Surgical Site Infection
Conditions
Keywords
Surgical site infection, Colorectal surgery
Brief summary
This is a randomized, double-blind, placebo controlled, safety, tolerability, and pharmacokinetic dose escalation Phase II study of DFA-02 in patients undergoing colorectal surgery to evaluate the safety, tolerability and pharmacokinetics of DFA-02.
Detailed description
Despite antibiotic prophylaxis and improvements in surgical techniques, surgical site infections (SSI) still occur. DFA-02 is a novel bioresorbable modified release gel containing both gentamicin and vancomycin to be applied during surgical incision closure for the prevention of surgical site infections (SSIs) in patients undergoing colorectal surgery.
Interventions
DRUGDFA-02
Modified release product containing gentamicin and vancomycin for application at the conclusion of surgery after closure of the fascia and prior to skin closure
DRUGPlacebo
DFA-02 placebo
Sponsors
Duke Clinical Research Institute
Dr. Reddy's Laboratories Limited
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Males and females 18 years of age or older; 2. If female, the patient must be: * postmenopausal (if amenorrheic for \< 1 year, postmenopausal status must be confirmed by an elevated follicle stimulating hormone \[FSH\] level \> 30 mIU/mL; if amenorrheic for \> 1 year, FSH level not required); * surgically sterilized (does not have a uterus or has had bilateral tubal ligation); or * if of child-bearing potential, she must have a negative serum pregnancy test on entry in the study, and agree to use adequate birth control during the study and for 30 days after the administration of study agent. Medically acceptable contraceptives include: (1) surgical sterilization (such as a tubal ligation or hysterectomy), (2) approved hormonal contraceptives (such as birth control pills, patches, implants or injections), (3) barrier methods (such as a condom or diaphragm) used with a spermicide, or (4) an intrauterine device (IUD); 3. BMI 25-40, inclusive; 4. Scheduled to undergo nonemergent colorectal surgery involving a laparotomy incision of 7 cm or greater (hand-assisted laparoscopic surgery is allowed). List of eligible procedures: left, right or transverse colectomy, segmental/sleeve left colon resection, total abdominal colectomy with ileorectal anastomosis, total abdominal colectomy with ileostomy, total abdominal proctocolectomy, low anterior resection, sigmoid resection, non-emergent Hartmann's procedure, colotomy with polypectomy distal to hepatic flexure, colostomy takedown through laparotomy (not peristomal) incision, ileo-pouch anal anastomosis, abdominal perineal resection of the rectum; 5. Willing and able to give informed consent; 6. Available for evaluation from baseline until final evaluation at 30 days post surgery.
Exclusion criteria
1. Known history of hypersensitivity to gentamicin or vancomycin, other aminoglycoside antibiotics or the excipients of the study products (soy bean products or sesame oil); 2. Emergency surgery (urgent surgery is allowed if informed consent is obtained and the study procedures can be performed); 3. Significant concomitant surgical procedure (Note: concomitant appendectomy, cholecystectomy, oophorectomy, and liver biopsy/wedge resection are allowed); 4. Prior laparotomy within the last 60 days of this planned procedure; 5. Planned second laparotomy or colorectal surgical procedure (e.g. colostomy or ileostomy takedown) within 30 days of this planned first procedure; 6. Expectation that a surgical drain will be placed; 7. Preoperative sepsis, severe sepsis, or septic shock; 8. Abdominal wall infection/surgical site infection from previous laparotomy/laparoscopy or for any reason; 9. Active systemic infection or systemic (oral or intravenous) antibiotic therapy within the 1 week prior to the date of surgery other than specified preoperative antimicrobial prophylaxis (Note: single dose antibiotic therapy for dental or other minor procedures is allowed as is the use of oral non-absorbable antibiotics for preoperative bowel decontamination); 10. Requirement for gentamicin or vancomycin preoperative antimicrobial prophylaxis (Note: systemic antibiotic therapy within 72 hours after surgery with gentamicin or vancomycin must be avoided and any systemic antibiotic therapy during that time should be discussed with the Coordinating Center PI or Medical Monitor); 11. Requirement for concomitant use or use during the 30 days prior to Day 1 of any prescription or OTC drug that would interfere with the study or place the patient at undue risk. Concurrent systemic or topical use of other potentially neurotoxic, nephrotoxic, and/or ototoxic drugs, such as gentamicin, cisplatin, cephaloridine, kanamycin, amikacin, polymyxin B, colistin, paromomycin, streptomycin, tobramycin, vancomycin, ethacrynic acid, furosemide, and viomycin, should be avoided; 12. Preoperative evaluation suggests an intra-abdominal process that might preclude full closure of the skin; 13. Ongoing treatment (e.g. chemotherapy, radiation) for non-colorectal cancer; 14. History of significant drug or alcohol abuse within the past year; 15. Serum Creatinine \> 1.3 mg/dL 16. Serum Bilirubin \> 2.5 times upper limit of normal; 17. History of uncontrolled diabetes mellitus (controlled diabetic patients whose hemoglobin A1c is ≤ 9.0% may be included); 18. Patients who are immunocompromised including but not limited to systemic corticosteroid use or chemotherapy/radiation during the 30 days prior to surgery, organ transplantation, or HIV infection (Note: inhaled corticosteroids are not exclusionary and single dose use of corticosteroids to prevent PONV is allowed.); 19. Any clinically meaningful hearing loss (from Medical History); 20. Clinically exclusionary results on clinical laboratory, ECG, or physical examination including but not limited to positive hepatitis B or C or HIV; 21. Pregnant or lactating, or if of childbearing potential not practicing a birth control method with a high degree of reliability; 22. Refusal to accept medically indicated blood products; 23. Participation within 30 days before the start of this study in any experimental drug or device study, or currently participating in a study in which the administration of investigational drug or device within 60 days is anticipated; 24. Patients with anterior abdominal wall mesh that is not planned to be completely removed during the planned procedure; 25. Unable to participate in the study for any reason in the opinion of the Principal Investigator; 26. Postsurgical life expectancy of less than 30 days, in the Investigator's or Sponsor's opinion; 27. Expected discharge from the hospital less than 3 days after surgery.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Adverse Events, Laboratory, Physical Examination Changes | Baseline up to Day 30 | Safety and tolerability measured by number of patients with adverse events or changes in laboratory or physical examination findings from baseline (DFA-02 application during surgery on Day 1) to 30 days after surgery. |
| Area Under Curve (AUC) | 1, 6, 24, 48 96 hours post-dose | Area under the curve (AUC) of plasma gentamicin and vancomycin levels using sparse sampling from baseline (DFA-02 application during surgery on Day 1) to 4 days after surgery |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximal Plasma Concentration (Cmax) | 1, 6, 24, 48, 96 hours post-dose | Maximal plasma concentration (Cmax)of gentamicin and vancomycin using sparse sampling from baseline (DFA-02 application during surgery on Day 1) to 4 days after surgery |
| Renal Function | Baseline up to Day 14 | Changes in serum creatinine from surgery on Day 1 until 14 days after surgery |
| Antibiotic Resistance | Baseline up to Day 5 | Methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococcus presence at surgery on Day 1 and 5 days after surgery |
| Incidence of Surgical Site Infection | Up to 30 Days After Surgery | The incidence of probable or definite surgical site infection as determined by the Investigator. |
Countries
United States
Participant flow
Recruitment details
Study Period: February 12, 2012 to June 27, 2013. Patients were enrolled at four hospital based sites in the US (Tampa, FL; Temple, Tx; Florence, AL; Houston, TX).
Participants by arm
| Arm | Count |
|---|---|
| DFA-02 Progressive cohorts of 8 subjects per cohort receiving up to 10, 20 or 30 mL of DFA-02 | 24 |
| DFA-02 Placebo Progressive cohorts of 2 subjects per cohort receiving up to 10, 20 or 30 mL of DFA-02 placebo | 6 |
| Total | 30 |
Baseline characteristics
| Characteristic | DFA-02 | DFA-02 Placebo | Total |
|---|---|---|---|
| Age, Continuous | 62.8 years STANDARD_DEVIATION 14.91 | 58.5 years STANDARD_DEVIATION 16.7 | 62.0 years STANDARD_DEVIATION 15.04 |
| Body Mass Index | 29.8 kg/m2 STANDARD_DEVIATION 4 | 27.8 kg/m2 STANDARD_DEVIATION 2.47 | 29.4 kg/m2 STANDARD_DEVIATION 3.79 |
| Race/Ethnicity, Customized Black/African American | 3 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized White | 21 Participants | 5 Participants | 26 Participants |
| Region of Enrollment United States | 24 participants | 6 participants | 30 participants |
| Sex: Female, Male Female | 14 Participants | 4 Participants | 18 Participants |
| Sex: Female, Male Male | 10 Participants | 2 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 23 / 24 | 6 / 6 |
| serious Total, serious adverse events | 5 / 24 | 2 / 6 |
Outcome results
Primary
Area Under Curve (AUC)
Area under the curve (AUC) of plasma gentamicin and vancomycin levels using sparse sampling from baseline (DFA-02 application during surgery on Day 1) to 4 days after surgery
Time frame: 1, 6, 24, 48 96 hours post-dose
Population: All Subjects Receiving Active Drug
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DFA-02 | Area Under Curve (AUC) | Gentamicin AUC (0-t) | 14.2 mcg/h/mL | Standard Deviation 12.6 |
| DFA-02 | Area Under Curve (AUC) | Vancomycin AUC (0-t) | 6.47 mcg/h/mL | Standard Deviation 8.12 |
Primary
Number of Patients With Adverse Events, Laboratory, Physical Examination Changes
Safety and tolerability measured by number of patients with adverse events or changes in laboratory or physical examination findings from baseline (DFA-02 application during surgery on Day 1) to 30 days after surgery.
Time frame: Baseline up to Day 30
Population: As Treated
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| DFA-02 | Number of Patients With Adverse Events, Laboratory, Physical Examination Changes | Any Adverse Event | 23 Participants |
| DFA-02 | Number of Patients With Adverse Events, Laboratory, Physical Examination Changes | Any Serious Adverse Event | 5 Participants |
| DFA-02 | Number of Patients With Adverse Events, Laboratory, Physical Examination Changes | Related Adverse Event | 3 Participants |
| DFA-02 | Number of Patients With Adverse Events, Laboratory, Physical Examination Changes | Death | 0 Participants |
| DFA-02 Placebo | Number of Patients With Adverse Events, Laboratory, Physical Examination Changes | Death | 1 Participants |
| DFA-02 Placebo | Number of Patients With Adverse Events, Laboratory, Physical Examination Changes | Any Adverse Event | 6 Participants |
| DFA-02 Placebo | Number of Patients With Adverse Events, Laboratory, Physical Examination Changes | Related Adverse Event | 0 Participants |
| DFA-02 Placebo | Number of Patients With Adverse Events, Laboratory, Physical Examination Changes | Any Serious Adverse Event | 2 Participants |
Secondary
Antibiotic Resistance
Methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococcus presence at surgery on Day 1 and 5 days after surgery
Time frame: Baseline up to Day 5
Population: As Treated
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| DFA-02 | Antibiotic Resistance | Nasal MRSA Conversion | 1 Participants |
| DFA-02 | Antibiotic Resistance | Rectal Vancomycin Resistant Enterococcus Conversio | 0 Participants |
| DFA-02 Placebo | Antibiotic Resistance | Nasal MRSA Conversion | 0 Participants |
| DFA-02 Placebo | Antibiotic Resistance | Rectal Vancomycin Resistant Enterococcus Conversio | 1 Participants |
Secondary
Incidence of Surgical Site Infection
The incidence of probable or definite surgical site infection as determined by the Investigator.
Time frame: Up to 30 Days After Surgery
Population: As treated
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DFA-02 | Incidence of Surgical Site Infection | 6 Participants |
| DFA-02 Placebo | Incidence of Surgical Site Infection | 1 Participants |
Secondary
Maximal Plasma Concentration (Cmax)
Maximal plasma concentration (Cmax)of gentamicin and vancomycin using sparse sampling from baseline (DFA-02 application during surgery on Day 1) to 4 days after surgery
Time frame: 1, 6, 24, 48, 96 hours post-dose
Population: All subjects receiving DFA-02 active gel
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DFA-02 | Maximal Plasma Concentration (Cmax) | Gentamicin Cmax | 0.642 mcg/mL | Standard Deviation 0.524 |
| DFA-02 | Maximal Plasma Concentration (Cmax) | Vancomycin Cmax | 0.164 mcg/mL | Standard Deviation 0.15 |
Secondary
Renal Function
Changes in serum creatinine from surgery on Day 1 until 14 days after surgery
Time frame: Baseline up to Day 14
Population: As treated
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| DFA-02 | Renal Function | Moderate Elevated Serum Creatinine Day 5 or Day 14 | 1 Participants |
| DFA-02 | Renal Function | Severe/LifeThreatening Elevated Serum Creatinine | 0 Participants |
| DFA-02 Placebo | Renal Function | Moderate Elevated Serum Creatinine Day 5 or Day 14 | 0 Participants |
| DFA-02 Placebo | Renal Function | Severe/LifeThreatening Elevated Serum Creatinine | 0 Participants |