Methicillin Susceptible Staphylococcus Aureus SepticemiaPhase 4SAFONCT03959345
Efficacy of Cloxacillin and Fosfomycin Combination Versus Cloxacillin Monotherapy in Patients With MSSA Bacteremia
A Phase 4 study testing Combination therapy group and Standard therapy group in people with Methicillin Susceptible Staphylococcus Aureus Septicemia, run by Miquel Pujol at 17 sites in Spain.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Methicillin Susceptible Staphylococcus Aureus Septicemia
- What is being tested?
- Combination therapy group and Standard therapy group
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 215 participants
- Where
- 17 sitesSpain
- Study dates
- 31 May 2019to 24 Feb 2022
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Show all 12Show fewer
- 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.
- Acute SARS-CoV2 infection.
Trial locations and contacts
17 sites in 1 country.
17 sites in 1 country
Spain17 sites
Hospital Universitari Germans Trias i Pujol
Badalona, Barcelona
University Hospital Cruces
Barakaldo
Bellvitge University Hospital
Barcelona
Hospital del Mar
Barcelona
University Hospital Clínic de Barcelona
Barcelona
University Hospital Santa Creu i Sant Pau
Barcelona
University Hospital Arnau de Vilanova
Lleida
University Hospital Lucus Agustí
Lugo
Hospital Universitario Ramón y Cajal
Madrid
University Hospital 12 de Octubre
Madrid
University Hospital Sant Joan
Reus
Corporació Sanitària Parc Taulí
Sabadell
Hospital Sant Joan Despí Moisés Broggi
Sant Joan Despí, Barcelona
University Hospital Virgen Macarena
Seville
University Hospital Joan XXIII
Tarragona
University Hospital Mùtua de Terrassa
Terrassa
Hospital Clínico Lozano Blesa
Zaragoza
About this study
Official title: Multicenter, Randomised, Open-label Phase III-IV Study to Evaluate the Efficacy of Cloxacillin and Fosfomycin Combination Versus Cloxacillin Monotherapy in Patients With Methicillin-susceptible Staphylococcus Aureus Bacteraemia: SAFO Trial
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.
Read more
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.
Read the detailed description
SAFO trial is a multicentre, superiority, open-label, randomized, phase IV-III, two-armed parallel (1:1) groups clinical trial comparing combination treatment with fosfomycin and cloxacillin with standard therapy with cloxacillin in adult patients with MSSA bacteremia.
Patients will be randomized to:
- Standard treatment group: patients will receive intravenous cloxacillin 2g/4h for the duration of 7 days IV treatment. If creatinine clearance is <30 mL/min cloxacillin will be administrated at dose of 2g every 6 hours.
- Combination therapy group: patients will receive intravenous cloxacillin as explained above and fosfomycin 3 g/6h for the duration of 7 days treatment. In case of renal failure, fosfomycin will be administrated as follow:
Creatinine clearance (mL/min) Fosfomycin dosage >40 3 g every 6 hours 20-40 3 g every 12 hours 10-20 3g every 24 hours <10 3 g every 48 hours Haemodialysis 3 g after haemodialysis Continuous renal replacement therapy 3 g every 24h hours
The duration of overall antibiotic treatment and the duration of intravenous treatment will be determined according to clinical criteria depending on status (complicated or uncomplicated bacteremia, source of infection) by responsible clinician according with current guidelines. Patient with complicated bacteremia will receive at least 4-6 week of antibiotic treatment.
Primary endpoint
Treatment success at day 7 is a composite outcome defined by all of the following criteria met after randomization:
- Patient alive at day 7 AND
- Clinical improvement measured by 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 statistical differences observed between groups in the primary endpoint, investigators will perform a hierarchical testing analyzing the treatment success at Test of Cure (TOC visit, 12 weeks after randomization).
Treatment success at TOC visit is defined by presence of all of the following:
- Patient alive at TOC;
- No isolation of MSSA in blood culture or in another sterile site from day 8 until Test of Cure visit (TOC, 12 weeks after randomisation). In case of patients with prolonged course of antibiotic treatment (more than 10 weeks), TOC visit will be performed two weeks after the end of treatment (EOT).
Treatment failure is defined by the presence of one of the following condition: all-cause mortality at TOC, positive blood cultures at day 7 or later, withdraw of the study because of adverse events related to study treatment, requirement of an additional MSSA-active antibiotic until day 7, lacking of clinical improvement at day 7.
Secondary endpoint
Clinical secondary endpoints:
- To compare all-cause mortality at days 7, 14, EOT and 90 after randomization in cloxacillin treatment group versus cloxacillin and fosfomycin treatment group.
- To evaluate persistent bacteremia (at least one positive blood culture) at day 3 and persistent bacteremia at day 7 after randomization in the two arms of treatment.
- To determine the microbiological relapse as defined by at least one positive blood culture for MSSA at least 72 hours after a preceding negative culture in the two arms of treatment.
- To evaluate microbiological treatment failure as defined by positive sterile site culture for MSSA at least 14 days after randomisation in the two arms.
- To determine the number of patients with persistent and relapsing bacteremia in the two arms of treatment.
- To evaluate the number of patients with complicated bacteremia, defined by persistent bacteremia, endocarditis or metastatic emboli, prosthetic devices) in the two arms of treatment.
- To determine the length of stay in intensive care unit and in hospital in both arms of treatment.
- Duration of intravenous antibiotic treatment. Sub group analysis for patients at high risk (persistent bacteraemia, metastatic infection, unknown focus of bacteraemia, endocarditis, pneumonia).
Microbiological secondary endpoints:
- To determine emergency of fosfomycin-resistant strains during therapy in the arm of combination treatment.
- To evaluate operon agr functionality and its relationship with Minimum Inhibitory Concentration (MIC) changes to vancomycin (VAN) and daptomycin (DAP) and with biofilm production.
- To analyze VAN and DAP MIC as markers of complications during bacteraemia.
- To determine the "in vitro" cloxacillin plus fosfomycin combination synergy.
- To realize whole genome sequencing and its changes in patients with treatment failure.
Pharmacological secondary endpoints:
- To determine minimum and maximum concentration in steady state of fosfomycin and cloxacillin.
- To evaluate pharmacokinetic variability of these concentration.
- To study the association between PK parameters and efficacy.
Security secondary endpoints:
To evaluate the security of cloxacillin and fosfomycin combination compared with cloxacillin monotherapy.
- Being tested
- Combination therapy group, Standard therapy group
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Combination therapy groupDrug
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.
Standard therapy groupDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| Combination therapy group | Experimental | intravenous cloxacillin 2g/4h and fosfomycin 3 g/6h for the duration of 7 days treatment Receives: Drug: Combination therapy group |
| Standard therapy group | Active comparator | intravenous cloxacillin 2g/4h for the duration of 7 days IV treatment Receives: Drug: Standard therapy group |
What is being measured
The primary outcome is the main question the study is designed to answer.
Treatment success at day 7
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.
Measured: Day 7 after randomization.
Treatment success at TOC
In case of achieving statistical differences in the primary endpoint, we will perform a hierarchical analysis of the treatment success at Test of Cure visit (TOC, 12 weeks after randomisation).
Treatment success at TOC visit, defined by presence of all of the following:
- Patient alive at TOC;
- No isolation of MSSA in blood culture or in another sterile site from day 8 until TOC.
Measured: 12 weeks after randomization
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 May 2019
- Study start31 May 2019
- Primary completion24 Feb 2022
- Study completion24 Feb 2022
Why it stopped: Data safety and monitoring board(DSMB) have been performed when half of sample size (SS)have been reached. Recruitment was slower than expected so SS was recalculated. After analysis of data, DSMB recommended to stop study.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (11)Papers the sponsor has linked to this study.
- Other trials for Methicillin Susceptible Staphylococcus Aureus SepticemiaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 215 participants (actual)
Sponsor and investigators
- Lead sponsor
- Miquel Pujol
- Sponsor type
- University, hospital or other
- Collaborators
- Institut d'Investigació Biomèdica de Bellvitge, Instituto de Salud Carlos III
- Responsible party
- Sponsor-investigator, Miquel Pujol, Institut d'Investigació Biomèdica de Bellvitge
- Investigators
- Miquel Pujol Rojo, MD, PhD, Principal investigator, Hospital Universitari Bellvitge
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03959345
- Sponsor's protocol ID
- 2018-001207-37
- Other IDs
- 2018
- Acronym
- SAFO
- Status last verified
- Apr 2022
- First submitted
- 20 May 2019
- Last updated
- 21 Apr 2022
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Sharing of data generated by this project is an essential part of our proposed activities and will be carried out in several different ways. We would wish to make our results available both to the community of scientists interested in infectious diseases and the biology of Staphylococcus aureus to avoid unintentional duplication of research. The preliminary results will be presented at international and national infectious diseases conferences and will be published in peer-reviewed journals. The results will also be made available through press and social media communications. Any formal presentation or publication of data collected from this study will be considered as a joint publication by the participating investigators and will follow the recommendations of the ICMJE. Individual participant data that underlie the results, after deidentification will be available. Proposals should be directed to the corresponding author.
Publications
Bergin SP, Holland TL, Fowler VG Jr, Tong SYC. Bacteremia, Sepsis, and Infective Endocarditis Associated with Staphylococcus aureus. Curr Top Microbiol Immunol. 2017;409:263-296. doi: 10.1007/82_2015_5001.
PubMed 26659121van Hal SJ, Jensen SO, Vaska VL, Espedido BA, Paterson DL, Gosbell IB. Predictors of mortality in Staphylococcus aureus Bacteremia. Clin Microbiol Rev. 2012 Apr;25(2):362-86. doi: 10.1128/CMR.05022-11.
PubMed 22491776Gasch O, Camoez M, Dominguez MA, Padilla B, Pintado V, Almirante B, Molina J, Lopez-Medrano F, Ruiz E, Martinez JA, Bereciartua E, Rodriguez-Lopez F, Fernandez-Mazarrasa C, Goenaga MA, Benito N, Rodriguez-Bano J, Espejo E, Pujol M; REIPI/GEIH Study Groups. Predictive factors for mortality in patients with methicillin-resistant Staphylococcus aureus bloodstream infection: impact on outcome of host, microorganism and therapy. Clin Microbiol Infect. 2013 Nov;19(11):1049-57. doi: 10.1111/1469-0691.12108. Epub 2013 Jan 17.
PubMed 23331461Minejima E, Mai N, Bui N, Mert M, Mack WJ, She RC, Nieberg P, Spellberg B, Wong-Beringer A. Defining the Breakpoint Duration of Staphylococcus aureus Bacteremia Predictive of Poor Outcomes. Clin Infect Dis. 2020 Feb 3;70(4):566-573. doi: 10.1093/cid/ciz257.
PubMed 30949675Gudiol F, Aguado JM, Almirante B, Bouza E, Cercenado E, Dominguez MA, Gasch O, Lora-Tamayo J, Miro JM, Palomar M, Pascual A, Pericas JM, Pujol M, Rodriguez-Bano J, Shaw E, Soriano A, Valles J. Diagnosis and treatment of bacteremia and endocarditis due to Staphylococcus aureus. A clinical guideline from the Spanish Society of Clinical Microbiology and Infectious Diseases (SEIMC). Enferm Infecc Microbiol Clin. 2015 Nov;33(9):625.e1-625.e23. doi: 10.1016/j.eimc.2015.03.015. Epub 2015 May 1.
PubMed 25937457Thwaites GE, Scarborough M, Szubert A, Nsutebu E, Tilley R, Greig J, Wyllie SA, Wilson P, Auckland C, Cairns J, Ward D, Lal P, Guleri A, Jenkins N, Sutton J, Wiselka M, Armando GR, Graham C, Chadwick PR, Barlow G, Gordon NC, Young B, Meisner S, McWhinney P, Price DA, Harvey D, Nayar D, Jeyaratnam D, Planche T, Minton J, Hudson F, Hopkins S, Williams J, Torok ME, Llewelyn MJ, Edgeworth JD, Walker AS; United Kingdom Clinical Infection Research Group (UKCIRG). Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2018 Feb 17;391(10121):668-678. doi: 10.1016/S0140-6736(17)32456-X. Epub 2017 Dec 14.
PubMed 29249276Grillo S, Cuervo G, Carratala J, Grau I, Pallares N, Tebe C, Guillem Tio L, Murillo O, Ardanuy C, Dominguez MA, Shaw E, Gudiol C, Pujol M. Impact of beta-Lactam and Daptomycin Combination Therapy on Clinical Outcomes in Methicillin-susceptible Staphylococcus aureus Bacteremia: A Propensity Score-matched Analysis. Clin Infect Dis. 2019 Oct 15;69(9):1480-1488. doi: 10.1093/cid/ciz018.
PubMed 30615122Grabein B, Graninger W, Rodriguez Bano J, Dinh A, Liesenfeld DB. Intravenous fosfomycin-back to the future. Systematic review and meta-analysis of the clinical literature. Clin Microbiol Infect. 2017 Jun;23(6):363-372. doi: 10.1016/j.cmi.2016.12.005. Epub 2016 Dec 9.
PubMed 27956267Chan AW, Tetzlaff JM, Altman DG, Laupacis A, Gotzsche PC, Krleza-Jeric K, Hrobjartsson A, Mann H, Dickersin K, Berlin JA, Dore CJ, Parulekar WR, Summerskill WS, Groves T, Schulz KF, Sox HC, Rockhold FW, Rennie D, Moher D. SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med. 2013 Feb 5;158(3):200-7. doi: 10.7326/0003-4819-158-3-201302050-00583.
PubMed 23295957Grillo S, Pujol M, Miro JM, Lopez-Contreras J, Euba G, Gasch O, Boix-Palop L, Garcia-Pais MJ, Perez-Rodriguez MT, Gomez-Zorrilla S, Oriol I, Lopez-Cortes LE, Pedro-Botet ML, San-Juan R, Aguado JM, Gioia F, Iftimie S, Morata L, Jover-Saenz A, Garcia-Pardo G, Loeches B, Izquierdo-Cardenas A, Goikoetxea AJ, Gomila-Grange A, Dietl B, Berbel D, Videla S, Hereu P, Padulles A, Pallares N, Tebe C, Cuervo G, Carratala J; SAFO study group. Cloxacillin plus fosfomycin versus cloxacillin alone for methicillin-susceptible Staphylococcus aureus bacteremia: a randomized trial. Nat Med. 2023 Oct;29(10):2518-2525. doi: 10.1038/s41591-023-02569-0. Epub 2023 Oct 2.
PubMed 37783969Grillo S, Cuervo G, Carratala J, San-Juan R, Aguado JM, Morata L, Gomez-Zorrilla S, Lopez-Contreras J, Gasch O, Gomila-Grange A, Iftimie S, Garcia-Pardo G, Calbo E, Boix-Palop L, Oriol I, Jover-Saenz A, Lopez-Cortes LE, Euba G, Aguirregabiria M, Garcia-Pais MJ, Gioia F, Pano JR, Pedro-Botet ML, Benitez RM, Perez-Rodriguez MT, Meije Y, Loeches-Yague MB, Horna G, Berbel D, Dominguez MA, Padulles A, Cobo S, Hereu P, Videla S, Tebe C, Pallares N, Miro JM, Pujol M; SAFO study group and the Spanish Network for Research in Infectious Diseases (REIPI). 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 Staphylococcus aureus bacteraemia: study protocol for the SAFO trial. BMJ Open. 2021 Aug 5;11(8):e051208. doi: 10.1136/bmjopen-2021-051208.
PubMed 34353808
Study at a glance
From the registry record, last updated by the sponsor on 21 Apr 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Multicenter, Randomised, Open-label Phase III-IV Study to Evaluate the Efficacy of Cloxacillin and Fosfomycin Combination Versus Cloxacillin Monotherapy in Patients With Methicillin-susceptible Staphylococcus Aureus Bacteraemia: SAFO Trial
- ClinicalTrials.gov ID
- NCT03959345
- Acronym / sponsor ID
- SAFO / 2018-001207-37
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Data safety and monitoring board(DSMB) have been performed when half of sample size (SS)have been reached. Recruitment was slower than expected so SS was recalculated. After analysis of data, DSMB recommended to stop study.
- Enrolment
- 215 participants (actual)
- Lead sponsor
- Miquel PujolUniversity, hospital or other
- Collaborators
- Institut d'Investigació Biomèdica de Bellvitge, Instituto de Salud Carlos III
- Study start
- 31 May 2019 (actual)
- Primary completion
- 24 Feb 2022 (actual)
- Study completion
- 24 Feb 2022 (actual)
- First posted
- 22 May 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
SAFO trial is a multicentre, superiority, open-label, randomized, phase IV-III, two-armed parallel (1:1) groups clinical trial comparing combination treatment with fosfomycin and cloxacillin with standard therapy with cloxacillin in adult patients with MSSA bacteremia.
Patients will be randomized to:
- Standard treatment group: patients will receive intravenous cloxacillin 2g/4h for the duration of 7 days IV treatment. If creatinine clearance is <30 mL/min cloxacillin will be administrated at dose of 2g every 6 hours.
- Combination therapy group: patients will receive intravenous cloxacillin as explained above and fosfomycin 3 g/6h for the duration of 7 days treatment. In case of renal failure, fosfomycin will be administrated as follow:
Creatinine clearance (mL/min) Fosfomycin dosage >40 3 g every 6 hours 20-40 3 g every 12 hours 10-20 3g every 24 hours <10 3 g every 48 hours Haemodialysis 3 g after haemodialysis Continuous renal replacement therapy 3 g every 24h hours
The duration of overall antibiotic treatment and the duration of intravenous treatment will be determined according to clinical criteria depending on status (complicated or uncomplicated bacteremia, source of infection) by responsible clinician according with current guidelines. Patient with complicated bacteremia will receive at least 4-6 week of antibiotic treatment.
Primary endpoint
Treatment success at day 7 is a composite outcome defined by all of the following criteria met after randomization:
- Patient alive at day 7 AND
- Clinical improvement measured by 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 statistical differences observed between groups in the primary endpoint, investigators will perform a hierarchical testing analyzing the treatment success at Test of Cure (TOC visit, 12 weeks after randomization).
Treatment success at TOC visit is defined by presence of all of the following:
- Patient alive at TOC;
- No isolation of MSSA in blood culture or in another sterile site from day 8 until Test of Cure visit (TOC, 12 weeks after randomisation). In case of patients with prolonged course of antibiotic treatment (more than 10 weeks), TOC visit will be performed two weeks after the end of treatment (EOT).
Treatment failure is defined by the presence of one of the following condition: all-cause mortality at TOC, positive blood cultures at day 7 or later, withdraw of the study because of adverse events related to study treatment, requirement of an additional MSSA-active antibiotic until day 7, lacking of clinical improvement at day 7.
Secondary endpoint
Clinical secondary endpoints:
- To compare all-cause mortality at days 7, 14, EOT and 90 after randomization in cloxacillin treatment group versus cloxacillin and fosfomycin treatment group.
- To evaluate persistent bacteremia (at least one positive blood culture) at day 3 and persistent bacteremia at day 7 after randomization in the two arms of treatment.
- To determine the microbiological relapse as defined by at least one positive blood culture for MSSA at least 72 hours after a preceding negative culture in the two arms of treatment.
- To evaluate microbiological treatment failure as defined by positive sterile site culture for MSSA at least 14 days after randomisation in the two arms.
- To determine the number of patients with persistent and relapsing bacteremia in the two arms of treatment.
- To evaluate the number of patients with complicated bacteremia, defined by persistent bacteremia, endocarditis or metastatic emboli, prosthetic devices) in the two arms of treatment.
- To determine the length of stay in intensive care unit and in hospital in both arms of treatment.
- Duration of intravenous antibiotic treatment. Sub group analysis for patients at high risk (persistent bacteraemia, metastatic infection, unknown focus of bacteraemia, endocarditis, pneumonia).
Microbiological secondary endpoints:
- To determine emergency of fosfomycin-resistant strains during therapy in the arm of combination treatment.
- To evaluate operon agr functionality and its relationship with Minimum Inhibitory Concentration (MIC) changes to vancomycin (VAN) and daptomycin (DAP) and with biofilm production.
- To analyze VAN and DAP MIC as markers of complications during bacteraemia.
- To determine the "in vitro" cloxacillin plus fosfomycin combination synergy.
- To realize whole genome sequencing and its changes in patients with treatment failure.
Pharmacological secondary endpoints:
- To determine minimum and maximum concentration in steady state of fosfomycin and cloxacillin.
- To evaluate pharmacokinetic variability of these concentration.
- To study the association between PK parameters and efficacy.
Security secondary endpoints:
To evaluate the security of cloxacillin and fosfomycin combination compared with cloxacillin monotherapy.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Combination therapy group | Experimental | Drug: Combination therapy groupintravenous cloxacillin 2g/4h and fosfomycin 3 g/6h for the duration of 7 days treatment |
| Standard therapy group | Active comparator | Drug: Standard therapy groupintravenous cloxacillin 2g/4h for the duration of 7 days IV treatment |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- 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.
Key exclusion criteria (12 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Combination therapy groupAdult 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. | Drug | Combination therapy group |
| Standard therapy groupAdult 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. | Drug | Standard therapy group |
Primary outcome
Treatment success at day 7
Time frame: Day 7 after 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 negative blood cultures for S. aureus at day 7.
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 Test of Cure visit (TOC, 12 weeks after randomisation). Treatment success at TOC visit, defined by presence of all of the following: * Patient alive at TOC; * No isolation of MSSA in blood culture or in another sterile site from day 8 until TOC.
Results and safety
The study was stopped early (reason given: Data safety and monitoring board(DSMB) have been performed when half of sample size (SS)have been reached. Recruitment was slower than expected so SS was recalculated. After analysis of data, DSMB recommended to stop study.). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Apr 2022.
- Background: PubMed 26659121Bergin SP, Holland TL, Fowler VG Jr, Tong SYC. Bacteremia, Sepsis, and Infective Endocarditis Associated with Staphylococcus aureus. Curr Top Microbiol Immunol. 2017;409:263-296. doi: 10.1007/82_2015_5001.
- Background: PubMed 22491776van Hal SJ, Jensen SO, Vaska VL, Espedido BA, Paterson DL, Gosbell IB. Predictors of mortality in Staphylococcus aureus Bacteremia. Clin Microbiol Rev. 2012 Apr;25(2):362-86. doi: 10.1128/CMR.05022-11.
- Background: PubMed 23331461Gasch O, Camoez M, Dominguez MA, Padilla B, Pintado V, Almirante B, Molina J, Lopez-Medrano F, Ruiz E, Martinez JA, Bereciartua E, Rodriguez-Lopez F, Fernandez-Mazarrasa C, Goenaga MA, Benito N, Rodriguez-Bano J, Espejo E, Pujol M; REIPI/GEIH Study Groups. Predictive factors for mortality in patients with methicillin-resistant Staphylococcus aureus bloodstream infection: impact on outcome of host, microorganism and therapy. Clin Microbiol Infect. 2013 Nov;19(11):1049-57. doi: 10.1111/1469-0691.12108. Epub 2013 Jan 17.
- Background: PubMed 30949675Minejima E, Mai N, Bui N, Mert M, Mack WJ, She RC, Nieberg P, Spellberg B, Wong-Beringer A. Defining the Breakpoint Duration of Staphylococcus aureus Bacteremia Predictive of Poor Outcomes. Clin Infect Dis. 2020 Feb 3;70(4):566-573. doi: 10.1093/cid/ciz257.
- Background: PubMed 25937457Gudiol F, Aguado JM, Almirante B, Bouza E, Cercenado E, Dominguez MA, Gasch O, Lora-Tamayo J, Miro JM, Palomar M, Pascual A, Pericas JM, Pujol M, Rodriguez-Bano J, Shaw E, Soriano A, Valles J. Diagnosis and treatment of bacteremia and endocarditis due to Staphylococcus aureus. A clinical guideline from the Spanish Society of Clinical Microbiology and Infectious Diseases (SEIMC). Enferm Infecc Microbiol Clin. 2015 Nov;33(9):625.e1-625.e23. doi: 10.1016/j.eimc.2015.03.015. Epub 2015 May 1.
- Background: PubMed 29249276Thwaites GE, Scarborough M, Szubert A, Nsutebu E, Tilley R, Greig J, Wyllie SA, Wilson P, Auckland C, Cairns J, Ward D, Lal P, Guleri A, Jenkins N, Sutton J, Wiselka M, Armando GR, Graham C, Chadwick PR, Barlow G, Gordon NC, Young B, Meisner S, McWhinney P, Price DA, Harvey D, Nayar D, Jeyaratnam D, Planche T, Minton J, Hudson F, Hopkins S, Williams J, Torok ME, Llewelyn MJ, Edgeworth JD, Walker AS; United Kingdom Clinical Infection Research Group (UKCIRG). Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2018 Feb 17;391(10121):668-678. doi: 10.1016/S0140-6736(17)32456-X. Epub 2017 Dec 14.
- Background: PubMed 30615122Grillo S, Cuervo G, Carratala J, Grau I, Pallares N, Tebe C, Guillem Tio L, Murillo O, Ardanuy C, Dominguez MA, Shaw E, Gudiol C, Pujol M. Impact of beta-Lactam and Daptomycin Combination Therapy on Clinical Outcomes in Methicillin-susceptible Staphylococcus aureus Bacteremia: A Propensity Score-matched Analysis. Clin Infect Dis. 2019 Oct 15;69(9):1480-1488. doi: 10.1093/cid/ciz018.
- Background: PubMed 27956267Grabein B, Graninger W, Rodriguez Bano J, Dinh A, Liesenfeld DB. Intravenous fosfomycin-back to the future. Systematic review and meta-analysis of the clinical literature. Clin Microbiol Infect. 2017 Jun;23(6):363-372. doi: 10.1016/j.cmi.2016.12.005. Epub 2016 Dec 9.
- Background: PubMed 23295957Chan AW, Tetzlaff JM, Altman DG, Laupacis A, Gotzsche PC, Krleza-Jeric K, Hrobjartsson A, Mann H, Dickersin K, Berlin JA, Dore CJ, Parulekar WR, Summerskill WS, Groves T, Schulz KF, Sox HC, Rockhold FW, Rennie D, Moher D. SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med. 2013 Feb 5;158(3):200-7. doi: 10.7326/0003-4819-158-3-201302050-00583.
- Derived from this study: PubMed 37783969Grillo S, Pujol M, Miro JM, Lopez-Contreras J, Euba G, Gasch O, Boix-Palop L, Garcia-Pais MJ, Perez-Rodriguez MT, Gomez-Zorrilla S, Oriol I, Lopez-Cortes LE, Pedro-Botet ML, San-Juan R, Aguado JM, Gioia F, Iftimie S, Morata L, Jover-Saenz A, Garcia-Pardo G, Loeches B, Izquierdo-Cardenas A, Goikoetxea AJ, Gomila-Grange A, Dietl B, Berbel D, Videla S, Hereu P, Padulles A, Pallares N, Tebe C, Cuervo G, Carratala J; SAFO study group. Cloxacillin plus fosfomycin versus cloxacillin alone for methicillin-susceptible Staphylococcus aureus bacteremia: a randomized trial. Nat Med. 2023 Oct;29(10):2518-2525. doi: 10.1038/s41591-023-02569-0. Epub 2023 Oct 2.
- Derived from this study: PubMed 34353808Grillo S, Cuervo G, Carratala J, San-Juan R, Aguado JM, Morata L, Gomez-Zorrilla S, Lopez-Contreras J, Gasch O, Gomila-Grange A, Iftimie S, Garcia-Pardo G, Calbo E, Boix-Palop L, Oriol I, Jover-Saenz A, Lopez-Cortes LE, Euba G, Aguirregabiria M, Garcia-Pais MJ, Gioia F, Pano JR, Pedro-Botet ML, Benitez RM, Perez-Rodriguez MT, Meije Y, Loeches-Yague MB, Horna G, Berbel D, Dominguez MA, Padulles A, Cobo S, Hereu P, Videla S, Tebe C, Pallares N, Miro JM, Pujol M; SAFO study group and the Spanish Network for Research in Infectious Diseases (REIPI). 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 Staphylococcus aureus bacteraemia: study protocol for the SAFO trial. BMJ Open. 2021 Aug 5;11(8):e051208. doi: 10.1136/bmjopen-2021-051208.
- Individual participant dataSharing planned: Yes. Sharing of data generated by this project is an essential part of our proposed activities and will be carried out in several different ways. We would wish to make our results available both to the community of scientists interested in infectious diseases and the biology of Staphylococcus aureus to avoid unintentional duplication of research. The preliminary results will be presented at international and national infectious diseases conferences and will be published in peer-reviewed journals. The results will also be made available through press and social media communications. Any formal presentation or publication of data collected from this study will be considered as a joint publication by the participating investigators and will follow the recommendations of the ICMJE. Individual participant data that underlie the results, after deidentification will be available. Proposals should be directed to the corresponding author.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Miquel Pujol Rojo, MD, PhD principal investigator
Hospital Universitari Bellvitge
17 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Combination therapy group and Standard therapy group in people with Methicillin Susceptible Staphylococcus Aureus Septicemia, run by Miquel Pujol at 17 sites in Spain.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 21 Apr 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 17 sites in Spain. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Data safety and monitoring board(DSMB) have been performed when half of sample size (SS)have been reached. Recruitment was slower than expected so SS was recalculated. After analysis of data, DSMB recommended to stop study.). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Treatment success at day 7 (time frame: Day 7 after randomization.). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03959345, which also lists 11 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Apr 2022.