NCT03959345: SAFO

Efficacy of Cloxacillin and Fosfomycin Combination Versus Cloxacillin Monotherapy in Patients With MSSA Bacteremia

Terminated Phase 4 Last updated 21 April 2022

What this trial tests

Phase 4 trial testing Combination therapy group in Methicillin Susceptible Staphylococcus Aureus Septicemia in 215 participants. Terminated before completion.

Timeline

31 May 2019

Primary endpoint
24 February 2022

24 February 2022

Quick facts

Lead sponsor	Miquel Pujol
Phase	Phase 4
Status	Terminated
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	215
Start date	31 May 2019
Primary completion	24 February 2022
Estimated completion	24 February 2022
Sites	17 locations across Spain

Drugs / interventions tested

• Combination therapy group
• Standard therapy group

Conditions studied

• Methicillin Susceptible Staphylococcus Aureus Septicemia — all drugs for Methicillin Susceptible Staphylococcus Aureus Septicemia →

Sponsor

Miquel Pujol — full company profile →

Who can join

18 and older, any sex, with Methicillin Susceptible Staphylococcus Aureus Septicemia. Patients with the condition only — healthy volunteers not accepted.

Sponsor's own description

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

Aim: 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 bacteremia 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 bacteremia 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 negative blood cultures for S. aureus at day 7.

In case of achieving statistical differences in the primary endpoint, investigators will perform a hierarchical analysis of the treatment success at Test of Cure visit (TOC, 12 weeks after randomization), defined by the presence of all of the following: patient alive at TOC AND no evidence of microbiological treatment failure defined as isolation of S. aureus from blood culture or other sterile site from day 8 after 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%.

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

Publications & conference data

3 peer-reviewed publications reference this trial (live from Europe PMC):

1. Cloxacillin plus fosfomycin versus cloxacillin alone for methicillin-susceptible Staphylococcus aureus bacteremia: a randomized trial.
   Grillo S, Pujol M, Miró JM, López-Contreras J, et al · · 2023 · cited 34× · PMID 37783969 · DOI 10.1038/s41591-023-02569-0
2. Multicentre, randomised, open-label, phase IV-III study to evaluate the efficacy of cloxacillin plus fosfomycin versus cloxacillin alone in adult patients with methicillin-susceptible <i>Staphylococcus aureus</i> bacteraemia: study protocol for the SAFO trial.
   Grillo S, Cuervo G, Carratala J, San-Juan R, et al · · 2021 · cited 5× · PMID 34353808 · DOI 10.1136/bmjopen-2021-051208
3. A case study on <i>Staphylococcus aureus</i> bacteraemia: available treatment options, antibiotic R&D and responsible antibiotic-use strategies.
   Monnier AA, Tacconelli E, Årdal C, Cavaleri M, et al · · 2020 · PMID 34222996 · DOI 10.1093/jacamr/dlaa034