Symptoms and General Pathology

All Conditions

Anastomotic Leak

Other Dietary Supplements

All Drugs and Chemicals

Herbal and Botanical

Inulin

Cola

Patients randomized to the intervention group will receive inulin supplementation for 14 days, preceding the surgery. Inulin will be given at a dosage of 10g/day divided in two doses.

Patients randomized to the control group will receive a placebo for 14 days, two times a day.

Inulin is a water soluble non-digestible carbohydrate, and it is available in more than 36,000 species of plants. It is often used as dietary fiber and has obtained the "Generally recognized as safe" status (GRAS) by the Food and Drug Administration (FDA).

Placebo

Carole Richard, MD

Nassima Taleb

Colorectal cancer (CRC) is the third most diagnosed cancer in Canada. The most common surgical procedure in patients with CRC is an intestinal resection followed by a reconnection to rejoin the ends of the remaining bowel. Among the postoperative complications, leaking of this intestinal connection is notably feared, affecting up to 20% of patients. These leaks are characterized by impaired intestinal healing and are associated with severe infections and even death.

Various studies have shown that gut microbiota, the bacteria that live in the digestive tract, plays an essential role in intestinal healing following surgery. These results support the possibility of enhancing intestinal healing through supplements that act as an energy source for gut bacteria. Indeed, animal studies have shown that inulin supplementation, a fiber commonly found in plants, improves intestinal healing following bowel surgery. However, no studies in humans have evaluated its effects on CRC surgery patients.

This study aims to determine feasibility of a randomized controlled trial that assesses the effects of inulin supplementation before elective colorectal surgery.

Based on preliminary data, our working hypotheses are that the gut microbiome plays a fundamental role in postoperative healing and that manipulation of preoperative microbiota using inulin will improve postoperative healing and prevent potential development of anastomotic leaks.

The pilot study aims to evaluate the feasibility of a randomized controlled trial that assesses the effects of inulin supplementation before elective colorectal surgery. The project has two main components, a clinical study, and a translational research. A randomized, multi-center, triple-blind, placebo-controlled clinical trial will be conducted to evaluate the impact of inulin supplementation on the clinical and oncological outcomes of inulin supplementation before elective colorectal oncological surgery. Mucosal, blood and fecal samples of patients with inulin supplementation will be compared with samples of patients without inulin supplementation.

The study objectives are:

1. Determine the tolerance of colorectal cancer patients to inulin supplementation before surgery.
2. Assess the effect of inulin supplementation on colonic healing and the rate of AL.
3. Determine the impact of inulin supplementation on the gut microbiota, the inflammatory markers, and the gut barrier function.
4. Assess the effect of inulin supplementation on CRC local and distant recurrence after surgery.

Identification of study participants

Patients who are about to undergo an oncological colorectal surgery will be recruited in the CHUM. Informed consent will be obtained from the patient before enrollment in the study.

Patients will be randomized to the inulin group (intervention group) or to the placebo group (control group). A stratified randomization will be conducted according to the sex (1- Male, 2-Female), the cancer location (1- Right and transverse colon, 2-Left colon and sigmoid, 3-Rectum) and the cancer grade.

Patients randomized to the intervention group will receive inulin supplementation for two weeks, preceding the surgery. Inulin will be given at a dosage of 10g/day divided in two doses. To foster compliance, the inulin will be provided in a calendar pill organizer. Patients randomized to the control group will receive a placebo for two weeks, twice a day. Placebo pills will be identical in appearance to the inulin pills. A total of 40 patients, 20 in each group, will be included in the pilot study.

Adequate colonic preparation will also be given to all the patients, including oral mechanical bowel preparation, oral antibiotics the day before surgery and intravenous antibiotics before surgical incision.

Collection of stool samples

Feces will be collected according to International Human Microbiome Standards (IHMS) guidelines (SOP 03). Two pre-operative specimens will be collected for each enrolled patient: pre-inulin/placebo supplementation and post-inulin/placebo supplementation.

Blood samples

Standard blood tests will be conducted for the participating patients. Supplementary volume will be collected during the per-operative test, before the surgery and at post-op day 3. Blood will be collected in two tubes to assess complete blood counts and to obtained serum.

Intraoperative mucosal sample

A mucosal biopsy coming from colonic anastomosis consist of a fragment from the transection line at the anastomosis. The specimen will be collected in a sterile tube and snap frozen.

Statistical Design

R, Stata and Prism will be used to perform the statistical analysis. Decision to use non-parametric tests is based on data normality (Shapiro-Wilk test) and homoscedasticity (Bartlett's test) tests. Multiple comparisons will be evaluated statistically by 1-way analysis of variance (ANOVA) or by Kruskal-Wallis test. Statistically significant differences will then be evaluated by two-tailed Student's t or Wilcoxon test. Multiple testing is corrected via False Discovery Rate estimation. For pre-supplementation and post-supplementation samples, a paired Student's t-test or paired Wilcoxon test will be used. For comparison of 2 groups, an unpaired Student's t-test or unpaired Wilcoxon test will be used.

The Effect of Inulin Supplementation on Colorectal Surgery Outcomes

The Effect of Inulin Supplementation on Colonic Healing and Surgical Outcomes Following Colorectal Surgery

The GSRS is a seven-point Likert-type scale with response options ranging from 1 (no discomfort at all) to 7 (very severe discomfort). It includes 15 questions that assess various gastrointestinal symptoms.

The DQLQ is a 9-item questionnaire that uses a seven-point Likert-type scale to assess the impact of gastrointestinal symptoms on quality of life. The response options range from 'never' to 'always'.

All patients presenting with suspicious clinical features, such as worrisome laboratory results, post-operative fever, or abnormal physical examination findings, will undergo radiological examinations to confirm an anastomotic leak.

The white blood cell count will be monitored on post-operative day 3 to check for signs of infection or inflammation.

The CRP will be monitored on post-operative day 3 to check for signs of infection or inflammation.

Changes in fecal calprotectin levels will be monitored to assess colonic inflammation.

MUC2 levels will assess the amount of mucin present in the mucosa, which is important for colonic healing after surgery

Centre hospitalier de l'Université de Montréal (CHUM)

Neoplasms

Digestive System Diseases

Rectal Neoplasms

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Intestinal Diseases

Rectal Diseases

Postoperative Complications

Anti-Infective Agents

Pharmaceutical Solutions

Antineoplastic Agents

Anti-Bacterial Agents

Metronidazole

Ciprofloxacin

Antibiotics, Antitubercular

Neomycin

Antiprotozoal Agents

Antiparasitic Agents

Enzyme Inhibitors

Cytochrome P-450 Enzyme Inhibitors

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.

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.

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

Cipro, metronidazole, neomycin combo

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.

Serial Endoscopic Surveillance

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

Saline

John C Alverdy, MD

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.

OBJECTIVES

* Perform repeated postoperative endoscopy of anastomotic tissue sites in patients undergoing low anterior resection for rectal cancer with diverting ileostomy.
* Demonstrate that SES can reliably discriminate those anastomoses that progress along a continuum toward normal healing versus those that heal pathologically when images are evaluated by a jury blinded to treatment.
* Demonstrate that those anastomoses that are judged to progress pathologically harbor distinct microbial species and predictive inflammatory mediators.
* Demonstrate that when anastomotic tissues are lavaged with antibiotics directly via endoscopy (ciprofloxacin, metronidazole, neomycin), microbial pathogens that escape conventional antibiotics are eliminated and anastomotic healing progresses normally.
* Determine if the anastomotic healing score, microbial analyses, and/or inflammatory mediator analyses identify or predict symptomatic and clinically relevant anastomotic complications.

STUDY This is a randomized, multicenter study. All patients undergo resection of rectal cancer with a low anterior resection with anastomoses within 10cm of the anal verge and diverting ileostomy. Patients will undergo three endoscopies: one intra-operative endoscopy (POD0) and two post-operative endoscopies (POD3-7, POD12-28) (POD = post-operative day). During the SES procedure, the anastomosis will be lavaged with saline, the fluid will be collected by suction, images will be taken and then the anastomosis will be lavaged with either saline or an antibiotic solution composed of metronidazole, ciprofloxacin and neomycin. Patients' clinical courses will be followed through chart review for 6 to 7 months following surgery.

PROJECTED ACCRUAL A total of 200 patients (approximately 100 per treatment arm) will be accrued for this study within 4 years.

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

A Multicenter, Phase II, Randomized, Double-Blinded, Placebo-Controlled Clinical Trial of Serial Endoscopic Surveillance (SES) and Direct Topical Antibiotics (DTA) to Define the Role of Microbes in Anastomotic Healing

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
The Effect of Inulin Supplementation on Colorectal Surgery Outcomes	NCT05860322	Anastomotic Com...	Inulin Placebo	18 Years -	Centre hospitalier de l'Université de Montréal (CHUM)
Serial Endoscopic Surveillance & Direct Topical Antibiotics to Define the Role of Microbes in Anastomotic Healing	NCT02682485	Anastomotic Lea... Rectal Cancer	Cipro, metronid... Serial Endoscop... Saline	18 Years -	University of Chicago
The Effect of Inulin Supplementation on Colorectal Surgery Outcomes	NCT05860322	Anastomotic Com...	Inulin Placebo	18 Years -	Centre hospitalier de l'Université de Montréal (CHUM)
Serial Endoscopic Surveillance & Direct Topical Antibiotics to Define the Role of Microbes in Anastomotic Healing	NCT02682485	Anastomotic Lea... Rectal Cancer	Cipro, metronid... Serial Endoscop... Saline	18 Years -	University of Chicago

Spots Global Cancer Trial Database for anastomotic healing