Clinical trial NCT02701595: Oral Switch During Treatment of Left-sided Endocarditis Due to Multi-susceptible Streptococcus
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)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Infective Endocarditis
Lead sponsor: University Hospital, Tours
Sponsor class: OTHER
First posted: 2016-03-08
Enrollment: 324
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Treatment failure
timeFrame: up to 6 months after the end of antibiotic treatment
Secondary outcomes:
measure: Death from all-cause
timeFrame: up to 6 months after the end of antibiotic treatment
measure: number of symptomatic embolic events
timeFrame: up to 6 months after the end of antibiotic treatment
measure: unplanned valvular surgery
timeFrame: up to 6 months after the end of antibiotic treatment
measure: relapse of positive blood cultures
timeFrame: up to 6 months after the end of antibiotic treatment
measure: microbiological relapse with a different pathogen from the primary pathogen
timeFrame: up to 6 months after the end of antibiotic treatment]
measure: Echocardiography
timeFrame: up to 6 months after the end of antibiotic treatment
measure: Catheter related adverse events
timeFrame: up to 6 months after the end of antibiotic treatment
measure: other healthcare-acquired infections
timeFrame: up to 6 months after the end of antibiotic treatment
measure: Number of participants with an antibiotic modification
timeFrame: up to the end of antibiotic treatment
measure: Quality of life
timeFrame: up to 6 months after the end of antibiotic treatment
measure: numer of participants with a switch back from oral to IV antibiotic treatment
timeFrame: up to the end of antibiotic treatment
measure: Compliance with oral antibiotic treatment
timeFrame: up to 4 weeks after randomisation
measure: Cost per patient
timeFrame: up to 6 months after the end of antibiotic treatment
measure: Budget impact analysis (BIA)
timeFrame: up to 6 months after the end of antibiotic treatment
measure: Utility score and incremental cost-utility ratio (ICUR)
timeFrame: up to 6 months after the end of antibiotic treatment
measure: Length of hospital stay
timeFrame: up to 6 months after the end of antibiotic treatment
measure: Residual concentration of antibiotics
timeFrame: 7 days
measure: Biological collection for further analysis on endocarditis
timeFrame: up to 6 months after the end of antibiotic treatment
Other outcomes:
Locations:
city: Aix en Provence
country: France
facility: Service des maladies infectieuses, Centre Hospitalier du Pays d'Aix
city: Alès
country: France
facility: Service de court séjour gériatrique - EMG, Centre hospitalier d'Alès
city: Amiens
country: France
facility: Service de Pathologies infectieuses et tropicales, Hôpital Nord, CHU d'Amiens
city: Angers
country: France
facility: CHU ANGERS - Service des maladies infectieuses et tropicales
city: Besançon
country: France
facility: Service des Maladies infectieuses et Tropicales, Hôpital Jean Minjoz, CHU de Besançon
city: Bobigny
country: France
facility: Service de maladies infectieuses et tropicales, Hôpital Avicenne, APHP
city: Bordeaux
country: France
facility: Service de Réanimation médicale, Hôpital St André, CHU de Bordeaux
city: Boulogne Billancourt
country: France
facility: Service de médecine interne, Hôpital Ambroise Paré, APHP
city: Brest
country: France
facility: Service de Maladies infectieuses, Hôpital de la Cavale Blanche, CHU Brest
city: Bron
country: France
facility: Service de Cardiologie, Hôpitall Louis Pradel, Hôpitaux Est, Hospices Civils de Lyon
city: Caen
country: France
facility: Service Maladies Infectieuses et tropicales, Hôpital Côte de Nacre, CHU de Caen
city: Chambéry
country: France
facility: Service de Maladies infectieuses et tropicales médecine interne, CH Métropole Savoie
city: Clermont-Ferrand
country: France
facility: Service des maladies infectieuses et tropicales, Hôpital G. Montpied, CHU de Clermont-Ferrand
city: Créteil
country: France
facility: APHP Henri-Mondor - Service des maladies infectieuses et tropicales
city: Dijon
country: France
facility: Département d'infectiologie, Complexe Bocage, Hôpital d'enfants, CHU de Dijon
city: Douai
country: France
facility: Service de Médecine interne polyvalente et neurologique CH de Douai
city: Garches
country: France
facility: Service de médecine aigue spécifique, Hôpital Raymond Poincaré, APHP
city: La Roche sur Yon
country: France
facility: Service de médecine post-urgence, infectiologie, Site de la Roche sur Yon, CHD Vendée
city: La Tronche
country: France
facility: Service de Médecine infectieuse, Hôpital Nord Michallon, CHU de Grenoble
city: Le Chesnay
country: France
facility: Service de Maladies infectieuses et tropicales, et pathologie VIH, Hôpital A Mignot, CH de Versailles
city: Le Kremlin-Bicêtre
country: France
facility: APHP BICETRE - Service des maladies infectieuses et tropicales
city: Le Mans
country: France
facility: Service des Maladies infectieuses et tropicales, CH Le Mans
city: Lille
country: France
facility: Unité médicale d'infectiologie, Hôpital Huriez, CHU de Lille
city: Limoges
country: France
facility: Service de Maladies Infectieuses et tropicales, Hôpital Dupuytren, CHU de Limoges
city: Lyon
country: France
facility: Clinique de la sauvegarde
city: Montpellier
country: France
facility: Service de Maladies infectieuses, Hôpital Gui de CHauliac, CHU de Montpellier
city: Nantes
country: France
facility: Service de Maladies infectieuses et tropicales, Hôpital Hôtel Dieu, CHU Nantes
city: Nice
country: France
facility: Service d'Infectiologie, Hôpital de l'Archet, CHU de Nice
city: Niort
country: France
facility: Service des Maladies infectieuses, CH de Niort
city: Nîmes
country: France
facility: Service des Maladies Infectieuses et Tropicales, Hôpital Carémeau, CHU de Nîmes
city: Orléans
country: France
facility: Service de Maladies infectieuses et tropicales, Hôpital de la Source, CHR Orléans
city: Paris
country: France
facility: APHP St Antoine
city: Paris
country: France
facility: Service de Microbiologie, Hôpital Européen Georges Pompidou, APHP
city: Paris
country: France
facility: Service de maladies infectieuses et tropicales, Hôpital Necker, APHP
city: Paris
country: France
facility: Service de maladies infectieuses, parasitaires et tropicales, Hôpital Bichat, APHP
city: Paris
country: France
facility: Institut Mutualiste Montsouris - Service de médecine interne
city: Pau
country: France
facility: CH PAU - Service de Médecine interne et Maladies infectieuses
city: Perpignan
country: France
facility: Service des Maladies infectieuses et tropicales, CH de Perpignan
city: Poitiers
country: France
facility: Service de Médecine interne, maladies infectieuses et tropicales, CHU de Poitiers
city: Pringy
country: France
facility: Infectiologie, médecine interne et médecine des voyages, CH d'Annecy
city: Quimper
country: France
facility: CH QUIMPER - Service d'infectiologie
city: Reims
country: France
facility: Service de Médecine interne, maladies infectieuses, immunologie clinique, Hôpital R. Debré, CHU de Reims
city: Rennes
country: France
facility: Service des maladies infectieuses et réanimation médicale, Hôpital Pontchaillou, CHU de Rennes
city: Rouen
country: France
facility: Service des Maladies infectieuses et tropicales, Hôpital Charles Nicolle, CHU de Rouen
city: Saint Malo
country: France
facility: Service des maladies respiratoires et infectieuses, CH de St Malo
city: Saint-Mande
country: France
facility: Service des Maladie infectieuses et tropicales, Hôpital d'instruction des armées Bégin
city: Saint-Priest-en-Jarez
country: France
facility: CHU St Etienne - Service des maladies infectieuses et tropicales
city: Toulouse
country: France
facility: Service des Maladies infectieuses et tropicales, Hôpital de Purpan, CHU de Toulouse
city: Toulouse
country: France
facility: CHU Toulouse (Rangueil) Service de Cardiologie
city: Tourcoing
country: France
facility: Service Universitaire des Maladies Infectieuses et du voyageur, CH de Tourcoing
city: Tours
country: France
facility: Service de Médecine interne et maladies infectieuses, Hôpital Bretonneau, CHU de Tours
city: Vandoeuvre les Nancy
country: France
facility: Service de Maladies infectieuses et tropicales, Hôpitaux de Brabois, CHU de Nancy
city: Villeneuve St Georges
country: France
facility: Consultation de Médecine Interne, maladies infectieuses et tropicales, CH intercommunal de Villeneuve St Georges
city: Villeurbanne
country: France
facility: Medipôle Lyon-Villeurbanne
Study officials:
affiliation: CHRU TOURS
name: Louis BERNARD, MD,PHD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lemaignen A, Bernard L, Tattevin P, Bru JP, Duval X, Hoen B, Brunet-Houdard S, Mainardi JL, Caille A; RODEO (Relais Oral Dans le traitement des Endocardites a staphylocoques ou streptOcoques) and AEPEI (Association pour l'Etude et la Prevention de l'Endocardite Infectieuse) study groups. Oral switch versus standard intravenous antibiotic therapy in left-sided endocarditis due to susceptible staphylococci, streptococci or enterococci (RODEO): a protocol for two open-label randomised controlled trials. BMJ Open. 2020 Jul 14;10(7):e033540. doi: 10.1136/bmjopen-2019-033540.