The Effects of Gut Micribiota Disruption on the Immune Response After Open Heart Surgery (REMEDI)

Randomized Placebo-controlled Study on the Effects of Antibiotic-induced Gut MicrobiomE Disruption on the Innate Immune Response Following Cardiac Surgery

In this randomized, double-blind, placebo-controlled study, the investigators will assess whether preoperative disruption of the gut microbiota by a course of broad spectrum antibiotics will attenuate the postoperative systemic inflammatory response after on-pump cardiac surgery

Study Overview

• Status: Not yet recruiting
• Conditions: Coronary Artery Disease; Systemic Inflammatory Response Syndrome; Extracorporeal Circulation; Complications; Postoperative Shock
• Intervention / Treatment: Drug: Vancomycin Oral; Drug: Metronidazole Oral; Drug: Ciprofloxacin Pill; Drug: Fluconazole Oral Product; Drug: Placebos

Detailed Description

During cardiac surgery, the use of cardiopulmonary bypass and extracorporeal circulation, operative trauma, and ischemia-reperfusion injury can induce a profound systemic innate immune response. This response contributes to postoperative morbidity and mortality, as increased proinflammatory cytokine levels are associated with several postoperative complications. Commensal microbiota in the gut can modulate systemic immune responses. The investigators hypothesize that reduction of systemic immune activation by disruption of the microbiome may be beneficial in patients undergoing cardiac surgery.

The objective of this trial is to assess the anti-inflammatory effects of disruption of the intestinal microbiota with broad-spectrum antibiotics in patients with systemic inflammation following cardiac surgery and to assess the effects on clinical outcomes in these patients.

To this end, subjects will be randomized into one of two treatment arms and will receive either active treatment or a placebo during the seven days prior to surgery. Active treatment consists of a seven day course of oral ciprofloxacin 500 mg twice a day, oral vancomycin 500 mg thrice per day, oral metronidazole 500 mg thrice per day and a six day course of oral fluconazole 200 mg once per day. Placebo treatment is randomly allocated in a double blind fashion in a 1:1 proportion to the active treatment. Stool samples will be obtained prior to and directly after study treatment to assess the effects on the richness and diversity of the gut microbiota. During and after surgery, plasma levels of circulating cytokines will be measured to assess the effects of microbiota disruption on the inflammatory response.

• Study Type: Interventional
• Enrollment (Anticipated): 80
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Aron Jansen, MD; Phone Number: +31 24 36 55618; Email: aron.jansen@radboudumc.nl
• Study Contact Backup: Name: Quirine Habes, MD; Email: quirine.habes@radboudumc.nl

Study Locations

• Netherlands
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6525 GA
      • Radboud University Medical Centre
      • Contact: Aron Jansen, MD; Phone Number: +31 24 36 55618; Email: aron.jansen@radboudumc.nl
      • Contact: Quirine Habes, MD; Email: quirine.habes@radboudumc.nl
      • Principal Investigator: Peter Pickkers, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age > 18 years
• Scheduled for elective on-pump cardiac surgery.
• Written informed consent to participate in this trial prior to any study-mandated procedure

Exclusion Criteria:

• Use of any antibiotic or antifungal therapies within 30 days prior to surgery
• History of inflammatory bowel disease
• History of bowel resection and / or short bowel syndrome
• Pre-operative creatinine clearance < 50 ml/min
• Severe hepatic impairment

• Immune compromised

  • Solid organ transplantation
  • Known HIV
  • Pregnancy
  • Use of immunosuppressive drugs
• Emergency surgery

• Haematological disorders

  • Disorders from myeloid and / or lymphoid origin
  • Leucopenia
• Known hypersensitivity to any of the investigational and/or non-investigational products or their excipients.
• Treatment with investigational drugs or participation in any other intervention clinical trial within 30 days prior to study drug administration
• Inability to personally provide written informed consent
• Suspected of not being able to comply with the trial protocol
• Use of vitamin K antagonists
• Use of tricyclic antidepressants
• Use of other drugs which have potential dangerous interactions with study treatment

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Active group; A preoperative seven day course of oral ciprofloxacin 500 mg twice a day, oral vancomycin 500 mg thrice per day, oral metronidazole 500 mg thrice per day and a six day course of oral fluconazole 200 mg once per day.	Drug: Vancomycin Oral; 500 mg thrice per day for seven days; Drug: Metronidazole Oral; 500 mg thrice per day for seven days; Drug: Ciprofloxacin Pill; 500 mg twice per day for seven days; Drug: Fluconazole Oral Product; 200 mg once per day for six days
Placebo Comparator: Control group; A preoperative seven day course of placebo, consisting of pills and capsules identical in appearance and number to the active group	Drug: Placebos; seven day course of placebo tablets and capsules identical in appearance and number to active treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Between group differences in Area Under the Curve (AUC) of the time-concentration curve of interleukin (IL)-6 plasma concentrations.	Blood samples will be obtained at predefined time points during and after surgery to assess plasma levels (in pg/mL) of circulating inflammatory mediators. To assess between group differences, the AUC of the time-concentration curve (expressed in arbitrary units) of each inflammatory mediator will be calculated.	During surgery and up to 24 hours after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Between group differences in AUC of the time-concentration curve of other inflammatory mediators.	Tumor Necrosis Factor (TNF)-α, IL-8, IL-10, IL-1β, IL-1RA, Monocyte Chemoattractant Protein (MCP)-1, Macrophage Inflammatory Protein (MIP)-1α MIP-1β, Vascular Cell Adhesion Molecule (VCAM), Intercellular Adhesion Molecule (ICAM)	During surgery and up to 24 hours after surgery

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Investigators: Principal Investigator: Peter Pickkers, MD, PhD, Radboud University Medical Center

Study record dates

Study Major Dates

• Study Start (Anticipated): March 1, 2022
• Primary Completion (Anticipated): March 1, 2023
• Study Completion (Anticipated): March 1, 2023

Study Registration Dates

• First Submitted: April 4, 2019
• First Submitted That Met QC Criteria: May 3, 2019
• First Posted (Actual): May 6, 2019

Study Record Updates

• Last Update Posted (Actual): March 12, 2021
• Last Update Submitted That Met QC Criteria: March 11, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: Microbiome; Innate Immunity; CABG; Gut microbiota; Coronary Artery Bypass Graft; Systemic Inflammation
• Additional Relevant MeSH Terms: Pathologic Processes; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Inflammation; Shock; Coronary Disease; Coronary Artery Disease; Systemic Inflammatory Response Syndrome; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; 14-alpha Demethylase Inhibitors; Cytochrome P-450 CYP1A2 Inhibitors; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Vancomycin; Metronidazole; Ciprofloxacin; Fluconazole
• Other Study ID Numbers: The REMEDI trial; 2019-000964-54 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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