Clinical trial NCT01297959: Study to Evaluate Efficacy and Safety of E-101 Solution for Preventing Surgical Site Infections After Colorectal Surgery
Official title: Phase 3 Study of Efficacy and Safety of Topical E-101 Solution to Prevent Incisional Infections Among Colorectal Surgery Patients (Triple IN Study --Inhibition of Incisional Infections)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Infections
Keywords: Surgical Wound Infection
Therapeutic Enzyme System
Singlet Oxygen
Peroxidase
Glucose Oxidase
Colorectal surgery
Incisional Surgical Site Infections (SSI)
Anti-infective Agents, Local
Clinical Trial, Phase III
Lead sponsor: Excited States, LLC
Sponsor class: INDUSTRY
Collaborators: name: Veristat, Inc.
name: Biotec Services International Ltd
name: Eurofins
name: CBR International Corp.
First posted: 2011-02-17
Enrollment: 503
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: This study is intended to determine the efficacy, safety and tolerability of topical application of E-101 Solution directly into the surgical incisional wound in the prevention of infection of superficial and deep surgical incisional wounds. E-101 Solution is an enzyme-based antiseptic that is being developed for direct application to a surgical incision.

Detailed description: The purpose of this standard-of-care, pivotal Phase 3 study is to evaluate the efficacy and safety of topical E-101 Solution after direct application into the principal surgical incision in the prevention of superficial and deep incisional surgical site infections (SSI) within 30 days after elective colorectal surgery. The study is intended to support a target indication statement of: "E-101 Solution is indicated for the prophylaxis of incisional surgical site infections following elective colorectal surgery". E-101 Solution is comprised of the active ingredients of glucose oxidase (GO) and porcine myeloperoxidase (pMPO) that produce coupled reactions after the addition of glucose substrate. The hypothesis is that E-101 Solution topically applied directly into the principal incision is safe and significantly reduces the incidence of incisional SSI compared to placebo topical application. (The principal surgical incision is ≥ 5cm and \< 35 cm used as a hand port, colorectal specimen extraction port, or extracorporeal manipulation port depending on the specific colorectal surgical approach.)

Eligibility criteria: Inclusion Criteria:

1. Scheduled to undergo elective colon and/or rectal surgical procedures involving open laparotomy, hand-assisted laparoscopy, and laparoscopic-assisted approaches. The principal incision must have a length of \> 5 cm and \< 35 cm in length. Eligible surgeries are: left hemicolectomy, right hemicolectomy, transverse colectomy, ileocolic resection, total abdominal colectomy with ileorectal anastomosis, total abdominal proctocolectomy (portion of specimen to be extracted via laparotomy), low anterior resection, sigmoid resection, non-emergent Hartmann procedure, colostomy takedown through laparotomy (not peristomal) incision, ileo-pouch anal anastomosis, and abdominal perineal resection of the rectum.
2. Able to give informed consent.
3. If female, is non-pregnant (negative pregnancy test result at the Screening/Randomization Visit) and non-lactating.
4. If female, is either not of childbearing potential (defined as postmenopausal for at least 1 year or surgically sterile \[status post bilateral tubal occlusion, bilateral oophorectomy, or hysterectomy\]) or practicing 1 of the following methods of birth control and agrees to continue with this regimen over the study surveillance period:

   * Oral, implantable, or injectable contraceptives for 3 consecutive months before the Baseline/Randomization Visit
   * Intrauterine device
   * Double barrier method (condoms, sponge, or diaphragm with spermicidal jellies or cream)
   * Not sexually-active. Agreement to be available for evaluation at the study site for scheduled visits.

Exclusion Criteria:

1. Hypersensitivity to porcine products.
2. History of known anti-myeloperoxidase autoantibodies (i.e., perinuclear anti-neutrophil cytoplasmic antibody \[pANCA\]), as well as participants with known idiopathic necrotizing glomerulonephritis and certain systemic vasculitis conditions \[e.g., microscopic polyangiitis of small blood vessels, Wegener's granulomatosis, and Churg-Strauss Syndrome\]).
3. Use of microbial sealant (IntegusealTM), any antibiotic-embedded suture, or any antimicrobial-embedded suture to close the principal incision or any suture in the surgical field that has not been formally approved by the relevant local national regulatory authority.
4. Absolute contraindication to general anesthesia.
5. Hypersensitivity reactions to steri-strip tapes, medical-surgery tapes, adhesives, or sutures. (Note: If there can be assurances that the participant will not be exposed to these materials that cause hypersensitivity, alternatives will be allowed.)
6. History of keloid or hypertrophic scarring within or near an incision from a prior surgery.
7. Body mass index \[BMI\]: \> 50 or \< 20 (both due to the extremely high risk of poor wound healing).
8. American Society of Anesthesiologists (ASA) Score \> 3.
9. Undergoing emergency colorectal surgery such that standard bowel preparation and other standard preoperative precautions and assessments cannot be performed in time before the index-surgery.
10. The planned index-surgery involves removal or placement of mesh (either synthetic or biological) as part of closure in the principal incision or traversing any part of a pre-existing mesh (either synthetic or biological) in the principal incision.
11. There are clinical signs of overt infection necessitating systemic antibiotics via oral, intramuscular, or intravenous routes (e.g., infection of the abdominal wall, peritonitis, pneumonia, and sepsis/septic shock) prior to the index-surgery.
12. Preoperative severe neutropenia (total neutrophil count ≤500 X 109/L). (Note: Testing should be performed at the local laboratory.)
13. Receiving any oral or intravenous antibiotics within 24 hours prior to the index-surgery. (Note: It is permissible to administer conventional oral prophylactic antibiotics as bowel preparation up to the time of the index- surgical procedure, as well as intravenous or intramuscular prophylactic antibiotics just prior to the index-surgery as per the treating surgeon's standard of care.)
14. Preoperative evaluation that the intra-abdominal process might preclude full closure of the skin incision due to severe or morbid obesity (i.e., any mechanical reason that would prevent/preclude primary intent wound healing) at the principal incision.
15. History of major organ transplantation (e.g., lung, liver, or kidney), including bone marrow transplantation, or intent to perform major organ transplant as a concomitant surgery.
16. History of a complicated laparotomy within 30 days prior to planned index-surgery.
17. Planning to undergo a second colorectal surgical procedure (e.g., colostomy or ileostomy takedown) or any other general surgery in less than 30 days of index-surgery.
18. Likely preoperative urinary tract infection, as evident by: i) symptoms of upper urinary tract infection (e.g., fever and/or flank pain) or ii) symptoms of lower urinary tract infection (e.g., urinary frequency, dysuria, urgency, and/or suprapubic pain); accompanied by any one of the following: 1) bacteriuria of ≥104 bacteria/mL urine or 2) positive urine leucocyte esterase or positive nitrite urine dipstick tests. Also exclude any man under age 60 years who has both positive urine nitrite and leucocyte esterase dipstick tests - even if he is asymptomatic (unless he has predisposing factors for urinary tract infection - e.g., spinal cord injury). (Note: Testing should be performed at the local laboratory.)
19. Undergoing a significant concomitant surgical procedure (e.g., hysterectomy) or any mesh repair (either synthetic or biological mesh) as part of closure. The following concomitant procedures are allowed: appendectomy, cholecystectomy, oophorectomy, removal of Meckel's diverticulum, primary repair of small ventral hernia (i.e., \<30 cm2), liver biopsy/wedge resection (but not liver resection).
20. Participants with a condition (e.g., recurrent urinary tract infections, nail infections, sinusitis, dental infections, vaginitis/vaginosis, or chronic bronchitis) requiring frequent or chronic administration of antimicrobials (received antibiotics/antimicrobials at least twice for ≥ 2 weeks during past 6 months).
21. Preoperative prothrombin time or international normalized ratio (INR) \> 2 x upper limit of normal. (Note: Testing should be performed at the local laboratory.)
22. Postsurgical life expectancy ≤ 60 days (in the Investigator's or Sponsor's opinion).
23. Any participant in which the planned surgery would include: i) placement of a stoma in the principal incision; ii) placement of a drain into the supra-peritoneal fascia space that emerges through the principal incision; iii) placement of a drain into the intraperitoneal space that emerges through the principal incision; and iv) supplementation of any of the irrigation fluid with antibiotic or antiseptic drugs.
24. Participant with severe Chronic obstructive pulmonary disease (COPD) that are likely to need \> 24 hours postoperative ventilator support (e.g. participant on chronic or intermittent supplemental oxygen or an estimated forced expiratory volume in 1 second (FEV1) less than 50% of expected based on bedside spirometry).
25. If, in the opinion of Investigator, the potential participant would likely be unable to maintain adequate care of the principal incision post-operatively.
26. Anticipate that participant will not be available for study visits/ procedures or if in the opinion of Investigator there is concern that participant might not comply with study visits/procedures (e.g., due to ongoing illicit drug usage or alcohol abuse).
27. Lack of willingness to have personal study-related data collected, archived, or transmitted under a blinded condition to regulatory agencies.
28. 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.

Primary outcomes:
measure: Number of Participants In Intent to Treat (ITT) Analysis Set With Superficial and Deep Incisional Surgical Site Infections (SSI) Involving Principal Incision Within 30 Days After Index-surgery as Determined by Blinded Assessors 30 Days Post-operatively
timeFrame: Surgery (Day 0) up to 30 days post-surgery
measure: Number of Participants In Per-Protocol (PP) Analysis Set With Superficial and Deep Incisional SSI Involving Principal Incision Within 30 Days After the Index-surgery as Determined by Blinded Assessors 30 Days Post-operatively
timeFrame: Surgery (Day 0) up to 30 days post-surgery
Secondary outcomes:
measure: Mean Clinical Infection Wound Scale Score (CIWS)
timeFrame: Surgery (Day 0) up to 30 days post-surgery
measure: Number of Participants With Objectively Determined Incisional Surgical Site Infections (SSI)
timeFrame: Surgery (Day 0) up to 30 days post-surgery
measure: Number of Participants With Superficial and Deep Incisional Surgical Site Infections (SSI) Involving the Principal Incision (PI) Within 30 Days After the Index-surgery as Determined by Blinded Assessors 14 Days Post-operatively
timeFrame: Surgery (Day 0) up to 14 days post-surgery
measure: Worst Post-Baseline Mobility Score Using European Quality of Life-5 Dimensions (EQ-5D) Questionnaire
timeFrame: Day 0 up to Day 30
measure: Worst Post-Baseline Self-Care Score Using European Quality of Life-5 Dimensions (EQ-5D) Questionnaire
timeFrame: Day 0 up to Day 30
measure: Worst Post-Baseline Usual Activity Score Using European Quality of Life-5 Dimensions (EQ-5D) Questionnaire
timeFrame: Day 0 up to Day 30
measure: Worst Post-Baseline Pain/Discomfort Using European Quality of Life-5 Dimensions (EQ-5D) Questionnaire
timeFrame: Day 0 up to Day 30
measure: Worst Post-Baseline Anxiety/Depression Score Using European Quality of Life-5 Dimensions (EQ-5D) Questionnaire
timeFrame: Day 0 up to Day 30
measure: Worst Post-Baseline Health State Score Using European Quality of Life-5 Dimensions (EQ-5D) Questionnaire
timeFrame: Day 0 up to Day 30
measure: Number of Participants With Re-Hospitalization
timeFrame: Surgery (Day 0) up to 30 days post-surgery
measure: Number of Participants With Clinical Wound Healing Score (CWHS) as Assessed by Blinded Assessors
timeFrame: Day 3 up to Day 30
measure: Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-Emergent Adverse Events (TEAEs), Adverse Drug Reactions (ADRs), Suspected Unexpected Serious Adverse Reactions (SUSARs) and Unexpected Adverse Reactions (UARs)
timeFrame: From first dose up to 30 days post-surgery
measure: Number of Participants With Clinically Significant Laboratory Findings
timeFrame: From first dose up to 30 days post-surgery
measure: Number of Participants With Clinically Significant Physical Examination Findings
timeFrame: From first dose up to 30 days post-surgery
measure: Number of Participants by Wound Pain Assessment Scores
timeFrame: Surgery (Day 0) up to 30 days post-surgery
measure: Number of Participants With pANCA Immunoglobulin G (IgG) Antibody, Serum Anti-glucose Oxidase (GO) IgG,M,A, pMPO IgG,M,A, Serum GO Neutralization, Serum pMPO Neutralization Antibody
timeFrame: Day 14 and Day 30
measure: Number of Participants With pANCA IgG Anti-body, Serum Anti-GO IgG,M,A, pMPO IgG,M,A, Serum Neutralization GO, Serum pMPO Neutralization Antibody
timeFrame: Month 3 and Month 6
measure: Number of Participants With Serum pANCA and pMPO Antibody Response
timeFrame: Day 30, Month 3 and Month 6
Other outcomes:
measure: Minimum Inhibitory Concentration (MIC) at 90%
timeFrame: Surgery (Day 0) up to to 30 days post surgery
measure: Minimum Bactericidal Concentration (MBC) at 90%
timeFrame: Surgery (Day 0) up to to 30 days post surgery
Locations:
city: Mobile
country: United States
facility: University of South Alabama Medical Center
state: Alabama
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: Stanford
country: United States
facility: Stanford University Medical Center
state: California
city: Sunrise
country: United States
facility: Sheridan Clinical Research, Inc.
state: Florida
city: Tampa
country: United States
facility: University of South Florida/Tampa General Hospital
state: Florida
city: Weston
country: United States
facility: Cleveland Clinic Florida
state: Florida
city: Chicago
country: United States
facility: Stoger Hospital of Cook County
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Louisville
country: United States
facility: University of Louisville
state: Kentucky
city: Metairie
country: United States
facility: Colon & Rectal Surgery Associates
state: Louisiana
city: New Orleans
country: United States
facility: Tulane University Health Sciences Center
state: Louisiana
city: New Orleans
country: United States
facility: Ochsner Clinic Foundation / Colon and Rectal Surgery
state: Louisiana
city: Pittsfield
country: United States
facility: Berkshire Medical Center, Inc
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Brandon
country: United States
facility: Medical IQ
state: Mississippi
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Omaha
country: United States
facility: Colon and Rectal Surgery, Inc.
state: Nebraska
city: Freehold
country: United States
facility: CentraState Medical Center
state: New Jersey
city: Livingston
country: United States
facility: Saint Barnabas Medical Center
state: New Jersey
city: Neptune
country: United States
facility: Meridian Health Jersey Shore University Medical Center
state: New Jersey
city: Albany
country: United States
facility: Albany Medical Center
state: New York
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: New York
country: United States
facility: Mount Sinai School of Medicine
state: New York
city: Stony Brook
country: United States
facility: Stony Brook University Medical Center
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical University
state: New York
city: Cincinnati
country: United States
facility: The Christ Hospital
state: Ohio
city: Portland
country: United States
facility: Oregon Health Sciences University
state: Oregon
city: Dallas
country: United States
facility: Baylor Research Institute
state: Texas
city: Houston
country: United States
facility: Methodist Hospital
state: Texas
city: Houston
country: United States
facility: Southwest Surgical Associates, L.L.P.
state: Texas
city: San Antonio
country: United States
facility: Methodist Hospital
state: Texas
city: Sugar Land
country: United States
facility: Southwest Surgical Associates, LLP
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia Health System
state: Virginia
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
city: Haifa
country: Israel
facility: Rambam Medical Center
city: Jerusalem
country: Israel
facility: Hadasit Medical Research Services & Development LTD
city: Petah Tikva
country: Israel
facility: Rabin Medical Center, Beilinson Hospital
city: Tel Aviv
country: Israel
facility: The Tel Aviv Sourasky Medical Center
city: Tel Hashomer
country: Israel
facility: The Chaim Sheba Medical Center
Study officials:
affiliation: Excited States, LLC
name: Peter O'Hanley, PhD, MD, MPH
role: STUDY_DIRECTOR
affiliation: Oregon Health and Science University
name: Robert Martindale, MD, PhD
role: STUDY_CHAIR
affiliation: University of California, Irvine
name: Michael J Stamos, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Emory Healthcare
name: Jerrold H Levy, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Denys, G.A., O'Hanley P, Stephens, JT. E-101 Solution demonstrates antiviral properties against Herpes Simplex Virus, Human Immunodeficiency Virus, and Human Influenza A/H1N1 Virus. American Society for Microbiology, 110th General meeting, San Diego, CA (Abstract # C-2061). May 2010.
citation: O'Hanley, P, Beausoleil C, O'Hanley K, Stephens, JT. E-101 Solution, a novel antiseptic intended for direct application within a surgical wound to prevent surgical site infection: Blinded, controlled Phase 1 skin irritation study in healthy volunteers. Annual Surgical Site Infection Meeting, Las Vegas, NV, May 2010.
citation: O'Hanley P, O'Hanley K, Beausoleil C, Stephens JT. E-101 Solution (E-101), a Myeloperoxidase (MPO) Antiseptic for Prevention of Surgical Site Infections (SSI): Phase 1 Sensitization and Microbial Reduction in Healthy Adult Volunteers. Program and Abstracts of the 50th Interscience Conference on Antimicrobial Agents and Chemotherapy, Boston, MA, October 2010.
citation: Pillar, C, Denys GA, O'Hanley P, Stephens JT, Sahm D. E-101, a novel in class topical anti-infective, has potent activity against clinical isolates of important pathogens in Europe collected from 2008-2010. 21st ECCMID/27th ICC, Milan, Italy, May 2011.
citation: Pillar C, Denys GA, O'Hanley P, Stephens JT, Sahm D. E-101, a novel in class topical anti-infective, maintains a high degree of potency in vitro against problematic resistant clinical pathogens (ESKAPE pathogens). 21st ECCMID/27th ICC, Milan, Italy, May 2011.
citation: Denys, GA, Goheen MP, Allen RC, O'Hanley P, Stephens JT. Effect of E-101 Solution and its oxidative products on microbial ultrastucture changes associated with microbicidal action. 21st ECCMID/27th ICC, Milan, Italy, May 2011.
citation: O'Hanley, P, Pete M, O'Hanley K, Sabo L, Allen R, Stephens JT. Antibody Responses Not Likely to Affect Efficacy and Safety of E-101 Solution, a Novel Myeloperoxidase (MPO)-based Topical Antiseptic for Prevention of Incisional Infections. Annual Surgical Site Infection Society Meeting, Palm Beach, FL, May 2011.
citation: Denys GA, Allen RC, O'Hanley P, Stephens JT. E-101 solution, a first in class topical anti- infective, shows fungicidal activity in vitro against Candida species. 11th ASM Conference on Candida and Candidiasis March 29-April 2, 2012 San Francisco, CA.
citation: Deane J, Simenauer A, Denys GA, O'Hanley P, Stephens JT, Sahm DF. In vitro activity of E-101, a rapidly bactericidal myeloperoxidase (MPO)-based agent, against key bacterial pathogens. 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), September 9-12, 2012 San Francisco, CA.
citation: Denys GA, Shah D, Deane D, Sahm DF, O'Hanley P, Stephens JT. Antimicrobial susceptibility of E-101 Solution against target aerobic pathogens: A 5-year longititudional study. 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), September 9-13, 2013 Denver, CO.
citation: Denys, GA, MP Goheen, RC Allen, P O'Hanley, JT Stephens Jr. Antifungal activity of two potent topical haloperoxidase-based formulations (EPO-based C-101 and MPO-based E- 101) against Candida albicans. American Society for Microbiology, 114th General Meeting, Boston MA (Abstract #681). May 17-20, 2014.
citation: Denys, GA, C Schneider, P O'Hanley, JT Stephens, Jr., K Babcock. Use of Affinity Biosensor's LifeScale resonant mass measurement to assess antimicrobial activity of E-101 solution, a novel haloperoxidase-based topical antimicrobial agent. American Society for Microbiology, Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Washington, DC (Abstract F-1573). September 5-9, 2014.
citation: Denys, GA, KM Koch, RC Allen, P O'Hanley, JT Stephens, Jr. Superiority of E- 101 solution, a haloperoxidase-containing enzyme product, to sodium oxychlorosene as an antiseptic agent in the presence of serum and whole blood. American Society for Microbiology, 115th General Meeting, New Orleans, LA. May 30-June 2, 2015.
citation: Denys GA, Shah D, Sahm DF, Allen RC, O'Hanley P. Stephens JT. In vitro activity of C- 101 solution, a new eosinophil peroxidase (EPO) containing enzyme system, against Gram- negative and Gram-positive pathogens. 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), September 9-12, 2012 San Francisco, CA.