Comparing the Effectiveness of IV Bezlotoxumab Versus Placebo in Decreasing Morbidity and Mortality in Patients With Fulminant C. Diff Requiring Surgery.

A Prospective, Double-blind, Randomized, and Controlled Clinical Trial to Compare the Effectiveness of Intravenous Bezlotoxumab (10 mg/kg) Versus Placebo in Decreasing Morbidity and Mortality in Patients With Fulminant Clostridioides Difficile Requiring Surgical Intervention.

A new medication, Bezlotoxumab, has been approved for treatment of recurrent Clostridium difficile diarrhea by the U.S. Food and Drug Administration. The way this new medication works, is by binding the toxin produced by C. difficile bacteria and preventing damage to the large bowel. The toxin, and not the bacteria, is responsible for the damage, resulting in the clinical symptoms seen in patients. Sometimes, the infection can make a patient severely ill with organ failure and death. If severe enough, the infection requires surgery to remove the large bowel and allow the patient a better chance at recovery. Even with surgery and removal of the bowel, patients can continue to be severely ill and have a very high rate of mortality. The toxin that injures the large bowel has been shown to obtain access to systemic circulation because of the injury to the bowel. At this time, the investigators continue antibiotics and supportive care to help patients recover post-operatively, as the investigators do not have other interventions in this critical population. Bezlotoxumab is known to bind this toxin and stop it from causing further injury in the bowel; it has the potential to bind the systemic toxin to prevent further damage throughout the body. This study is proposing that this new medication, Bezlotoxumab, can be added to the current standard of care for severe infection that requires surgery, and result in a decrease of the complications associated with this disease process. In this study, some patients will receive the medication after surgery; others will receive extra fluid. The investigators will not know who received which in order to decrease any bias in the results. All participants will receive similar post-operative care and be monitored closely. When enough patients are enrolled in the study, the results will be evaluated.

Study Overview

• Status: Terminated
• Conditions: Clostridia Difficile Colitis; Clostridium; Sepsis
• Intervention / Treatment: Other: Normal Saline; Biological: Bezlotoxumab

Detailed Description

Study Design This will be an interventional prospective, randomized, double-blinded controlled trial performed at a single center. Prospective data will be collected of all consenting patients with a diagnosis of either initial or recurrent fulminant C. difficile colitis requiring surgical intervention. The data to be collected includes standard-of-care blood draws; no extra lab draws are planned for this trial. In the event labs are not drawn, the investigators will plan to obtain serum creatinine, total bilirubin, and platelet counts to continue SOFA score evaluations while the patient is in the surgical ICU. Consent will be obtained either from the patient or their legally authorized representative. Inclusion criteria will be all patients over the age of eighteen with diagnosed fulminant C. difficile colitis requiring surgical colectomy with end ileostomy. Surgical intervention will be determined by the operating surgeon at the time of initial consult assessment and during the follow-up assessments while the patient is hospitalized. Patients may be excluded on the account they are pregnant, prisoners/ incarcerated, have a history of congestive heart failure, or have received IVIG within 30 days of randomization to exclusion criteria.

Randomization will be performed per best common practice guidelines with a computer-generated randomization process and hospital investigational pharmacy blinding processes into both a therapeutic arm (Bezlotoxumab) and a placebo (normal saline) arm of the study. All current standards of care will continue to be administered in these patients, regardless of their respective study arm. To control for the antibiotics administered, the patients will need to be stratified according to the standard-of-care antibiotics and balanced in regards to this variable. Current standard of care therapy at our institution for fulminant C. difficile colitis includes Vancomycin (both oral and rectal, if needed) and intravenous Metronidazole. Fulminant C. difficile colitis is defined, per our guidelines, as proven infection with hypotension/ shock, ileus, or megacolon.

Upon conclusion of the surgical intervention, the Anesthesia or nursing team will administer the trial medication, Bezlotoxumab, or the placebo, normal saline. Dosing is planned to be ten milligrams per kilogram, which is standard dosing for therapeutic Bezlotoxumab approved for use by the U.S. Food and Drug Administration. This dose will be administered as a one-time single-infusion dose administered over the span of one hour. The placebo administration of normal saline will be at the same dosing with a single-infusion over one hour. The patient will receive standard of care post-operative management and the information obtained from standard-of-care lab draws will be assessed throughout their hospital stay. The patient will be seen and evaluated in clinic during the post-operative period at the one-month follow-up and either in clinic or via telephone at their three-month and six-month follow-up.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Michael E Villarreal, MD; Phone Number: 2108602809; Email: michael.villarreal@osumc.edu

Study Locations

• United States
  • Ohio
    • Columbus, Ohio, United States, 43210
      • The Ohio State University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• > 18 years old, diagnosed C diff colitis requiring surgical intervention

Exclusion Criteria:

• CHF previously diagnosed, pregnancy, prisoners/ incarcerated, previous administration of IVIG within 30-days of randomization

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Bezlotoxumab; Patients receiving Bezlotoxumab post-operatively.	Biological: Bezlotoxumab; Patients receiving Bezlotoxumab post-operatively.
Placebo Comparator: Normal Saline; Patients receiving normal saline as a placebo post-operatively.	Other: Normal Saline; Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality	Monitor for 30-day mortality	30-days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Heart Failure	Monitor for development of heart failure	30-days
Respiratory Failure	Monitor for development of respiratory failure	30-days
Renal Failure	Monitor for development of renal failure	30-days
Hepatic Failure	Monitor for development of hepatic failure	30-days

Collaborators and Investigators

• Sponsor: Michael E Villarreal, MD
• Collaborators: Merck Sharp & Dohme LLC

Study record dates

Study Major Dates

• Study Start (Actual): August 19, 2019
• Primary Completion (Actual): May 23, 2022
• Study Completion (Actual): May 23, 2022

Study Registration Dates

• First Submitted: November 26, 2018
• First Submitted That Met QC Criteria: November 26, 2018
• First Posted (Actual): November 28, 2018

Study Record Updates

• Last Update Posted (Actual): May 12, 2023
• Last Update Submitted That Met QC Criteria: May 11, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Colonic Diseases; Intestinal Diseases; Colitis
• Other Study ID Numbers: 2018H0348

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes