Short vs Long of Usual Treatment for Non Complicated Enterococcal Bacteremia (INTENSE)

Randomized Non-inferiority Clinical Trial to Evaluate the Effectiveness and Security of Therapy for Non Complicated Enterococcal Bacteremia.

Randomized clinical trial to determine the optimal duration of antibiotic treatment for E. Faecalis or E. faecium bacteraemia, following an innovative DOOR / RADAR (Desirability of Outcome Ranking (DOOR) and Response Adjusted for Duration of Antibiotic Risk (RADAR)) analysis methodology.

Phase IV clinical trial, open-labelled, randomized, pragmatic, multicenter study to demonstrate non-inferiority of a 7-day antibiotic regimen vs. 14 days in the treatment of bacteremia due to E. faecalis or E. faecium.

Study Overview

• Status: Recruiting
• Conditions: Enterococcal Bacteremia
• Intervention / Treatment: Drug: Short-treatment of any active antibiotic regimen 7 days of any active antibiotic treatment for uncomplicated enterococcal bacteremia.; Drug: Long-treatment of any active antibiotic regimen 14 days of any active antibiotic treatment for uncomplicated enterococcal bacteremia.

Detailed Description

Phase IV clinical trial, open-labelled, randomized, pragmatic, multicenter study to demonstrate non-inferiority of a 7-day antibiotic regimen vs. 14 days in the treatment of bacteremia due to E. faecalis or E. faecium.

Adequate antibiotic regimen is included in the protocol; initially this regimen included ciprofloxacine but this has been modified si that in the last version 3 dated feb 6th ciprofloxacine is not allowed as a possible treatment for these patients.

Antibiotic regimen included as possible treatments in the study are the follows:

• Isolated strains sensitive to ampicillin: ampicillin 2g/6 or 8h (i.v)
• Strains resistant to ampicillin and/or patients with allergy to beta-lactam drugs:
• Vancomycin: 15 mg/kg/12h i.v (with determination of trough plasma levels on day 2-3 of treatment if available).
• Linezolid: 600 mg/12 hours (i.v)
• Daptomycin: 8-10 mg/kg/day (i.v).

Intra-abdominal or soft tissue infections meeting study criteria, for which a polymicrobial infection is suspected:

Amoxicillin/clavulanic acid (isolates sensitive to ampicillin) 1 g/8h iv - Piperacillin/tazobactam (isolates sensitive to ampicillin) 4 g/8h (i.v.) - Combination of vancomycin, linezolid or daptomycin with a drug active against Gram-negative and anaerobic bacteria to ensure complete coverage in the case of bacteremia with a presumably polymicrobial focus.

Oral Treatment: In order to facilitate discharge of patients in both arms and reduce the risk of complications, as well as in keeping with the increasing use of this practice, the option to switch to oral therapy is allowed at the discretion of the responsible clinician, in both arms in patients with hemodynamic stability who tolerate oral treatment, at the discretion of the physician.

responsable.

- Amoxicillin 1g/8h or amoxicillin/clavulanic acid 875/125mg/8h if polymicrobial infection is suspected Linezolid 600mg/12h The choice will be in this order, according to the sensitivity of the isolate and allergies or other common circumstances for the use of these drugs.

The previous version allowed the use of cipro at the discretion of the clinicians as a sequential treatment option based on the fact that it is a clinical trial for low-risk bacteraemias in order to facilitate early sequential treatment (and thus avoid unnecessarily prolonging the hospital admissions.We decided to withdraw it on the basis that currently the EUCAST breakpoints only apply to urinary tract infections.The direct consequence is that the number of sequential treatment options is reduced.

• Study Type: Interventional
• Enrollment (Anticipated): 284
• Phase: Phase 4

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain, 08003
    • Recruiting
    • Hospital del Mar
    • Principal Investigator: Silvia Castañeda Espinosa, MD
  • Barcelona, Spain, 08025
    • Recruiting
    • Hospital de la Santa Creu i Sant Pau
  • Granada, Spain, 18014
    • Recruiting
    • Hospital Universitario Virgen de las Nieves
  • Huelva, Spain, 210101
    • Recruiting
    • Hospital Universitario Juan Ramon Jimenez
  • Madrid, Spain, 28034
    • Recruiting
    • Hospital Universitario Ramón y Cajal
  • Murcia, Spain, 30120
    • Not yet recruiting
    • Complejo Hospitalario Universitario Virgen de la Arrixaca
  • San Sebastián, Spain, 20014.
    • Recruiting
    • Hospital Universitario de Donostia
  • Santander, Spain, 39008
    • Recruiting
    • Hospital Universitario Marques de Valdecilla
  • Sevilla, Spain, 41009
    • Recruiting
    • Hospital Universitario Virgen Macarena
  • Sevilla, Spain, 41013
    • Recruiting
    • Hospital Universitario Virgen del Rocío
  • Sevilla, Spain, 410303
    • Recruiting
    • Hospital Universitario Virgen de Valme
  • A Coruña
    • Coruña, A Coruña, Spain, 15006
      • Recruiting
      • COMPLEJO Universitario de La Coruña
  • Almeria
    • Almería, Almeria, Spain, 04009
      • Recruiting
      • Hospital Universitario Torrecárdenas
  • Baleares
    • Palma De Mallorca, Baleares, Spain, 07120
      • Recruiting
      • Hospital Universitario Son Espases
  • Barcelona
    • Terrassa, Barcelona, Spain, 08221
      • Recruiting
      • Hospital Universitario Mutua de Terrassa
  • Bizkaia
    • Barakaldo, Bizkaia, Spain, 48903
      • Recruiting
      • Hospital de Cruces
  • Cadiz
    • Jerez De La Frontera, Cadiz, Spain, 11408
      • Recruiting
      • Hospital Universitario de Jerez de la Frontera
    • Puerto Real, Cadiz, Spain, 11510
      • Not yet recruiting
      • Hospital Universitario de Puerto Real
  • Jaen
    • Jaén, Jaen, Spain, 23007
      • Recruiting
      • Hospital Universitario de Jaén
  • Malaga
    • Marbella, Malaga, Spain, 29603
      • Recruiting
      • Hospital Universitario Costa Del Sol
    • Málaga, Malaga, Spain, 29010
      • Recruiting
      • Hospital Universitario Regional de Málaga
  • Pontevedra
    • Vigo, Pontevedra, Spain, 36312
      • Recruiting
      • Hospital Universitario de Vigo

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adult patients (18 years of age or older) hospitalised with monomicrobial E. faecalis or E. faecium bacteremia.
• Negative follow-up blood cultures performed between days 2 and 3 of active treatment.
• Disappearance of fever (>37.8ºC) within the first 72 hours.
• Signed informed consent.

The previous version allowed this inclusion criterion "Early adequate control of the source of bacteremia within 72 hours in the cases in which it is feasible and necessary (urinary or biliary tract release; abscess drainage; catheter-removal, etc)", which is now removed because it is already an exclusion criterion.

Exclusion Criteria:

• patients with polymicrobial bacteremia
• Patients with limited life expectancy in whom only conservative clinical management had been decided.
• Hemodynamic instability on day 5-6 after the start of active treatment.
• Patients wearing endovascular devices or prosthetic heart valves.
• Source of uncontrolled bacteremia adequately defined as undrained abscess, bile duct infection associated with plastic prostheses not removed or not replaced within the first 72 hours of bacteraemia, other infections related to non-removed prostheses, prostatitis, and infective endocarditis, as well as infections that require prolonged treatment, such as joint and bone infections.
• Existence of a secondary focus, different from the initial one, or presence of metastatic focus of infection.
• Severe neutropenia (<500 cells / mm3) at the time of bacteremia diagnosis.
• Pregnancy and lactation.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Short-treatment of any active antibiotic regimen; 7 days from the initiation of an appropriate antimicrobial therapy and documented resolution of bacteremia (negative control blood cultures performed on day 2 or 3)	Drug: Short-treatment of any active antibiotic regimen 7 days of any active antibiotic treatment for uncomplicated enterococcal bacteremia.; Any active antibiotic with treatment with proven in vitro activity from a pre-stablished list of antibiotics included; Other Names: 7 days of active antibiotics
Active Comparator: Long-treatment of any active antibiotic regimen; 14 days of any active antibiotic treatment from the date of the last positive blood culture and documented resolution of bacteremia (negative control blood cultures performed on day 2 or 3)	Drug: Long-treatment of any active antibiotic regimen 14 days of any active antibiotic treatment for uncomplicated enterococcal bacteremia.; Any active antibiotic with treatment with proven in vitro activity a pre-stablished list of antibiotics included; Other Names: 14 days of active antibiotics

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical success	Clinical success , composite endpoint defined as all the following: (a) survival at TOC; (b) absence of enterococcal bacteremia relapse or infective endocarditis diagnosis at TOC; (c) no need to prolong therapy beyond the pre-established duration, or restart drugs against enterococci for any reason within 30 days.	TOC (Test of cure) visit (performed at day 28-32 after the end of suitable antibiotic treatment) or if drainage occurs after day 7 of treatment, TOC is to be done 7 days after that day.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rates of relapse or infective endocarditis diagnosis	Rates of relapse or infective endocarditis diagnosis in the CEP (Clinically Evaluable Population)	TOC visit (day 28-32 ) and follow-up visit at day 90
Survival	Number of live patients	TOC visit (day 28-32) and follow-up visit at day 90
Length of hospital stay	Number of days patient is in-hospital	From patient first day inhospital (day of admission) until patient hospital discharge due to cure or home follow up assessed up to 30 days of the initiation of antibiotic administration
Duration of intravenous and total therapy	Number of days of intravenous and total therapy in the CEP (Clinically Evaluable Population)	From date of randomization until the last follow up visit planned 30 days of the initiation of antibiotic administration
Incidence of diarrhoea by C. difficile	To evaluate the frequency of diarrhea by C. difficile	From date of randomization until the last follow up visit planned 30 days of the initiation of antibiotic administration
Number of participants with Adverse Events due to antibiotic treatment	Registration of all adverse events happening form the signature on informed consent form to 30 days after the study drugs administration.	From date of randomization until the last follow up visit planned 90 days of the initiation of antibiotic administration
Incidence of secondary infections	Number of patients with recurrent bacteremia	TOC visit (on day 28-32) and follow-up visit at day 90
Change in SOFA score (Sepsis related Organ Failure Assessment)	Calculation of the SOFA score valued from 0 to 4 (0 best to 4 worst punctuation)	Visit 0 (baseline) and TOC visit (on day 28-32) and follow-up visit at day 90

Collaborators and Investigators

• Sponsor: Fundación Pública Andaluza para la gestión de la Investigación en Sevilla
• Collaborators: Spanish Clinical Research Network - SCReN; Spanish Network for Research in Infectious Diseases

Study record dates

Study Major Dates

• Study Start (Actual): July 11, 2022
• Primary Completion (Anticipated): July 15, 2024
• Study Completion (Anticipated): December 15, 2024

Study Registration Dates

• First Submitted: April 11, 2022
• First Submitted That Met QC Criteria: May 26, 2022
• First Posted (Actual): May 27, 2022

Study Record Updates

• Last Update Posted (Actual): May 3, 2023
• Last Update Submitted That Met QC Criteria: May 2, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Bacteremia; Enterococcus
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Bacterial Infections; Bacterial Infections and Mycoses; Sepsis; Bacteremia; Anti-Infective Agents; Antitubercular Agents; Anti-Bacterial Agents; Antibiotics, Antitubercular
• Other Study ID Numbers: RCT- INTENSE; 2021-003891-15 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Planning for the study will be shared with potential sites pertaining to Spanish Network for Research in Infectious Disease (REIPI)for participation. IPD is not foreseen out of this groups due to the specific characteristics of patients and sites to be candidates for study participation.
• IPD Sharing Time Frame: From starting to three years of study completion planification
• IPD Sharing Access Criteria: Spanish Network for Research in Infectious Disease investigators
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No