FOUR-SIX TRIAL for the Treatment of Enterococcal Endocarditis (FOURSIX)

Four-week Duration Versus 6-week Duration of Therapy for the Treatment of Enterococcal Endocarditis

Duration of therapy in severe infections has a high impact in term of compliance, adverse events, and costs but also in term of antibiotic pressure on selection of multidrug-resistant pathogens. In this context, many advancements have been obtained for an early diagnosis of IE with a strict selection of criteria for surgery. Moreover, the use in antibiotic regimen of new drugs with peculiar PK/PD characteristics, as a quick bactericidal action, also for IE was not accompanied to a revaluation of duration of antibiotic treatment. On this basis, US and European guidelines recommend a 6-week duration of antibiotic treatment for IE due to enterococcal species.

AIM 1: To evaluate a 4-week duration of antibiotic therapy versus a 6-week duration according to international guidelines.

AIM 2: Second aim is to evaluate the PK/PD of antimicrobials in relation to the probability of target attainment (PTA) of optimal exposure against enterococci.

AIM 3: Finally, we will analyze the bactericidal activities of antibiotic combinations used in patients with IE and the survival of the subgroup of patients who underwent surgery.

Open-label, multicenter, randomized, non-inferiority trial to be conducted in a 3-year period. The institutional review board at each site will approve the protocol, and all patients or their authorized representatives will provide written informed consent. Eligible patients will be 18 years of age or older with a documented IE due to enterococcal strains, according to the modified Duke criteria.

63 patients in each of the two arms. The study will be conducted at Italian sites. Data on demographic characteristics, comorbidities, antibiotic and concomitant therapies will be collected. Baseline treatments will be defined according to the patients' pharmacological history. IE will be defined according to modified Duke criteria. Antibiotic treatment, indications and timing of surgery will be based on the 2015 American Heart Association and European Society of Cardiology guidelines.

Blood samples for determining antibiotic concentrations of ampicillin, gentamicin, vancomycin, daptomycin and linezolid will be collected at predetermined times in order to allow estimation of PK/PD.

Randomization:

1. 4-week duration of antibiotic therapy
2. standard 6-week duration of antibiotic therapy The intention-to-treat population (ITT) will include all randomized patients. The modified intention-to-treat population (mITT) will include all randomized patients receiving at least one dose of study medication. The clinically evaluable (CE) population will include ITT patients demonstrating sufficient adherence to study protocol.

Primary endpoint: non-inferiority of a 4-week course in terms of outcome at 60 days.

Secondary endpoints: microbiological eradication, pharmacological concentrations of antibiotic regimens, patients undergoing surgery, duration of therapy according with resistance profile of enterococcal species.

Study Overview

• Status: Not yet recruiting
• Conditions: Enterococcal Endocarditis
• Intervention / Treatment: Drug: 4-week duration of antibiotic therapy; Drug: 6-week duration of antibiotic therapy

• Study Type: Interventional
• Enrollment (Anticipated): 130
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Alessandro Russo, Prof.; Phone Number: +39 09613647552; Email: a.russo@unicz.it

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• documented infective endocarditis due to enterococcal strains, according to the modified Duke criteria.

Exclusion Criteria:

• patients candidate for chronic suppressive antibiotic treatment

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
Experimental: 4-week duration of antibiotic therapy	Drug: 4-week duration of antibiotic therapy; The aim is to show non-inferiority of a 4-week duration of antibiotic therapy versus a standard 6-week duration according to international guidelines
Active Comparator: standard 6-week duration of antibiotic therapy	Drug: 6-week duration of antibiotic therapy; The aim is to show non-inferiority of a 4-week duration of antibiotic therapy versus a standard 6-week duration according to international guidelines

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
A 4-week course of effective antimicrobial therapy	To evaluate clinical cure after 4 weeks of therapy	at 30 days and after 60 days from enrollment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Microbiological clearance of Enterococcus spp from blood cultures	Time to microbiological clearance from blood	From inclusion, up to 30 days
Surgical Procedure	Time to surgery	From inclusion, up to 30 days

Collaborators and Investigators

• Sponsor: University Magna Graecia

Study record dates

Study Major Dates

• Study Start (Anticipated): January 1, 2024
• Primary Completion (Anticipated): September 1, 2024
• Study Completion (Anticipated): September 1, 2026

Study Registration Dates

• First Submitted: May 19, 2022
• First Submitted That Met QC Criteria: May 26, 2022
• First Posted (Actual): May 31, 2022

Study Record Updates

• Last Update Posted (Actual): May 10, 2023
• Last Update Submitted That Met QC Criteria: May 9, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Endocarditis; Anti-Infective Agents; Antitubercular Agents; Anti-Bacterial Agents; Antibiotics, Antitubercular
• Other Study ID Numbers: FST_2022

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
• product manufactured in and exported from the U.S.: No