Rifampin-free regimen versus rifampin-containing regimen in the treatment of staphylococcal prosthetic valve endocarditis: a multicenter randomized controlled non-inferiority study (RIFREE)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Universitaire De Nantes

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Bacterial Infections and Mycoses [C01], Diseases [C] - Cardiovascular Diseases [C14]

Decision date (initial)

2025-08-28

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

DGOS PHRC national 2023

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy

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

Secondary objectives 17

1. 1)a)To compare, according to the treatment group within 6 months: Microbiological failure
2. 1)b)To compare, according to the treatment group within 6 months: Relapse
3. 1)c)To compare, according to the treatment group within 6 months: Clinically evident embolic event
4. 1)d)To compare, according to the treatment group within 6 months: Valvular surgery after randomization
5. 1)e)To compare, according to the treatment group within 6 months: Clinical failure
6. 1)f)To compare, according to the treatment group within 6 months: Time to clinical failure
7. 1)g)To compare, according to the treatment group within 6 months: (g) Adverse events related to antibiotic endocarditis treatment
8. 1)h)To compare, according to the treatment group within 6 months: Bleeding complication
9. 1)i)To compare, according to the treatment group within 6 months: Length of stay in hospital
10. 1)j)To compare, according to the treatment group within 6 months: Duration of curative antibiotic treatment for endocarditis
11. 2)To compare all-cause mortality at discharge and at 3 months.
12. 3)a)To compare according to the treatment group at 12 months: Readmissions in hospital
13. 3)b)To compare according to the treatment group at 12 months: Valvular surgery
14. 3)c)To compare according to the treatment group at 12 months: All-cause mortality
15. 3)d)To compare according to the treatment group at 12 months: Relapse
16. 4)To analyze characteristics of relapse in staphylococcal PVE regardless of randomization arm
17. 5)To assess the economic efficiency of rifampin-free regimen compared to rifampin-containing regimen from a collective perspective and with a one-year time horizon

Conditions and MedDRA coding

staphylococcal endocarditis

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

1. Definite infective endocarditis according to the 2023 Duke ISCVID criteria or confirmed by the endocarditis team if the endocarditis was classified as possible
2. Prosthetic valve endocarditis
3. Infective endocarditis due to Staphylococcus sp (S. aureus or coagulase negative staphylococci) susceptible to rifampin
4. At least one positive blood culture due to Staphylococcus sp (S. aureus or CoNS)
5. After the first positive blood culture, at least one negative blood culture (after a minimum of 72 hours of incubation)
6. Antistaphylococcal treatment for endocarditis introduced less than 14 days ago. We do not consider all antibiotic received before the first positive blood culture
7. Age ≥ 18-year-old
8. Informed, written consent obtained from patient or from patient’s near in kin
9. Patients insured under a health insurance scheme
10. Women must meet one of the following criteria at the time of inclusion: see protocol V1.1 09/07/2025 for details
11. Male patients must be prepared to use male contraception (condoms) for: 5*half-life (t1/2) plus 3 months after the last dose of the antibiotic with the longest half-life at the last dose of the antibiotic with the longest half-life at the “end of endocarditis treatment” visit.
12. For male patients, sperm donation is prohibited for the same period as the obligation to use condoms
13. For female patients, egg donation is prohibited for the same period as contraception
14. Female partners of male patients use adequate contraceptive measures considered as acceptable according recommendations of CTCG for: 5*half-life (t1/2) plus 3 months after the last dose of the antibiotic with the longest half-life at the “end of endocarditis treatment” visit
15. Male partners of female patients must be prepared to use male contraception (condoms) for: 5*half-life (t1/2) plus 6 months after the last dose of the antibiotic with the longest half-life at the last dose of the antibiotic with the longest half-life at the “end of endocarditis treatment” visit

Exclusion criteria 20

1. Presence of cardiovascular implanted electronic device with suspected device-related infective endocarditis without removal of the device
2. Patients treated with rifampicin for infections other than endocarditis, such as tuberculosis
3. Extreme weight (< 45 kg or > 150 kg)
4. Expected duration of follow-up <6 months at the time of randomization
5. Patients already receiving more than 72 hours of rifampin for the endocarditis treatment prior to randomization
6. Positive blood cultures less than 72 hours before randomization
7. Medical history of infective endocarditis in the last 3 months
8. Patients under court protection, guardianship or trusteeship
9. Patient who do not speak or understand French language
10. True allergy to rifampin or a severe intolerance to rifampin
11. Patients requiring treatment contraindicated or not recommended with rifampin or incompatible with the inducer effect of rifampicin according to the marketing authorisation, if replacement by another treatment or adaptation of the dosage of this treatment to be compatible with rifampicin is not possible (contraindicated : bictegravir, cabotegravir, cobicistat, daclatasvir, dasabuvir, delamanid, fostemsavir, grazoprevir/elbasvir, ritonavir-boosted protease inhibitors, isavuconazole, ledipasvir, lenacapavir, lurasidone, midostaurin, ombitasvir/paritaprevir, praziquantel, rilpivirine, sofosbuvir, velpatasvir, voriconazole, voxilaprevir; not recommended : abiraterone, apixaban, dabigatran, rivaroxaban, apremilast, aprepitant, atorvastatin, simvastatin, atovaquone, bedaquiline, bosentan, cannabidiol, clopidogrel, cyclophosphamide, cyproterone, darolutamide, docetaxel, dolutegravir, dronedarone, estroprogestogens, progestin contraceptives, etoposide, fentanyl, fluconazole, glasdegib, idelalisib, dutasteride, finasteride, tyrosine kinase inhibitors, irinotecan, itraconazole, ivacaftor, ketoconazole, macitentan, maribavir, mianserin, naloxegol, netupitant, nevirapine, nimodipine, olaparib, oxycodone, ozanimod, paclitaxel, posaconazole, quetiapine, quinine, raltegravir, ranolazine, regorafenib, rolapitant, sertraline, sotorasib, telithromycin, tenofovir alafenamide, ticagrelor, ulipristal, vemurafenib, venetoclax, vinca alkaloids, vismodegib, voxelotor, zidovudine). While midazolam is not recommended with the use of rifampicin such as mentioned in rifampicin marketing authorisation, however midazolam is not listed in non inclusion criteria for the following reasons: rifampicin reduces the concentration of midazolam. There is a risk of no effect of midazolam with a very significant reduction in plasma concentrations due to an increase in the hepatic metabolism. In situation where midazolam is needed, it is requested to adjust the dose and to perform regular therapeutic drug monitoring.
12. Pregnancy or breastfeeding woman
13. Inclusion in another drug clinical trial
14. Patients who have already been included in the study for a previous episode of endocarditis
15. ALAT increase greater than 3 times the upper laboratory range
16. Patient with confirmed prosthetic vascular graft infection or orthopedic-device-related infection
17. Patient moribund (expected to die in next 48 hours with or without treatment)
18. Patient unable to collect information in a daily journal
19. Patient unable to understand a follow-up by phone contact.
20. Contraindication to rifampin.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. All-cause mortality rate at 6 months post randomization

Secondary endpoints 17

1. 1)a)Within 6 months after randomization: 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
2. 1)b)Within 6 months after randomization: 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
3. 1)c)Within 6 months after randomization: Proportions of patients with at least one clinically evident embolic event defined as secondary osteoarticular, splenic, brain or other symptomatic localizations
4. 1)d)Within 6 months after randomization: Proportions of patients with at least one valvular surgery
5. 1)e)Within 6 months after randomization: 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
6. 1)f)Within 6 months after randomization: Time to clinical failure
7. 1)g)Within 6 months after randomization: Proportions of patients with at least one adverse event grade III/IV related to treatment
8. 1)h)Within 6 months after randomization: Proportions of patients with at least one bleeding complication
9. 1)i)Within 6 months after randomization: Length of stay in hospital
10. 1)j)Within 6 months after randomization: Duration of curative antibiotic treatment for endocarditis
11. 2)All-cause mortality rates at discharge and at 3 months after randomization
12. 3)a) Within 12 months after randomization: Proportions of patients with at least one readmission in hospital (whatever the reason)
13. 3)b)Within 12 months after randomization: Proportions of patients with at least one valvular surgery
14. 3)c)Within 12 months after randomization: All-cause mortality rates
15. 3)d)Within 12 months after randomization: Proportions of patients with at least one relapse
16. 4) Microbiological analysis of relapse: Proportions of patients with reclassification of relapse/failure as reinfection, Identification of clinical and biological factors associated with relapse, Proportions of patients with relapse in patients with surgery and without surgery, Identify a common heritable trait in the staphylococcal strains associated with the occurrence of relapse
17. 5)Incremental cost-effectiveness ratio (cost per quality-adjusted life year (QALYs) gained) comparing the two arms.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 3

Auxiliary 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Universitaire De Nantes

Sponsor organisation

Centre Hospitalier Universitaire De Nantes

Address

5 Allee De L Ile Gloriette, Cs 69301 Cs 69301

City

Nantes Cedex 1

Postcode

44093

Country

France

Scientific contact point

Organisation

Centre Hospitalier Universitaire De Nantes

Contact name

Doctor Raphael Lecomte

Public contact point

Organisation

Centre Hospitalier Universitaire De Nantes

Contact name

Doctor Raphael Lecomte

Locations

1 EU/EEA country · 31 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 10 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications