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

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ClinicalTrials.gov Identifier: NCT02701608
Recruitment Status : Recruiting
First Posted : March 8, 2016
Last Update Posted : September 4, 2019
Sponsor:
Information provided by (Responsible Party):
University Hospital, Tours

Tracking Information
First Submitted Date  ICMJE January 28, 2016
First Posted Date  ICMJE March 8, 2016
Last Update Posted Date September 4, 2019
Actual Study Start Date  ICMJE February 29, 2016
Estimated Primary Completion Date October 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 2, 2016)
Treatment failure [ Time Frame: 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).
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 23, 2017)
  • death from all-cause [ Time Frame: up to 6 months after the end of antibiotic treatment ]
    death from all-cause
  • number of symptomatic embolic events [ Time Frame: up to 6 months after the end of antibiotic treatment ]
    secondary osteo-articular, splenic or brain localization
  • unplanned valvular surgery [ Time Frame: up to 6 months after the end of antibiotic treatment ]
    unplanned valvular surgery
  • relapse of positive blood cultures [ Time Frame: up to 6 months after the end of antibiotic treatment ]
    relapse of positive blood cultures with the primary pathogen
  • microbiological relapse with a different pathogen from the primary pathogen [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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).
  • other healthcare-acquired infections [ Time Frame: 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 an antibiotic modification [ Time Frame: up to the end of antibiotic treatment ]
    All change regarding antibiotic treatment administered will be recorded (drug, dose or duration)
  • Quality of life [ Time Frame: 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)
  • number of participants with a switch back from oral to IV antibiotic treatment [ Time Frame: 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.
  • Compliance with oral antibiotic treatment [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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.
  • Utility score and incremental cost-utility ratio (ICUR) [ Time Frame: 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.
  • Length of hospital stay [ Time Frame: 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.
  • Residual concentration of antibiotics [ Time Frame: 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 [ Time Frame: 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).
Original Secondary Outcome Measures  ICMJE
 (submitted: March 2, 2016)
  • death from all-cause [ Time Frame: up to 3 months after the end of antibiotic treatment ]
    death from all-cause
  • number of symptomatic embolic events [ Time Frame: up to 3 months after the end of antibiotic treatment ]
    secondary osteo-articular, splenic or brain localization
  • unplanned valvular surgery [ Time Frame: up to 3 months after the end of antibiotic treatment ]
    unplanned valvular surgery
  • relapse of positive blood cultures [ Time Frame: up to 3 months after the end of antibiotic treatment ]
    relapse of positive blood cultures with the primary pathogen
  • microbiological relapse with a different pathogen from the primary pathogen [ Time Frame: up to 3 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 [ Time Frame: 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 [ Time Frame: 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).
  • other healthcare-acquired infections [ Time Frame: 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 an antibiotic modification [ Time Frame: up to 6 months after the end of antibiotic treatment ]
    All change regarding antibiotic treatment administered will be recorded (drug, dose or duration)
  • Quality of life [ Time Frame: 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)
  • number of participants with a switch back from oral to IV antibiotic treatment [ Time Frame: up to 6 months after the end of antibiotic treatment ]
    For experimental group only . An assessment of the need for a return to parenteral antibiotic in the experimental group.
  • Compliance with oral antibiotic treatment [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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.
  • Utility score and incremental cost-utility ratio (ICUR) [ Time Frame: 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.
  • Length of hospital stay [ Time Frame: 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.
  • Residual concentration of antibiotics [ Time Frame: 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 [ Time Frame: 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).
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Oral Switch During Treatment of Left-sided Endocarditis Due to Multi-susceptible Staphylococcus
Official Title  ICMJE Oral Switch During Treatment of Left-sided Endocarditis Due to Multi-susceptible Staphylococcus (Relais Oral Dans le Traitement Des Endocardites à Staphylocoques Multi-sensibles)
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Infective Endocarditis
Intervention  ICMJE
  • Drug: Levofloxacin
    levofloxacin 500 mg x1/day (for patients ≤70kg) or levofloxacin 750 mg x1/day (for patients >70kg)
    Other Name: Fluoroquinolones
  • Drug: Rifampicin
    rifampicin 600mg x1/day (for patients ≤70kg) or rifampicin 900mg x1/day (for patients >70kg)
  • Procedure: Conventional IV treatment of staphylococci IE following European guidelines 2015 including cloxacilline, oxacilline,gentamicine,vancomycine,rifampicine
    Conventional IV treatment of staphylococci IE following European guidelines 2015 including cloxacilline, oxacilline,gentamicine,vancomycine,rifampicine
Study Arms  ICMJE
  • Experimental: Oral switch treatment
    Oral switch to the combination of levofloxacin and rifampicin
    Interventions:
    • Drug: Levofloxacin
    • Drug: Rifampicin
  • Active Comparator: Conventional IV treatment according to european guidelines
    Conventional IV treatment of staphylococci IE (European guidelines 2015)
    Intervention: Procedure: Conventional IV treatment of staphylococci IE following European guidelines 2015 including cloxacilline, oxacilline,gentamicine,vancomycine,rifampicine
Publications * 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 à staphylocoques ou streptOcoques) and AEPEI (Association pour l'Etude et la Prévention 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 2, 2016)
324
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE October 2021
Estimated Primary Completion Date October 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Louis BERNARD, MD, PHD L.BERNARD@chu-tours.fr
Contact: Elodie MOUSSET 02.47.47.46.65 e.mousset@chu-tours.fr
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02701608
Other Study ID Numbers  ICMJE RODEO 1
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description:

There are no plans to grant public access to the full protocol, participant-level data or statistical code. Data from the RODEO trials is stored by the promotor of the trial. Data and the personal identifiers are stored separately and a special permit is required for access to the data. Data can be available on request for academic researchers when it have been analysed and published. Qualified researchers can ask for data sharing by the first author LB after the study finalization.

Open Access This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work noncommercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http:// creativecommons.org/licenses/by-nc/4.0/

Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Supporting Materials: Clinical Study Report (CSR)
Time Frame: After publication of the main manuscript
Responsible Party University Hospital, Tours
Study Sponsor  ICMJE University Hospital, Tours
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Louis BERNARD, MD,PHD CHRU TOURS
PRS Account University Hospital, Tours
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP