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
试验速览
- 阶段
- 4 期
- 状态
- 终止
- 发起方
- 入组人数
- 215
- 试验地点
- 17
- 主要终点
- Treatment success at day 7
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
- •Acute SARS-CoV2 infection.
研究组 & 干预措施
Combination therapy group
intravenous cloxacillin 2g/4h and fosfomycin 3 g/6h for the duration of 7 days treatment
干预措施: Combination therapy group (Drug)
Standard therapy group
intravenous cloxacillin 2g/4h for the duration of 7 days IV treatment
干预措施: Standard therapy group (Drug)
结局指标
主要结局
Treatment success at day 7
时间窗: 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
时间窗: 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.
次要结局
未报告次要终点
研究者
Miquel Pujol
Principal Investigator, Medical Doctor
Institut d'Investigació Biomèdica de Bellvitge