PLACEBO for Staphylococcal prosthetic valve endocarditis|Staphylococcal endocarditis

Inclusion criteria

• {"criterion_text":"- Definite infective endocarditis according to the 2023 Duke ISCVID criteria or confirmed by the endocarditis team if the endocarditis was classified as possible\n- Women must meet one of the following criteria at the time of inclusion: see protocol V1.1 09/07/2025 for details\n- 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.\n- For male patients, sperm donation is prohibited for the same period as the obligation to use condoms\n- For female patients, egg donation is prohibited for the same period as contraception\n- 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\n- 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\n- Prosthetic valve endocarditis\n- Infective endocarditis due to Staphylococcus sp (S. aureus or coagulase negative staphylococci) susceptible to rifampin\n- At least one positive blood culture due to Staphylococcus sp (S. aureus or CoNS)\n- After the first positive blood culture, at least one negative blood culture (after a minimum of 72 hours of incubation)\n- Antistaphylococcal treatment for endocarditis introduced less than 14 days ago. We do not consider all antibiotic received before the first positive blood culture\n- Age ≥ 18-year-old\n- Informed, written consent obtained from patient or from patient’s near in kin\n- Patients insured under a health insurance scheme"}

Exclusion criteria

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

Primary endpoints

• {"endpoint_text":"- All-cause mortality rate at 6 months post randomization","definition_or_measurement_approach":"Measured as all-cause mortality rate at 6 months post randomization."}

Secondary endpoints

• {"endpoint_text":"- 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","definition_or_measurement_approach":"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 (within 6 months after randomization)."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"Proportions of patients with at least one relapse defined by bacteremia with the primary pathogen obtained during follow-up after the end of curative treatment (within 6 months)."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"Proportions of patients with at least one clinically evident embolic event (secondary osteoarticular, splenic, brain or other symptomatic localizations) within 6 months."}
• {"endpoint_text":"- 1)d)Within 6 months after randomization: Proportions of patients with at least one valvular surgery","definition_or_measurement_approach":"Proportions of patients undergoing at least one valvular surgery within 6 months after randomization."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"Composite proportion of patients meeting any of: all-cause mortality, microbiological failure, relapse, embolic event, or valvular surgery within 6 months."}
• {"endpoint_text":"- 1)f)Within 6 months after randomization: Time to clinical failure","definition_or_measurement_approach":"Time from randomization to clinical failure (as defined by study) within 6 months."}
• {"endpoint_text":"- 1)g)Within 6 months after randomization: Proportions of patients with at least one adverse event grade III/IV related to treatment","definition_or_measurement_approach":"Proportions of patients experiencing at least one treatment-related adverse event of grade III or IV within 6 months."}
• {"endpoint_text":"- 1)h)Within 6 months after randomization: Proportions of patients with at least one bleeding complication","definition_or_measurement_approach":"Proportions of patients with one or more bleeding complications within 6 months."}
• {"endpoint_text":"- 1)i)Within 6 months after randomization: Length of stay in hospital","definition_or_measurement_approach":"Hospital length of stay measured within 6 months after randomization."}
• {"endpoint_text":"- 1)j)Within 6 months after randomization: Duration of curative antibiotic treatment for endocarditis","definition_or_measurement_approach":"Duration (time) of curative antibiotic treatment for endocarditis measured within 6 months."}
• {"endpoint_text":"- 2)All-cause mortality rates at discharge and at 3 months after randomization","definition_or_measurement_approach":"All-cause mortality measured at hospital discharge and at 3 months after randomization."}
• {"endpoint_text":"- 3)a) Within 12 months after randomization: Proportions of patients with at least one readmission in hospital (whatever the reason)","definition_or_measurement_approach":"Proportions of patients with ≥1 hospital readmission for any reason within 12 months."}
• {"endpoint_text":"- 3)b)Within 12 months after randomization: Proportions of patients with at least one valvular surgery","definition_or_measurement_approach":"Proportions of patients undergoing at least one valvular surgery within 12 months."}
• {"endpoint_text":"- 3)c)Within 12 months after randomization: All-cause mortality rates","definition_or_measurement_approach":"All-cause mortality measured at 12 months after randomization."}
• {"endpoint_text":"- 3)d)Within 12 months after randomization: Proportions of patients with at least one relapse","definition_or_measurement_approach":"Proportions of patients with at least one relapse (as defined) within 12 months."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"Microbiological analyses of relapse including reclassification of relapse vs reinfection, identification of clinical/biological factors, relapse proportions by surgery status, and genomic trait identification in staphylococcal strains."}
• {"endpoint_text":"- 5)Incremental cost-effectiveness ratio (cost per quality-adjusted life year (QALYs) gained) comparing the two arms.","definition_or_measurement_approach":"Economic evaluation measuring incremental cost-effectiveness ratio (cost per QALY gained) comparing the two arms over specified horizon."}

France

Earliest CTIS Part Ii Submission Date

27-06-2025

Latest Decision Or Authorization Date

28-08-2025

Processing Time Days

62

Number Of Sites

31

Number Of Participants

422

Primary sponsor

Full Name

Centre Hospitalier Universitaire De Nantes

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

France