Oral Switch During Treatment of Left-sided Endocarditis Due to Multi-susceptible Staphylococcus

Study Overview
=================
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.

Official Title
-----------------
Oral Switch During Treatment of Left-sided Endocarditis Due to Multi-susceptible Staphylococcus (Relais Oral Dans le Traitement Des Endocardites à Staphylocoques Multi-sensibles)

Conditions
-----------------
Infective Endocarditis

Intervention / Treatment
-----------------
* Drug: Levofloxacin
* Drug: Rifampicin
* Procedure: Conventional IV treatment of staphylococci IE following European guidelines 2015 including cloxacilline, oxacilline,gentamicine,vancomycine,rifampicine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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 Exclusion Criteria: 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oral switch treatment<br>Oral switch to the combination of levofloxacin and rifampicin | Drug: Levofloxacin<br>* levofloxacin 500 mg x1/day (for patients ≤70kg) or levofloxacin 750 mg x1/day (for patients >70kg)<br>* Other names: Fluoroquinolones;Drug: Rifampicin<br>* rifampicin 600mg x1/day (for patients ≤70kg) or rifampicin 900mg x1/day (for patients >70kg)<br>|
| Active Comparator: Conventional IV treatment according to european guidelines<br>Conventional IV treatment of staphylococci IE (European guidelines 2015) | Procedure: Conventional IV treatment of staphylococci IE following European guidelines 2015 including cloxacilline, oxacilline,gentamicine,vancomycine,rifampicine<br>* Conventional IV treatment of staphylococci IE following European guidelines 2015 including cloxacilline, oxacilline,gentamicine,vancomycine,rifampicine<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment failure | 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). | up to 3 months after the end of antibiotic treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| death from all-cause | death from all-cause | up to 6 months after the end of antibiotic treatment | 
| number of symptomatic embolic events | secondary osteo-articular, splenic or brain localization | up to 6 months after the end of antibiotic treatment | 
| unplanned valvular surgery | unplanned valvular surgery | up to 6 months after the end of antibiotic treatment | 
| relapse of positive blood cultures | relapse of positive blood cultures with the primary pathogen | up to 6 months after the end of antibiotic treatment | 
| microbiological relapse with a different pathogen from the primary pathogen | Relapse of positive blood cultures with a different pathogen within 3 months after the end of antibiotic therapy | up to 6 months after the end of antibiotic treatment | 
| Echocardiography | 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 | up to 6 months after the end of antibiotic treatment | 
| Catheter related adverse events | Catheter-related AE: infectious (e.g. catheter-related bacteraemia) or non-infectious catheter-related complications (e.g. extravasation). | up to 6 months after the end of antibiotic treatment | 
| other healthcare-acquired infections | other healthcare-acquired infections, including urinary tract infections, pneumonia, surgical site infection, Clostridium difficile infections | up to 6 months after the end of antibiotic treatment | 
| Number of participants with an antibiotic modification | All change regarding antibiotic treatment administered will be recorded (drug, dose or duration) | up to the end of antibiotic treatment | 
| Quality of life | 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) | up to 6 months after the end of antibiotic treatment | 
| number of participants with a switch back from oral to IV antibiotic treatment | For experimental group only . An assessment of the need for a return to parenteral antibiotic in the experimental group. | up to the end of antibiotic treatment | 
| Compliance with oral antibiotic treatment | For experimental group only. The assessment of compliance with oral antibiotic treatment will be carried out at each visit during the treatment period. | up to 4 weeks after randomisation | 
| Cost per patient | Analysis using data from three centers (Tours, Rennes, Nancy) to compare both strategy (oral switch vs. pan-IV) for the cost per patient | up to 6 months after the end of antibiotic treatment | 
| Budget impact analysis (BIA) | 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. | up to 6 months after the end of antibiotic treatment | 
| Utility score and incremental cost-utility ratio (ICUR) | 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. | up to 6 months after the end of antibiotic treatment | 
| Length of hospital stay | 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. | up to 6 months after the end of antibiotic treatment | 
| Residual concentration of antibiotics | 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). | 7 days | 
| Biological collection for further analysis on endocarditis | 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). | up to 6 months after the end of antibiotic treatment |