Cytokine REmoval in CRitically Ill pAtients Requiring Surgical Therapy for Infective Endocarditis (RECReATE) (RECREATE)

Cytokine REmoval in CRitically Ill pAtients Requiring Surgical Therapy for Infective Endocarditis (RECReATE) - an Investigator-initiated Prospective Randomized Controlled Clinical Trial Comparing Two Established Clinical Protocols

Infectious endocarditis (IE) and other severe infections are well-known to induce significant changes in the immune response including immune functionality in a considerable number of affected patients. In fact, numerous patients with IE develop a persistent functional immunological phenotype that can best be characterized by a profound anti-inflammation and/or functional anergy. This was previously referred to as "injury-associated immunosuppression (IAI)" by Pfortmüller et al., published in Intensive Care Medicine Experimental 2017. IAI can be assessed by measurement of cellular (functional) markers. Persistence of IAI is associated with prolonged ICU length of stay, increased secondary infection rates, and death. Immunomodulation to reverse IAI was shown beneficial in immunostimulatory (randomized controlled) clinical trials. CytoSorb® treatment is currently used as standard of care in some institutions in surgically treated IE patients. The investigators aim to investigate two accepted treatment protocols and aim to explore whether adsorption with a cytokine adsorption filter can increase immune competence in treated individuals.

Study Overview

• Status: Recruiting
• Conditions: Sepsis; Septic Shock; Endocarditis
• Intervention / Treatment: Other: Treatment protocol with adsorption

• Study Type: Interventional
• Enrollment (Anticipated): 54
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Joerg C Schefold, MD; Phone Number: 5397 0041-31-632; Email: joerg.schefold@insel.ch

Study Locations

• Switzerland
  • Bern, Switzerland, 3010
    • Recruiting
    • Dept of Intensive Care Medicine
    • Contact: Joerg C Schefold, MD; Email: Joerg.Schefold@insel.ch
    • Contact: Lars Englberger, MD; Email: lars.englberger@insel.ch

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Subjects scheduled for routine cardiac surgery for infectious endocarditis (diagnosed according to the predefined "DUKE" criteria) with antibiotic therapy for ≤ 14 days.
• Presence of informed consent
• Age ≥18 yrs.

Exclusion Criteria:

• Previous treatment (last 6 months) with immunologically-active biologicals or specific immunomodulatory drugs (e.g. Rituximab)
• high-dose chronic (i.e. before onset of infectious endocarditis) steroid medication with prednisone equivalent of >30 mg/d
• Patients on Extracorporeal membrane oxygenation (ECMO), or any other (pre-operative) cardiac assist device
• Moribund patient (life expectancy <14 days)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Treatment protocol without adsorption
Active Comparator: Treatment protocol with adsorption	Other: Treatment protocol with adsorption; Adsorption while patients are in the OR on the extracorporeal circuit

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in quantitative expression of monocytic Human Leukocyte Antigen (mHLA)-DR expression (Antibodies per cell on Cluster of Differentiation (CD)14+ monocytes/macrophages, assessed using a quantitative standardized assay)	From baseline (pre-OR, t1) to day 1 post-OR (t3)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in mHLA-DR from baseline (pre-OR) to post-Or and 3 days post-Or.	Course of mHLA-DR	Baseline (pre-OP) to post-OR and 3 days post-Or
Area under the curve of quantitative mHLA-DR expression	Area under the curves mHLA-DR	Between baseline (pre-OR), post-OR, and day 1 and 3 post-OR (multiple assessments).
Change in inflammatory markers including cytokines (Interleukin (IL)-6, IL-10, C-reactive protein, White blood cell count, multiplex Enzyme linked immunosorbent assay, and inflammatory prohormones)	Change in inflammatory parameters	From baseline (pre-OR) to post-OR, and day 1 and 3 post-OR
Change in organ dysfunction (Sepsis-related organ failure (SOFA) scores incl. subscores and Simplified acute physiology score (SAPS II scores) daily	Course of organ dysfunction	7-day timeframe (starting from ICu admission, assessed at day 90)
Length of ICU and hospital stay (days after surgical intervention).	Length of stay	Number of days on ICU and in hospital (assessed at day 90)
Cumulative Therapeutic Intervention Scoring System (TISS) points (resource need) until ICU-discharge	Resource use	Total number of TISS points on ICU (cumulative), assessed at day 90
Total amount of infused volume/transfusions on ICU	Need for fluid therapy	90 days
Duration of vasoactive drug therapy	Vasopressor use	90 days
Duration of invasive mechanical ventilation	Use of organ support therapy (number of days on mechanical ventilation)	90 days
ICU mortality rate	Number of non-surviving patients in both study groups	ICU stay (assessed at day 90)
Hospital mortality rate	Number of non-surviving patients in both study groups	hospital stay (assessed at day 90)
28 day mortality rate	Number of non-surviving patients in both study groups	28 days beginning from ICU admission (assessed at day 90)
90 day mortality rate	Number of non-surviving patients in both study groups	90 days beginning from ICU admission (assessed at day 90)
Duration of renal replacement therapy	Use of organ support therapy (number of days on renal replacement therapy)	90 days

Collaborators and Investigators

• Sponsor: University Hospital Inselspital, Berne
• Investigators: Study Director: Lars Englberger, MD, Inselspital, Bern University Hospital

Publications and helpful links

General Publications

• Gisler F, Spinetti T, Erdoes G, Luedi MM, Pfortmueller CA, Messmer AS, Jenni H, Englberger L, Schefold JC. Cytokine Removal in Critically Ill Patients Requiring Surgical Therapy for Infective Endocarditis (RECReATE): An Investigator-initiated Prospective Randomized Controlled Clinical Trial Comparing Two Established Clinical Protocols. Medicine (Baltimore). 2020 Apr;99(15):e19580. doi: 10.1097/MD.0000000000019580.

Study record dates

Study Major Dates

• Study Start (Actual): November 14, 2019
• Primary Completion (Anticipated): October 1, 2024
• Study Completion (Anticipated): December 1, 2024

Study Registration Dates

• First Submitted: March 22, 2019
• First Submitted That Met QC Criteria: March 25, 2019
• First Posted (Actual): March 27, 2019

Study Record Updates

• Last Update Posted (Estimate): January 26, 2023
• Last Update Submitted That Met QC Criteria: January 25, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Infections; Bacterial Infections; Bacterial Infections and Mycoses; Cardiovascular Infections; Endocarditis, Bacterial; Endocarditis
• Other Study ID Numbers: RECREATE

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: No
• Studies a U.S. FDA-regulated device product: No