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Efficacy of Cloxacillin and Fosfomycin Combination Versus Cloxacillin Monotherapy in Adult Patients With Methicillin-susceptible Staphylococcus Aureus Bacteraemia: the SAFO Trial. (SAFO)

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ClinicalTrials.gov Identifier: NCT03959345
Recruitment Status : Not yet recruiting
First Posted : May 22, 2019
Last Update Posted : May 24, 2019
Sponsor:
Collaborators:
Institut d'Investigació Biomèdica de Bellvitge
Instituto de Salud Carlos III
Information provided by (Responsible Party):
Miquel Pujol, Institut d'Investigació Biomèdica de Bellvitge

Brief Summary:

Background: Despite management improvement in lasts years, Staphylococcus aureus bacteraemia leads to high morbidity and mortality. For over 50 years, methicillin-susceptible S.aureus (MSSA) bacteraemia standard treatment was cloxacillin. Previous studies using different therapies and combination treatment fall to improve survival in these patients.

Investigator's study aims to demonstrate the efficacy of the cloxacillin and fosfomycin combination administered during the first week of treatment, compared with cloxacillin monotherapy in patients with MSSA bacteraemia in treatment success. Methods: A multicentre, superiority, open-label, randomized, phase IV-III, two-armed parallel (1:1) groups clinical trial. Adult patients with MSSA bacteraemia will be randomized to Combination therapy group: patients will receive intravenous cloxacillin 2g/4h and fosfomycin 3 g/6h for the duration of 7 days treatment, or Standard therapy group: patients will receive intravenous cloxacillin 2g/4h for the duration of 7 days IV treatment. After the first week, antibiotic treatment and duration will be decided by responsible clinician following clinical practice.

The primary endpoint is the treatment success measured at day 7 of treatment; a composite endpoint defined by all of the following criteria met after randomization: patient alive at day 7 AND stable or improved quick SOFA score (compared with baseline) at day 7 AND fever resolved at day 7 AND blood cultures negative for S. aureus starting at day 7 until Test of Cure visit (TOC, 12 weeks after randomization) and no isolation of S. aureus in another sterile site from day 8 until TOC. In case of achieving statistical differences in the primary endpoint, investigators will perform a hierarchical analysis of the treatment success at TOC, defined by presence of all of the following: patient alive AND no evidence of microbiological treatment failure defined as persistence of S. aureus bloodstream infection > 7 days and no isolation of S. aureus from sterile site > 14 days from randomization until TOC. Investigators have assumed a 74% of treatment success in monotherapy group. Accepting an alpha risk of 0.05 and a beta risk of 0.2 in a two-sided test, 183 subjects are necessary in first group and 183 in the second to find a statistically significant difference of 12%. It has been anticipated a drop-out rate of 5%.

Treatment failure is defined by the presence of one of the following condition: all cause mortality at 7 days, withdraw of the study because of adverse events, requirement of an additional MSSA-active antibiotic until day 7, lacking of clinical improvement.

Discussion: Randomized studies assessing efficacy of different treatment in MSSA bacteraemia are lacking. This study could help to improve knowledge about MSSA bacteraemia and whether combined treatment with cloxacillin and fosfomycin could improve outcomes compared with standard treatment.


Condition or disease Intervention/treatment Phase
Methicillin Susceptible Staphylococcus Aureus Septicemia Drug: Combination therapy group Drug: Standard therapy group Phase 4

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 366 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Multicenter, Randomised, Open-label Phase III-IV Study to Evaluate the Efficacy of Cloxacillin and Fosfomycin Combination Versus Cloxacillin Monotherapy in Adult Patients With Methicillin-susceptible Staphylococcus Aureus Bacteraemia: the SAFO Trial.
Estimated Study Start Date : May 21, 2019
Estimated Primary Completion Date : August 31, 2021
Estimated Study Completion Date : August 31, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Combination therapy group
intravenous cloxacillin 2g/4h and fosfomycin 3 g/6h for the duration of 7 days treatment
Drug: Combination therapy group
Adult patients with MSSA bacteraemia will be randomized to Combination therapy group: patients will receive intravenous cloxacillin 2g/4h and fosfomycin 3 g/6h for the duration of 7 days treatment. After the first week, antibiotic treatment and duration will be decided by responsible clinician following clinical practice.

Active Comparator: Standard therapy group
intravenous cloxacillin 2g/4h for the duration of 7 days IV treatment
Drug: Standard therapy group
Adult patients with MSSA bacteraemia will be randomized to Standard therapy group: patients will receive intravenous cloxacillin 2g/4h for the duration of 7 days IV treatment. After the first week, antibiotic treatment and duration will be decided by responsible clinician following clinical practice.




Primary Outcome Measures :
  1. Treatment success at day 7 [ Time Frame: Day 7 after randomization. No microbiological failure after 12 weeks of randomization ]
    Composite endpoint defined by all of the following criteria met after randomization: patient alive at day 7 AND stable or improved quick SOFA score (compared with baseline) at day 7 AND fever resolved at day 7 AND blood cultures negative for S. aureus starting at day 7 until Test of Cure visit (TOC, 12 weeks after randomization) and no isolation of S. aureus in another sterile site from day 8 until TOC.

  2. Treatment success at TOC [ Time Frame: 12 weeks after randomization ]
    In case of achieving statistical differences in the primary endpoint, we will perform a hierarchical analysis of the treatment success at TOC, defined by presence of all of the following: patient alive AND no evidence of microbiological treatment failure defined as persistence of S. aureus bloodstream infection > 7 days and no isolation of S. aureus from sterile site > 14 days from randomization until TOC.



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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:

  • Subjects, aged ≥ 18 years;
  • MSSA bacteraemia: ≥ 1 positive blood culture(s) for MSSA in the first 72 h up to randomisation in patients with clinical suspicion of infection;
  • Written informed consent of the participant or the legal representative.

Exclusion Criteria:

  • Severe clinical status with expected death <48h.
  • Severe hepatic cirrhosis (Child-Pugh C).
  • Moderate-severe cardiac chronic failure (NYHA III-IV).
  • Prosthetic endocarditis (need for concomitant antibiotic therapy active against S. aureus together with the study antibiotics for the first 7 days of the study).
  • No pre-existing evidence of S. aureus fosfomycin non-susceptibility.
  • Known hypersensitivity to cloxacillin or fosfomycin.
  • Polymicrobial bacteraemia with more than one microorganism in blood cultures.
  • A positive pregnancy test or pregnancy or lactation at the time of inclusion.
  • Miastenia gravis.
  • Participation in another clinical trial.
  • Previous participation in the present clinical trial.

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): NCT03959345


Contacts
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Contact: Sara Grillo, MD 0034 932 60 75 00 sarris.grillo@gmail.com
Contact: Miquel Pujol Rojo, Md, PhD mpujol@bellvitgehospital.cat

Locations
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Spain
University Hospital Cruces
Baracaldo, Spain
Hospital del Mar Not yet recruiting
Barcelona, Spain
Contact: Silvia Gomez-Zorrilla         
University Hospital Clínic de Barcelona Not yet recruiting
Barcelona, Spain
Contact: Laura Morata         
University Hospital Santa Creu i Sant Pau Not yet recruiting
Barcelona, Spain
Contact: Joaquín Lopez Contreras         
University Hospital Josep Trueta Not yet recruiting
Girona, Spain
Contact: Xavier Salgado         
University Hospital Arnau de Vilanova Not yet recruiting
Lleida, Spain
Contact: Alfredo Jover         
University Hospital Lucus Agustí Not yet recruiting
Lugo, Spain
Contact: Maria José García País         
University Hospital 12 de Octubre Not yet recruiting
Madrid, Spain
Contact: Rafael Sanjuan         
University Hospital Sant Joan Not yet recruiting
Reus, Spain
Contact: Simona Iftimie         
Corporació Sanitària Parc Taulí Not yet recruiting
Sabadell, Spain
Contact: Oriol Gasch         
University Hospital Virgen Macarena Not yet recruiting
Sevilla, Spain
Contact: Luis Eduardo López-Cortés         
University Hospital Joan XXIII Not yet recruiting
Tarragona, Spain
Contact: Graciano García Pardo         
University Hospital Mùtua de Terrassa Not yet recruiting
Terrassa, Spain
Contact: Lucia Boix         
Sponsors and Collaborators
Miquel Pujol
Institut d'Investigació Biomèdica de Bellvitge
Instituto de Salud Carlos III

Publications:

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Responsible Party: Miquel Pujol, Principal Investigator, Medical Doctor, Institut d'Investigació Biomèdica de Bellvitge
ClinicalTrials.gov Identifier: NCT03959345     History of Changes
Other Study ID Numbers: 2018-001207-37
First Posted: May 22, 2019    Key Record Dates
Last Update Posted: May 24, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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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

Additional relevant MeSH terms:
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Bacteremia
Sepsis
Bacterial Infections
Infection
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Methicillin
Fosfomycin
Cloxacillin
Anti-Bacterial Agents
Anti-Infective Agents