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

NCT ID: NCT03939273

Last Updated: 2021-03-12

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: NA
• Total Enrollment: 80 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-03-31
• Study Completion Date: 2023-03-31

Brief 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

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.

Conditions

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

Vancomycin Oral

Intervention Type: DRUG

500 mg thrice per day for seven days

Metronidazole Oral

Intervention Type: DRUG

500 mg thrice per day for seven days

Ciprofloxacin Pill

Intervention Type: DRUG

500 mg twice per day for seven days

Fluconazole Oral Product

Intervention Type: DRUG

200 mg once per day for six days

Control group

A preoperative seven day course of placebo, consisting of pills and capsules identical in appearance and number to the active group

Group Type: PLACEBO_COMPARATOR

Placebos

Intervention Type: DRUG

seven day course of placebo tablets and capsules identical in appearance and number to active treatment

Interventions

Vancomycin Oral

500 mg thrice per day for seven days

Intervention Type: DRUG

Metronidazole Oral

500 mg thrice per day for seven days

Intervention Type: DRUG

Ciprofloxacin Pill

500 mg twice per day for seven days

Intervention Type: DRUG

Fluconazole Oral Product

200 mg once per day for six days

Intervention Type: DRUG

Placebos

seven day course of placebo tablets and capsules identical in appearance and number to active treatment

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 99 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Radboud University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Peter Pickkers, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Radboud University Medical Center

Locations

Radboud University Medical Centre

Nijmegen, Gelderland, Netherlands

Countries

Netherlands

Central Contacts

Aron Jansen, MD

Role: CONTACT

aron.jansen@radboudumc.nl

+31 24 36 55618

Quirine Habes, MD

Role: CONTACT

quirine.habes@radboudumc.nl

Facility Contacts

Aron Jansen, MD

Role: primary

aron.jansen@radboudumc.nl

+31 24 36 55618

Quirine Habes, MD

Role: backup

quirine.habes@radboudumc.nl

Other Identifiers

2019-000964-54

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

The REMEDI trial

Identifier Type: -

Identifier Source: org_study_id