollment Poland | 17 Participants | 8 Participants | 9 Participants |
| Region of Enrollment Romania | 168 Participants | 82 Participants | 86 Participants |
| Region of Enrollment Slovakia | 14 Participants | 5 Participants | 9 Participants |
| Region of Enrollment United States | 37 Participants | 18 Participants | 19 Participants |
| Sex: Female, Male Female | 395 Participants | 197 Participants | 198 Participants |
| Sex: Female, Male Male | 579 Participants | 288 Participants | 291 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 16 / 485 | 17 / 489 |
| other Total, other adverse events | 381 / 478 | 398 / 498 |
| serious Total, serious adverse events | 69 / 478 | 98 / 498 |
Outcome results
Primary
To Assess the Anti-infective Efficacy of D-PLEX Over a Period of 30 Days Post Operation, by Preventing Surgical Site Infection (SSI), Defined as Superficial and Deep Infection, in the Target Incision(s), Compared to the SoC Treated Control.
Infection rate as measured by the proportion of subjects with at least one abdominal incisional infection event, as determined by a blinded and independent adjudication committee, within 30 days post-abdominal surgery. \[Abdominal incisional infection is composed of Deep Incisional Surgical Site Infection (DSSI) and Superficial Incisional Surgical Site Infection (SSSI)\]. The blinded and independent adjudication committee review will include all index surgery incisions, regardless of any re-intervention at the target site, for the determination of infection status. The committee will also assess re-interventions at the primary incision site through the abdominal incision (target) for the determination of re-intervention due to suspected SSI or due to poor wound healing, including wound dehiscence. Such events, as well as all-cause mortality within 30 days post-index surgery will be analyzed as treatment failure.
Time frame: By day 30 post surgery
Population: Intent to treat population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| D-PLEX+SoC | To Assess the Anti-infective Efficacy of D-PLEX Over a Period of 30 Days Post Operation, by Preventing Surgical Site Infection (SSI), Defined as Superficial and Deep Infection, in the Target Incision(s), Compared to the SoC Treated Control. | 9.3 percentage of participants |
| Standard of Care | To Assess the Anti-infective Efficacy of D-PLEX Over a Period of 30 Days Post Operation, by Preventing Surgical Site Infection (SSI), Defined as Superficial and Deep Infection, in the Target Incision(s), Compared to the SoC Treated Control. | 12.1 percentage of participants |
p-value: 0.15295% CI: [-6.7, 1]Cochran-Mantel-Haenszel
Secondary
Assessment of Infection Rate in Patient Undergoing Abdominal Colon Surgery
infection rate as measured by the proportion of subjects with at least one abdominal incisional infection event, as determined by a blinded and independent adjudication committee, within 30 days post abdominal surgery. \[abdominal incisional infection is composed of Deep Incisional Surgical Site Infection (DSSI) and Superficial Incisional Surgical Site Infection (SSSI)\].
Time frame: 30 days post-surgery
Population: Intent to treat population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| D-PLEX+SoC | Assessment of Infection Rate in Patient Undergoing Abdominal Colon Surgery | 6.2 Percentage of the participants |
| Standard of Care | Assessment of Infection Rate in Patient Undergoing Abdominal Colon Surgery | 6.9 Percentage of the participants |
p-value: 0.621995% CI: [-3.9, 2.3]Cochran-Mantel-Haenszel
Other Pre-specified
All-cause Mortality
All-cause mortality within 30 days post index surgery will be analysed as treatment failure.
Time frame: 30 day post surgery
Population: All-cause mortality is calculated out of the ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| D-PLEX+SoC | All-cause Mortality | 2.3 percentage of participants |
| Standard of Care | All-cause Mortality | 3.1 percentage of participants |
p-value: 0.437395% CI: [-2.8, 1.2]Kaplan-Meier Analysis