Oral Switch During Treatment of Left-sided Endocarditis Due to Multi-susceptible Staphylococcus
- Conditions
- Infective Endocarditis
- Interventions
- Procedure: Conventional IV treatment of staphylococci IE following European guidelines 2015 including cloxacilline, oxacilline,gentamicine,vancomycine,rifampicine
- Registration Number
- NCT02701608
- Lead Sponsor
- University Hospital, Tours
- Brief Summary
Infective endocarditis (IE) is a serious infection with a significant burden for patients and hospitals (in France, median length of hospital stay = 43 days), partly due to the long duration of intravenous (IV) antibacterial treatment recommended by international guidelines, between 4 and 6 weeks in most situations.
A recent survey of practices regarding the management of IE in France showed that a switch from IV to oral antibiotics is feasible, when patients with left-sided Staphylococcus IE are stable after an initial course of IV antibiotic treatment, with or without valvular surgery.
These practices have not been associated with unfavourable outcome, while significantly reducing the duration and cost of hospitalization, the risk of nosocomial infection, and patients' discomfort.
There has been no randomized controlled trial (RCT) in the field of IE over the last 20 years; current guidelines are mostly based on expert advice, in vitro studies, animal experiments, or clinical studies performed before the 90's.
The RODEO 1 project is an unprecedented opportunity to bring back evidence-based medicine in the field of IE.
Most experts acknowledge that the pharmacological PK/PD characteristics of antibiotics such as fluoroquinolones and rifampicin allow a high level of efficacy in the treatment of IE when orally administrated after an IV period of induction.
It's needed to conduct RCTs that clearly demonstrate the clinical non-inferiority of this strategy for multisusceptible staphylococci with a benefit regarding costs.
The RODEO 1 project corresponds to one pragmatic trial assessing the impact of a switch strategy, making it a comparative effectiveness trial that should be able to feed the next revision of IE international guidelines and to change practices in IE management.
- Detailed Description
The RODEO 1 study is designed to determine the safety and efficacy of partial oral treatment of IE compared with traditional full-length parenteral treatment. Our primary objective is to demonstrate that in patients with left-sided multi-susceptible Staphylococcus who have received at least 10 days of IV antibiotic treatment with or without valvular surgery, a switch to an oral combination of rifampicin and fluoroquinolones between Day 10 and Day 28 after initiation of the IV antibiotic treatment, is not inferior to the continuation of the conventional IV antibiotic treatment regarding to treatment failure within 3 months after the end of antibiotic treatment.
Nationwide, noninferiority, multicenter, randomized, controlled, open-label trials.
Randomisation will only be offered to patients who have received at least 10 days of IV conventional antibiotic treatment of IE, and fulfil the inclusion criteria.
Randomisation will take place between Day 10 and Day 28 after initiation of parenteral antibiotic therapy or valvular surgery, thus ensuring to have at least 14 days of oral therapy in the experimental group.
Patients will be eligible whether they have undergone valvular surgery or not. This will imply that surgery procedure prior to randomisation will be heterogeneous, but randomisation will be stratified on the requirement of valvular surgery as part of the treatment of the current episode of IE or not.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 324
- Left-sided IE (Defined according to Duke criteria) on native or prosthetic valve
- due to one isolate of Staphylococcus sp. (S. aureus or coagulase negative staphylococci, CNS) susceptible to levofloxacin and rifampicin
- in an adult ≥18 year old
- appropriate parenteral antibiotics treatment received for at least 10 days
- in case of valvular surgery, appropriate parenteral antibiotics treatment received for at least 10 days after valvular surgery
- planned duration of antibiotics will extend for at least 14 days at the time of randomisation i.e. a potential switch to oral treatment between Day 10 and Day 28 thus ensuring to have at least 14 days of oral therapy remaining in the experimental group
- apyrexia (temperature < 38°C) at each time point during the last 48 hours (at least two measures/day) at the time of randomisation
- blood cultures have been sterile for at least 5 days at the time of randomisation
- informed, written consent obtained from patient
- subject covered by or having the rights to French social security
- body mass index <15 kg/m² or > 40 kg/m²
- glomerular filtration rate < 50 ml/min/1,73m²
- patient unable or unwilling to take oral treatment (digestive intolerance, significant malabsorption) at the time of randomisation
- expected difficulties regarding compliance with oral antibiotic treatment or follow-up (e.g. severe cognitive impairment, severe psychiatric disease...)
- patient without entourage to support and watch him at discharge
- valvular surgery planned within the next 6 months
- patients with cardiac devices (pace-maker, implantable cardiac defibrillator) and suspected device-related IE (vegetation on the leads) if removal of the device was not performed
- breast feeding or pregnant women, or women on childbearing age without effective contraception
- expected duration of follow-up < 7 months at the time of randomisation (e.g. expected life expectancy < 7 months, patient living abroad...)
- past medical history of IE in the last 3 months
- other infection requiring parenteral antibiotic therapy
- taking of an estrogen-progesterone treatment interacting with rifampicin
- patient with contra-indication to oral antibiotics administered in the experimental arm (i.e. fluoroquinolones or rifampicin ) - including anticipated non-manageable drug interactions with rifampicin, and allergy.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Oral switch treatment Rifampicin Oral switch to the combination of levofloxacin and rifampicin Conventional IV treatment according to european guidelines Conventional IV treatment of staphylococci IE following European guidelines 2015 including cloxacilline, oxacilline,gentamicine,vancomycine,rifampicine Conventional IV treatment of staphylococci IE (European guidelines 2015) Oral switch treatment Levofloxacin Oral switch to the combination of levofloxacin and rifampicin
- Primary Outcome Measures
Name Time Method Treatment failure up to 3 months after the end of antibiotic treatment Failure is a composite outcome defined by death from all causes and/or symptomatic embolic events and/or unplanned valvular surgery and/or a microbiological relapse (with the primary pathogen).
- Secondary Outcome Measures
Name Time Method microbiological relapse with a different pathogen from the primary pathogen up to 6 months after the end of antibiotic treatment Relapse of positive blood cultures with a different pathogen within 3 months after the end of antibiotic therapy
Echocardiography up to 6 months after the end of antibiotic treatment An apparition, an increase or decrease of the following items: vegetation, abscess, perforation, fistula, dehiscence of a prosthetic valve, will be searched at each ultrasound examination at : the end of antibiotic treatment, at 3 months and 6 months after the end of antibiotic treatment
Catheter related adverse events up to 6 months after the end of antibiotic treatment Catheter-related AE: infectious (e.g. catheter-related bacteraemia) or non-infectious catheter-related complications (e.g. extravasation).
number of symptomatic embolic events up to 6 months after the end of antibiotic treatment secondary osteo-articular, splenic or brain localization
death from all-cause up to 6 months after the end of antibiotic treatment death from all-cause
unplanned valvular surgery up to 6 months after the end of antibiotic treatment unplanned valvular surgery
other healthcare-acquired infections up to 6 months after the end of antibiotic treatment other healthcare-acquired infections, including urinary tract infections, pneumonia, surgical site infection, Clostridium difficile infections
number of participants with a switch back from oral to IV antibiotic treatment up to the end of antibiotic treatment For experimental group only . An assessment of the need for a return to parenteral antibiotic in the experimental group.
relapse of positive blood cultures up to 6 months after the end of antibiotic treatment relapse of positive blood cultures with the primary pathogen
Number of participants with an antibiotic modification up to the end of antibiotic treatment All change regarding antibiotic treatment administered will be recorded (drug, dose or duration)
Quality of life up to 6 months after the end of antibiotic treatment An assessment of patient's quality of life will be done at the end of antibiotic treatment, at 3 months and 6 months after the end of antibiotic treatment, using the EuroQol Five Dimensions (EQ5D3L)
Compliance with oral antibiotic treatment up to 4 weeks after randomisation For experimental group only. The assessment of compliance with oral antibiotic treatment will be carried out at each visit during the treatment period.
Cost per patient up to 6 months after the end of antibiotic treatment Analysis using data from three centers (Tours, Rennes, Nancy) to compare both strategy (oral switch vs. pan-IV) for the cost per patient
Budget impact analysis (BIA) up to 6 months after the end of antibiotic treatment With data from three centers (Tours, Nancy, Rennes). With data from three centers (Tours, Nancy, Rennes). Allow to estimate the financial consequences of the adoption and diffusion of a new health intervention (the oral strategy). BIA must be calculated on a yearly basis.
Length of hospital stay up to 6 months after the end of antibiotic treatment With data from all centers. Length of hospital stay will be calculated as duration between day of start of hospitalization and day of discharge (distinguishing rehabilitation care unit). In case a patient dies during hospitalization, death will be considered as a competing event to discharge.
Utility score and incremental cost-utility ratio (ICUR) up to 6 months after the end of antibiotic treatment With data from all centers. An assessment of the health related quality of life of the patient will be carried out using a simple generic questionnaire, the EuroQol Five Dimensions (EQ5D3L), recommended by the Washington Panel on Cost Effectiveness (utility) in Health and Medicine, with a cardinal scale and validated French version (http://www.euroqol.org)Quality of life will be assessed 4 times: at baseline, at the end of antibiotic treatment, at 3 months after end of antibiotic treatment and at the final visit.
Residual concentration of antibiotics 7 days Pharmacokinetic analysis for the experimental group only: residual concentrations of levofloxacin and rifampicin, or amoxicillin, after 7 days of oral treatment (i.e. at visit 2).
Biological collection for further analysis on endocarditis up to 6 months after the end of antibiotic treatment A biological collection will be constituted in order to perform further biological and genetic analysis of endocarditis (i.e. inflammatory markers of efficacy and genetic markers that predispose to endocarditis).
Trial Locations
- Locations (54)
Service des Maladies infectieuses et Tropicales, Hôpital Jean Minjoz, CHU de Besançon
🇫🇷Besançon, France
Service de Réanimation médicale, Hôpital St André, CHU de Bordeaux
🇫🇷Bordeaux, France
Service de Médecine interne, Hôpital Ambroise Paré, APHP
🇫🇷Boulogne Billancourt, France
Service de Maladies infectieuses, Hôpital de la Cavale Blanche
🇫🇷Brest, France
Service de Cardiologie, Hôpitall Louis Pradel, Hôpitaux Est, Hospices Civils de Lyon
🇫🇷Bron, France
Service Maladies Infectieuses et tropicales, Hôpital Côte de Nacre, CHU de Caen
🇫🇷Caen, France
Service des Maladies infectieuses et tropicales, CH Le Mans
🇫🇷Le Mans, France
Service de Maladies infectieuses et tropicales, médecine interne, CH de Chambéry
🇫🇷Chambéry, France
Service des maladies infectieuses et tropicales, Hôpital G. Montpied, CHU de Clermont-Ferrand
🇫🇷Clermont-Ferrand, France
APHP Henri-Mondor - Service des maladies infectieuses et tropicales
🇫🇷Créteil, France
Département d'infectiologie, Complexe Bocage, Hôpital d'enfants, CHU de Dijon
🇫🇷Dijon, France
Service de Médecine interne polyvalente et neurologique CH de Douai
🇫🇷Douai, France
Service de Médecine aigue spécifique, Hôpital Raymond Poincaré, APHP
🇫🇷Garches, France
Service de Médecine post-urgence, infectiologie, Site de la Roche sur Yon, CHD Vendée
🇫🇷La Roche sur Yon, France
Service de Maladies infectieuses et tropicales, et pathologie VIH
🇫🇷Le Chesnay, France
APHP BICETRE - Service des maladies infectieuses et tropicales
🇫🇷Le Kremlin-Bicêtre, France
Unité médicale d'infectiologie, Hôpital Huriez, CHU de Lille
🇫🇷Lille, France
Service de Maladies Infectieuses et tropicales, Hôpital Dupuytren, CHU de Limoges
🇫🇷Limoges, France
Service de Maladies infectieuses et tropicales, Hôpital Hôtel Dieu, CHU Nantes
🇫🇷Nantes, France
Service des Maladies infectieuses, CH de Niort
🇫🇷Niort, France
Service des Maladies Infectieuses et Tropicales, Hôpital Carémeau, CHU de Nîmes
🇫🇷Nîmes, France
Institut Mutualiste Montsouris - Service de médecine interne
🇫🇷Paris, France
Infectiologie, médecine interne et médecine des voyages, CH d'Annecy
🇫🇷Pringy, France
CH QUIMPER - Service d'infectiologie
🇫🇷Quimper, France
Service de Médecine interne, maladies infectieuses, immunologie clinique, Hôpital R. Debré, CHU de Reims
🇫🇷Reims, France
Service des maladies infectieuses et réanimation médicale, Hôpital Pontchaillou, CHU de Rennes
🇫🇷Rennes, France
Service des Maladies infectieuses et tropicales, Hôpital Charles Nicolle, CHU de Rouen
🇫🇷Rouen, France
CHU St Etienne - Service des maladies infectieuses et tropicales
🇫🇷Saint-Priest-en-Jarez, France
CHU Toulouse (Rangueil) Service de Cardiologie
🇫🇷Toulouse, France
Service de Médecine interne et maladies infectieuses, Hôpital Bretonneau, CHU de Tours
🇫🇷Tours, France
Médipôle Lyon Villeurbanne
🇫🇷Villeurbanne, France
Service de Maladies infectieuses et tropicales, Hôpital Avicenne, APHP
🇫🇷Bobigny, France
Service des Maladies infectieuses, Centre Hospitalier du Pays d'Aix
🇫🇷Aix en Provence, France
Service de court séjour gériatrique - EMG, Centre hospitalier d'Alès
🇫🇷Alès, France
CHU ANGERS - Service des maladies infectieuses et tropicales
🇫🇷Angers, France
Service de Pathologies infectieuses et tropicales, Hôpital Nord, CHU d'Amiens
🇫🇷Amiens, France
Service de Médecine infectieuse, Hôpital Nord Michallon, CHU de Grenoble
🇫🇷La Tronche, France
Service de Maladies infectieuses, Hôpital Gui de CHauliac, CHU de Montpellier
🇫🇷Montpellier, France
Clinique de la Sauvegarde
🇫🇷Lyon, France
Service d'Infectiologie, Hôpital de l'Archet, CHU de Nice
🇫🇷Nice, France
APHP St Antoine
🇫🇷Paris, France
Service de Microbiologie, Hôpital Européen Georges Pompidou, APHP
🇫🇷Paris, France
Service de Maladies infectieuses et tropicales, Hôpital de la Source, CHR Orléans
🇫🇷Orléans, France
Service de Maladies infectieuses et tropicales, Hôpital Necker, APHP
🇫🇷Paris, France
CH PAU - Service de Médecine interne et Maladies infectieuses
🇫🇷Pau, France
Service des Maladies infectieuses et tropicales, CH de Perpignan
🇫🇷Perpignan, France
Service de Maladies infectieuses, parasitaires et tropicales, Hôpital Bichat, APHP
🇫🇷Paris, France
Service de Médecine interne, maladies infectieuses et tropicales, CHU de Poitiers
🇫🇷Poitiers, France
Service des Maladies infectieuses et tropicales, Hôpital de Purpan, CHU de Toulouse
🇫🇷Toulouse, France
Service des maladies respiratoires et infectieuses, CH de St Malo
🇫🇷Saint Malo, France
Service des Maladie infectieuses et tropicales, Hôpital d'instruction des armées Bégin
🇫🇷Saint-Mande, France
Service Universitaire des Maladies Infectieuses et du voyageur, CH de Tourcoing
🇫🇷Tourcoing, France
Consultation de Médecine Interne, maladies infectieuses et tropicales, CH intercommunal de Villeneuve St Georges
🇫🇷Villeneuve St Georges, France
Service de Maladies infectieuses et tropicales, Hôpitaux de Brabois, CHU de Nancy
🇫🇷Vandoeuvre les Nancy, France