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

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ClinicalTrials.gov Identifier: NCT02701595
Recruitment Status : Recruiting
First Posted : March 8, 2016
Last Update Posted : September 27, 2018
Sponsor:
Information provided by (Responsible Party):
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 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.


Condition or disease Intervention/treatment Phase
Infective Endocarditis Drug: Amoxicillin Procedure: Conventional IV treatment of streptococci/enterococci IE following European guidelines 2015 including amoxicillin, gentamicin, amicillin, vancomycin, penicillin G, ceftriaxone, netilmicin Phase 3

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 324 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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 Start Date : March 2016
Estimated Primary Completion Date : October 2019
Estimated Study Completion Date : October 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Endocarditis

Arm Intervention/treatment
Experimental: Oral switch treatment
Oral switch to amoxicillin
Drug: Amoxicillin
amoxicillin 1500 mg x3/day (for patients ≤70kg) or 2000 mg x3/day (for patients >70kg)

Active Comparator: Conventional IV treatment according to european guidelines
Conventional IV treatment of streptococci/enterococci IE (European guidelines 2015)
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




Primary Outcome Measures :
  1. Treatment failure [ Time Frame: up to 6 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 :
  1. Death from all-cause [ Time Frame: up to 6 months after the end of antibiotic treatment ]
    death from all-causes

  2. number of symptomatic embolic events [ Time Frame: up to 6 months after the end of antibiotic treatment ]
    secondary osteo-articular, splenic or brain localization

  3. unplanned valvular surgery [ Time Frame: up to 6 months after the end of antibiotic treatment ]
    unplanned valvular surgery

  4. 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

  5. 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

  6. 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

  7. 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)

  8. 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

  9. 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)

  10. 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)

  11. numer 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.

  12. 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 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.


  13. 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

  14. 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.

  15. 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

  16. 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

  17. 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).

  18. 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).



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02701595


Contacts
Contact: Louis BERNARD, MD, PHD L.BERNARD@chu-tours.fr
Contact: Elodie MOUSSET 02 47 47 46 65 e.mousset@chu-tours.fr

  Show 53 Study Locations
Sponsors and Collaborators
University Hospital, Tours
Investigators
Principal Investigator: Louis BERNARD, MD,PHD CHRU TOURS

Responsible Party: University Hospital, Tours
ClinicalTrials.gov Identifier: NCT02701595     History of Changes
Other Study ID Numbers: RODEO 2
First Posted: March 8, 2016    Key Record Dates
Last Update Posted: September 27, 2018
Last Verified: September 2018

Additional relevant MeSH terms:
Endocarditis
Endocarditis, Bacterial
Bacterial Infections
Cardiovascular Infections
Infection
Anti-Bacterial Agents
Heart Diseases
Cardiovascular Diseases
Amoxicillin
Vancomycin
Gentamicins
Ceftriaxone
Penicillins
Penicillin G
Penicillin G Benzathine
Penicillin G Procaine
Netilmicin
Anti-Infective Agents
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action