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

• ClinicalTrials.gov Identifier: NCT03756454
• Recruitment Status: Recruiting
• First Posted: November 28, 2018
• Last Update Posted: August 28, 2019
• Sponsor: Michael E Villarreal, MD
• Collaborator: Merck Sharp & Dohme Corp.
• Information provided by (Responsible Party): Michael E Villarreal, MD, Ohio State University

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Clostridia Difficile Colitis; Clostridium; Sepsis	Biological: Bezlotoxumab; Other: Normal Saline	Phase 4

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 100 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: 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.
• Masking: Triple (Participant, Care Provider, Investigator)
• Masking Description: 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 in 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.
• Primary Purpose: Treatment
• Official Title: 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.
• Actual Study Start Date: August 19, 2019
• Estimated Primary Completion Date: July 2021
• Estimated Study Completion Date: July 2021

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Mortality [ Time Frame: 30-days ]
   Monitor for 30-day mortality

Secondary Outcome Measures :

1. Heart Failure [ Time Frame: 30-days ]
   Monitor for development of heart failure
2. Respiratory Failure [ Time Frame: 30-days ]
   Monitor for development of respiratory failure
3. Renal Failure [ Time Frame: 30-days ]
   Monitor for development of renal failure
4. Hepatic Failure [ Time Frame: 30-days ]
   Monitor for development of hepatic failure

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Contacts

Contact: Michael E Villarreal, MD; 2108602809; michael.villarreal@osumc.edu

Locations

United States, Ohio

The Ohio State University; Recruiting

Columbus, Ohio, United States, 43210

Contact: Michael E Villarreal, MD 614-293-8000 michael.villarreal@osumc.edu

Sponsors and Collaborators

Michael E Villarreal, MD

Merck Sharp & Dohme Corp.

More Information

• Responsible Party: Michael E Villarreal, MD, Clinical Instructor House Staff - General Surgery, Ohio State University
• ClinicalTrials.gov Identifier: NCT03756454
• Other Study ID Numbers: 2018H0348
• First Posted: November 28, 2018
• Last Update Posted: August 28, 2019
• Last Verified: August 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Additional relevant MeSH terms:

Colitis; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Colonic Diseases; Intestinal Diseases