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

Coronary Artery Disease Clinical Trial

— REMEDI  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT03939273
• Other study ID #: The REMEDI trial
• Secondary ID: 2019-000964-54
• Status: Not yet recruiting
• Phase: N/A
• Start date: March 2022
• Est. completion date: March 2023

Study information

• Verified date: March 2021
• Source: Radboud University
• Contact: Aron Jansen, MD
• Phone: +31 24 36 55618
• Email: aron.jansen[@]radboudumc.nl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 80
• Est. completion date: March 2023
• Est. primary completion date: March 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

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

Related Conditions & MeSH terms

• Coronary Artery Disease
• Extracorporeal Circulation; Complications
• Postoperative Shock
• Systemic Inflammatory Response Syndrome

Intervention

Drug:
• Vancomycin Oral
500 mg thrice per day for seven days
• Metronidazole Oral
500 mg thrice per day for seven days
• Ciprofloxacin Pill
500 mg twice per day for seven days
• Fluconazole Oral Product
200 mg once per day for six days
• Placebos
seven day course of placebo tablets and capsules identical in appearance and number to active treatment

Locations

Country	Name	City	State
Netherlands	Radboud University Medical Centre	Nijmegen	Gelderland

Sponsors (1)

Lead Sponsor	Collaborator
Radboud University

Country where clinical trial is conducted

Netherlands, 

Outcome

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