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Rifampin-free regimen versus rifampin-containing regimen in the treatment of staphylococcal prosthetic valve endocarditis: a multicenter randomized controlled non-inferiority study (RIFREE)
EU CTIS ID: 2024-518018-22-00
What this study is testing
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
- Therapeutic confirmatory (Phase III)
A plain-language read of the study's public EU CTIS listing. The study team confirms the details.
Who can take part
You may be able to join if
- Definite infective endocarditis according to the 2023 Duke ISCVID criteria or confirmed by the endocarditis team if the endocarditis was classified as possible
- Women must meet one of the following criteria at the time of inclusion: see protocol V1.1 09/07/2025 for details
- 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.
- For male patients, sperm donation is prohibited for the same period as the obligation to use condoms
- For female patients, egg donation is prohibited for the same period as contraception
- 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
You likely can't join if
- Presence of cardiovascular implanted electronic device with suspected device-related infective endocarditis without removal of the device
- True allergy to rifampin or a severe intolerance to rifampin
- 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.
- 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
See the full eligibility criteria
Who can join
- Definite infective endocarditis according to the 2023 Duke ISCVID criteria or confirmed by the endocarditis team if the endocarditis was classified as possible
- Women must meet one of the following criteria at the time of inclusion: see protocol V1.1 09/07/2025 for details
- 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.
- For male patients, sperm donation is prohibited for the same period as the obligation to use condoms
- For female patients, egg donation is prohibited for the same period as contraception
- 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
- 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
- Prosthetic valve endocarditis
- Infective endocarditis due to Staphylococcus sp (S. aureus or coagulase negative staphylococci) susceptible to rifampin
- 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)
- 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
- Patients insured under a health insurance scheme
What rules you out
- Presence of cardiovascular implanted electronic device with suspected device-related infective endocarditis without removal of the device
- True allergy to rifampin or a severe intolerance to rifampin
- 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.
- 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
- ALAT increase greater than 3 times the upper laboratory range
- Patient with confirmed prosthetic vascular graft infection or orthopedic-device-related infection
- Patient moribund (expected to die in next 48 hours with or without treatment)
- Patient unable to collect information in a daily journal
- Patient unable to understand a follow-up by phone contact.
- Patients treated with rifampicin for infections other than endocarditis, such as tuberculosis
- Contraindication to rifampin.
- Extreme weight (< 45 kg or > 150 kg)
- Expected duration of follow-up <6 months at the time of randomization
- 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
- Patients under court protection, guardianship or trusteeship
- Patient who do not speak or understand French language
The study team makes the final eligibility decision.
Questions & answers
Do participants get paid in this trial?
This listing doesn't specify compensation. Many trials still reimburse travel or offer a stipend, so it's worth asking the study team when you connect.
Is it free to join, and do I need insurance?
Searching and applying through BridgeMD is free. In clinical trials the study-related treatment and visits are generally provided at no cost to you. You usually don't need insurance to take part - confirm specifics with the study team.
How long does this study last?
The listing doesn't state an exact length. The study team walks you through the schedule and number of visits before you decide to enroll.
Who can join this trial?
This study is enrolling all sexes, 18-64 years, 65+ years. The study team makes the final eligibility decision.
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BridgeMD is an information and trial-matching tool - not medical advice, and not the study sponsor. Details come from EU CTIS; the study team decides eligibility.