Short vs Long of Usual Treatment for Non Complicated Enterococcal Bacteremia

Enterococcal Bacteremia Clinical Trial

— INTENSE  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05394298
• Other study ID #: RCT- INTENSE
• Secondary ID: 2021-003891-15
• Status: Recruiting
• Phase: Phase 4
• Start date: July 11, 2022
• Est. completion date: December 15, 2024

Study information

• Verified date: May 2023
• Source: Fundación Pública Andaluza para la gestión de la Investigación en Sevilla
• Contact: Clara María Rosso Fernández
• Phone: 0034 955 013414
• Email: claram.rosso.sspa[@]juntadeandalucia.es
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 284
• Est. completion date: December 15, 2024
• Est. primary completion date: July 15, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Bacteremia
• Enterococcal Bacteremia

Intervention

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
• 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

Locations

Country	Name	City	State
Spain	Hospital Universitario Torrecárdenas	Almería	Almeria
Spain	Hospital de Cruces	Barakaldo	Bizkaia
Spain	Hospital de la Santa Creu i Sant Pau	Barcelona
Spain	Hospital del Mar	Barcelona
Spain	COMPLEJO Universitario de La Coruña	Coruña	A Coruña
Spain	Hospital Universitario Virgen de Las Nieves	Granada
Spain	Hospital Universitario Juan Ramón Jiménez	Huelva
Spain	Hospital Universitario de Jaén	Jaén	Jaen
Spain	Hospital Universitario de Jerez de La Frontera	Jerez De La Frontera	Cadiz
Spain	Hospital Universitario Ramón y Cajal	Madrid
Spain	Hospital Universitario Regional de Málaga	Málaga	Malaga
Spain	Hospital Universitario Costa Del Sol	Marbella	Malaga
Spain	Complejo Hospitalario Universitario Virgen de la Arrixaca	Murcia
Spain	Hospital Universitario Son Espases	Palma De Mallorca	Baleares
Spain	Hospital Universitario de Puerto Real	Puerto Real	Cadiz
Spain	Hospital Universitario de Donostia	San Sebastián
Spain	Hospital Universitario Marqués de Valdecilla	Santander
Spain	Hospital Universitario Virgen de Valme	Sevilla
Spain	Hospital Universitario Virgen Del Rocío	Sevilla
Spain	Hospital Universitario Virgen Macarena	Sevilla
Spain	Hospital Universitario Mutua de Terrassa	Terrassa	Barcelona
Spain	Hospital Universitario de Vigo	Vigo	Pontevedra

Sponsors (3)

Lead Sponsor	Collaborator
Fundación Pública Andaluza para la gestión de la Investigación en Sevilla	Spanish Clinical Research Network - SCReN, Spanish Network for Research in Infectious Diseases

Country where clinical trial is conducted

Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	Survival	Number of live patients	TOC visit (day 28-32) and follow-up visit at day 90
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Incidence of secondary infections	Number of patients with recurrent bacteremia	TOC visit (on day 28-32) and follow-up visit at day 90
Secondary	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