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

Infective Endocarditis Clinical Trial

Official title:

Oral Switch During Treatment of Left-sided Endocarditis Due to Multi-susceptible Streptococcus (Relais Oral Dans le Traitement Des Endocardites à Streptocoques Multi-sensibles)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02701595
• Other study ID #: RODEO 2
• Status: Recruiting
• Phase: Phase 3
• Start date: February 29, 2016
• Est. completion date: September 2024

Study information

• Verified date: May 2021
• Source: University Hospital, Tours
• Contact: Louis BERNARD, MD, PHD
• Email: L.BERNARD[@]chu-tours.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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 Streptococcus-Enterococcus 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 2 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 amoxicillin 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 streptococci, and enterococci IE with a benefit regarding costs.

The RODEO 2 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.

Description:

The RODEO 2 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 Streptococcus-Enterococcus IE who have received at least 10 days of IV antibiotic treatment with or without valvular surgery, a switch to an oral combination of amoxicillin 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 information / eligibility

• Status: Recruiting
• Enrollment: 324
• Est. completion date: September 2024
• Est. primary completion date: May 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Left-sided IE (Defined according to Duke criteria) on native or prosthetic valve

• due to one isolate of Streptococcus/Enterococcus sp. susceptible to amoxicillin (MCI = 0.5 mg/l)

• 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 < 30 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

• for 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. amoxicillin) - including anticipated non-manageable drug interactions, and allergy.

Related Conditions & MeSH terms

• Endocarditis
• Endocarditis, Bacterial
• Infective Endocarditis

Intervention

Drug:
• Amoxicillin
amoxicillin 1500 mg x3/day (for patients =70kg) or 2000 mg x3/day (for patients >70kg)

Procedure:
• Conventional IV treatment of streptococci/enterococci IE following European guidelines 2015 including amoxicillin, gentamicin, amicillin, vancomycin, penicillin G, ceftriaxone, netilmicin
Conventional IV treatment of streptococci/enterococci IE following European guidelines 2015 including amoxicillin, gentamicin, amicillin, vancomycin, penicillin G, ceftriaxone, netilmicin

Locations

Country	Name	City	State
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	Service de Pathologies infectieuses et tropicales, Hôpital Nord, CHU d'Amiens	Amiens
France	CHU ANGERS - Service des maladies infectieuses et tropicales	Angers
France	Service des Maladies infectieuses et Tropicales, Hôpital Jean Minjoz, CHU de Besançon	Besançon
France	Service de maladies infectieuses et tropicales, Hôpital Avicenne, APHP	Bobigny
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, CHU Brest	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 de Maladies infectieuses et tropicales médecine interne, CH Métropole Savoie	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 Médecine infectieuse, Hôpital Nord Michallon, CHU de Grenoble	La Tronche
France	Service de Maladies infectieuses et tropicales, et pathologie VIH, Hôpital A Mignot, CH de Versailles	Le Chesnay
France	APHP BICETRE - Service des maladies infectieuses et tropicales	Le Kremlin-Bicêtre
France	Service des Maladies infectieuses et tropicales, CH Le Mans	Le Mans
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	Clinique de la sauvegarde	Lyon
France	Service de Maladies infectieuses, Hôpital Gui de CHauliac, CHU de Montpellier	Montpellier
France	Service de Maladies infectieuses et tropicales, Hôpital Hôtel Dieu, CHU Nantes	Nantes
France	Service d'Infectiologie, Hôpital de l'Archet, CHU de Nice	Nice
France	Service des Maladies Infectieuses et Tropicales, Hôpital Carémeau, CHU de Nîmes	Nîmes
France	Service des Maladies infectieuses, CH de Niort	Niort
France	Service de Maladies infectieuses et tropicales, Hôpital de la Source, CHR Orléans	Orléans
France	APHP St Antoine	Paris
France	Institut Mutualiste Montsouris - Service de médecine interne	Paris
France	Service de maladies infectieuses et tropicales, Hôpital Necker, APHP	Paris
France	Service de maladies infectieuses, parasitaires et tropicales, Hôpital Bichat, APHP	Paris
France	Service de Microbiologie, Hôpital Européen Georges Pompidou, 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 Médecine interne, maladies infectieuses et tropicales, CHU de Poitiers	Poitiers
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	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	CHU St Etienne - Service des maladies infectieuses et tropicales	Saint-Priest-en-Jarez
France	CHU Toulouse (Rangueil) Service de Cardiologie	Toulouse
France	Service des Maladies infectieuses et tropicales, Hôpital de Purpan, CHU de Toulouse	Toulouse
France	Service Universitaire des Maladies Infectieuses et du voyageur, CH de Tourcoing	Tourcoing
France	Service de Médecine interne et maladies infectieuses, Hôpital Bretonneau, CHU de Tours	Tours
France	Service de Maladies infectieuses et tropicales, Hôpitaux de Brabois, CHU de Nancy	Vandoeuvre les Nancy
France	Consultation de Médecine Interne, maladies infectieuses et tropicales, CH intercommunal de Villeneuve St Georges	Villeneuve St Georges
France	Medipôle Lyon-Villeurbanne	Villeurbanne

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Tours

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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 6 months after the end of antibiotic treatment
Secondary	Death from all-cause	death from all-causes	up to 6 months after the end of antibiotic treatment
Secondary	number of symptomatic embolic events	secondary osteo-articular, splenic or brain localization	up to 6 months after the end of antibiotic treatment
Secondary	unplanned valvular surgery	unplanned valvular surgery	up to 6 months after the end of antibiotic treatment
Secondary	relapse of positive blood cultures	relapse of positive blood cultures with the primary pathogen	up to 6 months after the end of antibiotic treatment
Secondary	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]
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	numer 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
Secondary	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 though a "patient book" which will permit to note take/omissions of treatment; and though the return of the treatments to the pharmacy of the investigational site.; Calculation of the duration and cumulative dose of antibiotic treatment actually received will be performed, and compared to the regimen prescribed.	up to 4 weeks after randomisation
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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