Rifampin-free Regimen Versus Rifampin-containing Regimen in the Treatment of Staphylococcal Prosthetic Valve Endocarditis (RIFREE)

January 8, 2026 updated by: Nantes University Hospital

Rifampin-free Regimen Versus Rifampin-containing Regimen in the Treatment of Staphylococcal Prosthetic Valve Endocarditis: a Multicenter Randomized Controlled Non-inferiority Study

The primary objective of this study is to demonstrate that a rifampin-free regimen is non-inferior to the rifampin-containing regimen in terms of all-cause mortality in staphylococcal prosthetic valve endocarditis within 6 months after randomization.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

A rifampin-based treatment is recommended for prosthetic valve infective endocarditis caused by staphylococcus to act on the biofilm. However, the use of this molecule is associated with numerous adverse effects (digestive disorders, hepatotoxicity, hypersensitivity…) and drug interactions, particularly common in patients with prosthetic valves. In a retrospective study comparing patients receiving antibiotic therapy with rifampin versus without rifampin in staphylococcal prosthetic infective endocarditis (Le Bot et al. CID 2021, PMID: 32706879), there was no difference in terms of mortality or relapse between the two groups, but a longer hospital length of stay in the rifampin-treated group.

The aim of this multicentre randomized controlled trial is to demonstrate the non-inferiority of a rifampin-free regimen compared to a rifampin-combined regimen.

Study Type

Interventional

Enrollment (Estimated)

422

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • France
      • Aix-les-Bains, France, 73100
      • Angers, France, 49933
        • CHU Angers
        • Contact:
        • Principal Investigator:
          • Pierre DANNEELS, MD
      • Besançon, France, 25030
        • CHU Besançon
        • Contact:
        • Principal Investigator:
          • Noémie TISSOT, MD
      • Bordeaux, France, 33600
        • CHU Bordeaux, Cardiologic hospital of Haut lévêque
        • Principal Investigator:
          • Julien TERNACLE, MD
        • Contact:
      • Bordeaux, France, 33600
        • CHU Bordeaux, Haut Lévêque Hospital, Infectious disease department
        • Contact:
        • Principal Investigator:
          • Fabrice CAMOU, MD
      • Brest, France, 29200
        • CHU Brest
        • Contact:
        • Principal Investigator:
          • Scheherazade REZIG, MD
      • Créteil, France, 94010
        • AP-HP, Groupe hospitalier Henri Mondor
        • Contact:
        • Principal Investigator:
          • Raphaël LEPEULE, MD
      • Dijon, France, 21000
        • Chu Dijon Bourgogne
        • Principal Investigator:
          • Lionel PIROTH, MD
        • Contact:
      • Grenoble, France, 38043
        • CHU Grenoble
        • Principal Investigator:
          • Patricia PAVESE, MD
        • Contact:
      • La Roche-sur-Yon, France, 85000
        • CHD Vendee
        • Contact:
        • Principal Investigator:
          • Thomas GUIMARD, MD
      • Lyon, France, 69317
        • CHU Lyon, La Croix-Rousse Hospital, Infective disease department
        • Contact:
        • Principal Investigator:
          • Florent VALOUR, MD
      • Lyon, France, 69677
        • CHU Lyon, Louis Pradel Hospital, Cardiology Institute
        • Contact:
        • Principal Investigator:
          • Gaultier SEILLIER, MD
      • Montpellier, France, 34090
        • CHU Montpellier
        • Contact:
        • Principal Investigator:
          • Vincent LE MOING, MD
      • Nancy, France, 54035
        • CHU Nancy
        • Contact:
        • Principal Investigator:
          • Benjamin LEFEVRE, MD
      • Nantes, France, 44093
        • CHU Nantes, Hôtel Dieu Hospital, Infective disease department
        • Contact:
        • Principal Investigator:
          • Raphaël LECOMTE, MD
      • Nantes, France, 44800
        • CHU Nantes, Laennec Hospital, Cardiology department
        • Contact:
        • Principal Investigator:
          • Thierry LE TOURNEAU, MD
      • Nice, France, 06202
        • CHU Nice
        • Contact:
        • Principal Investigator:
          • Elisa DEMONCHY, MD
      • Orléans, France, 45067
        • CHR Orléans
        • Contact:
        • Principal Investigator:
          • Guillaume BERAUD, MD
      • Paris, France, 75018
        • AP-HP, Hôpital Bichat-Claude Bernard
        • Principal Investigator:
          • Xavier DUVAL, MD
        • Contact:
      • Paris, France, 75012
        • AP-HP hôpital St Antoine
        • Contact:
        • Principal Investigator:
          • Laure SURGERS, MD
      • Paris, France, 75013
        • AP-HP, Hôpital Pitié Salpétrière
        • Contact:
      • Pau, France, 64000
        • CH PAU
        • Contact:
        • Principal Investigator:
          • Mélanie LEHOUX, MD
      • Poitiers, France, 86000
        • CHU Poitiers
        • Principal Investigator:
          • Jean-Marie TURMEL, MD
        • Contact:
      • Quimper, France, 29000
        • CH intercommunal Cornouaille Quimper
        • Contact:
        • Principal Investigator:
          • Pauline MARTINET, MD
      • Rennes, France, 35000
        • Chu Rennes
        • Contact:
        • Principal Investigator:
          • Audrey LE BOT, MD
      • Saint-Etienne, France, 42270
      • Strasbourg, France, 67000
        • CHU Strasbourg
        • Principal Investigator:
          • Yvon RUCH, MD
        • Contact:
      • Toulouse, France, 31059
        • CHU Toulouse, Purpan Hospital, Infectious disease department
        • Contact:
        • Principal Investigator:
          • Guillaume MARTIN BLONDEL, MD
      • Toulouse, France, 31400
        • CHU Toulouse, Rangueil Hospital, Cardiology department
        • Contact:
        • Principal Investigator:
          • Yoan LAVIE-BADIE, MD
      • Tourcoing, France, 59200
        • Ch Tourcoing
        • Contact:
        • Principal Investigator:
          • Benoit GACHET, MD
      • Tours, France, 37044
        • CHU Tours
        • Contact:
        • Principal Investigator:
          • Adrien LEMAIGNEN, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Definite infective endocarditis according to the 2023 Duke ISCVID criteria or confirmed by the endocarditis team if the endocarditis was classified as possible
  • Prosthetic valve endocarditis
  • At least one positive blood culture due to Staphylococcus sp (S. aureus or CoNS)
  • After the first positive blood culture, at least one negative blood culture (after a minimum of 72 hours of incubation)
  • Infective endocarditis due to Staphylococcus sp (S. aureus or coagulase negative staphylococci) susceptible to rifampin
  • Antistaphylococcal treatment for endocarditis introduced less than 14 days ago. We do not consider all antibiotic received before the first positive blood culture
  • Age ≥ 18-year-old
  • Informed, written consent obtained from patient or from patient's near in kin
  • Patient insured under a health insurance scheme
  • Patient with adequate contraceptive measure

Exclusion Criteria:

  • Presence of cardiovascular implanted electronic device with suspected device-related IE without removal of the device
  • Expected duration of follow-up <6 months at the time of randomization
  • Patient moribund (expected to die in next 48 hours with or without treatment)
  • Patients already receiving more than 72 hours of rifampin for the endocarditis treatment prior to randomization
  • Positive blood cultures less than 72 hours before randomization
  • Medical history of infective endocarditis in the last 3 months
  • True allergy to rifampin or a severe intolerance to rifampin
  • Contraindication to rifampin
  • Patients requiring treatment contraindicated or not recommended with rifampin or incompatible with the inducer effect of rifampicin according to the marketing authorisation.
  • ALAT increase greater than 3 times the upper laboratory range
  • Extreme weight (< 45 kg or > 150 kg)
  • Patients with confirmed prosthetic vascular graft infection or orthopedic-device-related infection
  • Patients treated with rifampin for infections other than endocarditis, such as tuberculosis
  • Pregnancy or breastfeeding woman
  • Inclusion in another drug clinical trial
  • Patients who have already been included in the study for a previous episode of endocarditis
  • Patients under court protection, guardianship or trusteeship
  • Patients who do not speak or understand French language
  • Patient unable to collect information in a daily journal
  • Patient unable to understand a follow-up by phone contact

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Rifampin-free regimen.
The experimental arm of the study involves the removal of rifampicin from the antibiotic regimen recommended by the 2023 ESC (European Society of Cardiology) guidelines and the 2025 French guidelines (AEPEI/SPILF) for the treatment of staphylococcal prosthetic valve endocarditis.
Drug: Rifampin-free regimen
Rifampin-free regimen. The choice of other antibiotics is at the discretion of the physicians in charge but should be in accordance with the 2023 ESC guidelines and 2025 French guidelines (AEPEI/SPILF).
Active Comparator: Rifampin containing regimen
Rifampin containing regimen (900 mg/day). Antibiotic treatment of endocarditis in accordance with the 2023 ESC guidelines and the 2025 French guidelines (AEPEI/SPILF).
Drug: Rifampin containing regimen
Rifampin containing regimen (900 mg/day). Antibiotic treatment of endocarditis in accordance with the 2023 ESC guidelines and 2025 French guidelines.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
All-cause mortality rate at 6 months
Time Frame: Up to 6 months
Deaths of all causes from randomizaton until 6 months
Up to 6 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Microbiological failure
Time Frame: Up to 6 months
Proportions of patients with at least one microbiological failure defined by bacteremia with the primary pathogen obtained during follow-up but before the end of curative treatment.
Up to 6 months
Relapse
Time Frame: Up to 12 months
Proportions of patients with at least one relapse defined by bacteremia with the primary pathogen obtained during follow-up after the end of treatment of endocarditis until 6 months, then until 12 months.
Up to 12 months
Clinically evident embolic event
Time Frame: Up to 6 months
Proportions of patients with at least one clinically evident embolic event (defined as secondary osteoarticular, splenic, brain or other symptomatic localizations) from randomization until 6 months.
Up to 6 months
Valvular surgery
Time Frame: Up to 12 months
Proportions of patients with at least one valvular surgery at 6 months and at 12 months
Up to 12 months
Clinical failure
Time Frame: Up to 6 months
Proportions of patients with clinical failure (defined by a composite criterion: all-cause mortality or microbiological failure or relapse or embolic event or valvular surgery) at 6 months.
Up to 6 months
Time to clinical failure
Time Frame: Up to 6 months
Time between randomization and occurence of a clinical failure
Up to 6 months
Adverse events
Time Frame: Up to 6 months
Proportions of patients with at least one adverse event grade III or IV related to treatment
Up to 6 months
Bleeding complications
Time Frame: Up to 6 months
Proportions of patients with at least one bleeding complication
Up to 6 months
Lenght of stay in hospital
Time Frame: Up to 6 months
Lenght of stay in hospital
Up to 6 months
Duration of curative antibiotic treatment for endocarditis
Time Frame: Up to 6 months
Duration of curative antibiotic treatment for endocarditis
Up to 6 months
All-cause mortality rate at discharge, at 3 and at 12 months
Time Frame: Up to 12 months
Deaths of all causes from randomization until discharge, then until 3 months and then until 12months
Up to 12 months
Readmission in hospitals
Time Frame: Up to 12 months
Proportions of patients with at least one readmission in hospital (whatever the reason).
Up to 12 months
Reclassification of relapse or microbiological failure as reinfection.
Time Frame: Up to 12 months
Proportions of patients with reclassification of relapse or microbiological failure as reinfection. To determine the proportion of relapses or microbiological failures that are in fact reinfections, the genome of the strain isolated at the time of the suspected microbiological failure or relapse will be compared with the genome of the strain isolated at the time of the initial infection. This will be performed by the national reference center for staphylococci based in Lyon CHU.
Up to 12 months
Cost-Effectiveness ratio
Time Frame: Up to 12 months
Incremental cost-effectiveness ratio (cost per quality-adjusted life year (QALYs) gained)
Up to 12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Nantes University Hospital

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

January 1, 2026

Primary Completion (Estimated)

July 1, 2030

Study Completion (Estimated)

January 1, 2031

Study Registration Dates

First Submitted

December 12, 2025

First Submitted That Met QC Criteria

January 8, 2026

First Posted (Actual)

January 15, 2026

Study Record Updates

Last Update Posted (Actual)

January 15, 2026

Last Update Submitted That Met QC Criteria

January 8, 2026

Last Verified

December 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • RC24_0404
  • 2024-518018-22-00 (Ctis)

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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