Serial Endoscopic Surveillance & Direct Topical Antibiotics to Define the Role of Microbes in Anastomotic Healing

NCT02682485 | Withdrawn Phase 2 DMC FDA Drug

• 1 other identifier: IRB15-0971
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

Rationale: The surgical complication of intestinal anastomotic leak remains a clear and present danger to patients despite advances in surgical technique and ever more powerful antibiotics. No surgeon is immune from this complication and leak rates have not changed in decades. The consequences of a leak (peritonitis, sepsis, death) can be so severe that in the case of rectal cancer, diverting ileostomies are routinely performed to divert the fecal stream away from the healing anastomosis. We have recently discovered that certain intestinal bacteria, with the capacity to express collagenase and cleave MMP9 (Matrix metallopeptidase 9) to its active collagen degrading form, play a key and causative role in anastomotic leak. These bacteria often escape elimination due to the failure of current antibiotic regimens and their delivery methods to remain functionally durable at anastomotic tissue sites. Purpose: This phase II clinical trial will track, in real time, the process of anastomotic healing and its associated microbiome by performing serial endoscopic surveillance (SES) following rectal cancer resection. By capturing anastomotic images and the associated microbial and inflammatory mediators from anastomotic fluids via SES performed at three time points following rectal cancer resection, we will correlate healing to microbial composition and inflammatory mediator status. Patients will be randomized and, at each time point, will receive lavage of their anastomosis with either saline or a triple antibiotic solution (ciprofloxacin, metronidazole, neomycin). An anastomotic healing score captured during SES will be compared between the two treatment arms and correlated to microbial and inflammatory mediator analyses of fluid samples to determine how intestinal microbes influence the process of anastomotic healing.

Conditions

Anastomotic Leak; Rectal Cancer

Keywords

Rectal Cancer; low anterior resection; SES; SES-DTA; anastomotic leak; anastomotic healing; intestinal healing; anastomosis

Outcome Measures

Primary Outcomes (1)

• Anastomotic Healing Score (ordinal scale ranging from 0 to a maximum of 18)

  Post-operative day 12-28

Secondary Outcomes (2)

• Anastomotic Healing Score (ordinal scale ranging from 0 to a maximum of 18)

  Post-operative day 0

• Anastomotic Healing Score (ordinal scale ranging from 0 to a maximum of 18)

  Post-operative day 3-7

Study Arms (2)

Cipro, metronidazole, neomycin combo

EXPERIMENTAL

As part of each serial endoscopic surveillance, a second lavage of the anastomosis will be performed prior to removing the endoscope. In this arm, the lavage will be with a direct topical antibiotics solution composed of metronidazole, ciprofloxacin and neomycin.

Drug: Cipro, metronidazole, neomycin combo; Procedure: Serial Endoscopic Surveillance

Saline

PLACEBO COMPARATOR

As part of each serial endoscopic surveillance, a second lavage of the anastomosis will be performed prior to removing the endoscope. In this arm, the lavage will be with direct topical saline.

Procedure: Serial Endoscopic Surveillance; Drug: Saline

Interventions

Cipro, metronidazole, neomycin combo DRUG

During endoscopies after imaging, the anastomosis will be lavaged with an antibiotic solution composed of metronidazole, ciprofloxacin and neomycin

Also known as: Cipro/CiproXR/CiproIV; Flagyl/FlagylER/Metro; Neomycin

Cipro, metronidazole, neomycin combo

Serial Endoscopic Surveillance PROCEDURE

Patients will undergo serial endoscopic surveillance consisting of three endoscopies: one intra-operative endoscopy (POD0) and two post-operative endoscopies (POD3-7, POD12-28). During endoscopies, the anastomosis will be lavaged with saline, the fluid will be collected by suction and images will be taken.

Also known as: SES

Cipro, metronidazole, neomycin combo; Saline

Saline DRUG

During endoscopies after imaging, the anastomosis will be lavaged with a placebo direct topical saline solution

Also known as: 0.9% saline solution

Saline

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of rectal cancer
• Scheduled to undergo a low anterior resection (with the planned anastomosis within 10cm of the anal verge) and a diverting ileostomy
• years of age or older
• Able to provide informed consent

You may not qualify if:

• Prior medical history of or suspected diagnosis of inflammatory bowel disease or irritable bowel syndrome
• Pregnant or breastfeeding
• Allergy to lidocaine, ciprofloxacin, metronidazole or neomycin

Sponsors & Collaborators

• University of Chicago: lead

Related Publications (2)

• Olivas AD, Shogan BD, Valuckaite V, Zaborin A, Belogortseva N, Musch M, Meyer F, Trimble WL, An G, Gilbert J, Zaborina O, Alverdy JC. Intestinal tissues induce an SNP mutation in Pseudomonas aeruginosa that enhances its virulence: possible role in anastomotic leak. PLoS One. 2012;7(8):e44326. doi: 10.1371/journal.pone.0044326. Epub 2012 Aug 31.

  PMID: 22952955 BACKGROUND

• Shogan BD, Belogortseva N, Luong PM, Zaborin A, Lax S, Bethel C, Ward M, Muldoon JP, Singer M, An G, Umanskiy K, Konda V, Shakhsheer B, Luo J, Klabbers R, Hancock LE, Gilbert J, Zaborina O, Alverdy JC. Collagen degradation and MMP9 activation by Enterococcus faecalis contribute to intestinal anastomotic leak. Sci Transl Med. 2015 May 6;7(286):286ra68. doi: 10.1126/scitranslmed.3010658.

  PMID: 25947163 BACKGROUND

MeSH Terms

Conditions

Anastomotic Leak; Rectal Neoplasms

Interventions

Ciprofloxacin; Metronidazole; Neomycin; Sodium Chloride; Saline Solution

Condition Hierarchy (Ancestors)

Postoperative Complications; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Nitroimidazoles; Nitro Compounds; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Aminoglycosides; Glycosides; Carbohydrates; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Study Officials

• John C Alverdy, MD

  University of Chicago

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 8, 2016
• First Posted: February 15, 2016
• Study Start: March 3, 2017
• Primary Completion: March 3, 2017
• Study Completion: March 3, 2017
• Last Updated: April 26, 2023

Record last verified: 2023-04

Data Sharing

• IPD Sharing: Will not share