RCT Cefiderocol vs BAT for Treatment of Gram Negative BSI

Study Overview
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Brief Summary
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The purpose of this study is to determine whether a new antibiotic, Cefiderocol which works against a wide variety of gram negative bacteria, is equally effective as the antibiotics that are currently used as current standard of care.

Detailed Description
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Infections with antibiotic resistant bacteria cause a significant burden of disease worldwide. Bloodstream infections may arise from a variety of sources, are commonly encountered in clinical practice, and are associated with significant morbidity and mortality. Antibiotics that have activity against a broad spectrum of pathogens are commonly suggested in treatment guidelines to adequately cover bloodstream infections. Increasing rates of resistance to antibiotics commonly used for bloodstream infection are problematic and may lead to initial empiric therapy not having activity against the pathogen isolated. In patients with bloodstream infections and sepsis, delay until the receipt of effective therapy is associated with an increase in mortality . Increasing rates of antibiotic resistance in Gram-negative organisms due to the presence of extended spectrum beta lactamases (ESBL), hyperproduction of AmpC enzymes, carbapenemases and other mechanisms of resistance are identified in common hospital and healthcare associated pathogens including Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii. Uncommonly, Gram-negative organisms such as Klebsiella pneumoniae and, in tropical areas such as south-east Asia and northern Australia, Burkholderia pseudomallei can cause severe community-acquired pneumonia resulting in bloodstream infection. Cefiderocol (previously S-649266) is a novel siderophore cephalosporin antibiotic with a catechol moiety on the 3-position side chain. The catechol side chain enables ferric iron ion binding, and the resulting complex of cefiderocol and iron ions is actively transported into bacteria via ferric iron transporter systems with subsequent destruction of cell wall synthesis. Cefiderocol has been shown to be potent in vitro against a broad range of Gram-negative organisms, including carbapenem-resistant Enterobacteriaceae (CRE) and multi-drug resistant (MDR) P. aeruginosa and A. baumannii . This activity is considered to be due to not only efficient uptake via the active siderophore systems but also the high stability of cefiderocol against carbapenemase hydrolysis. Limited in vitro data suggests cefiderocol may have activity against B. pseudomallei . Recent clinical data has shown cefiderocol to be effective in the setting of complicated urinary tract infections , including patients with concomitant bacteremia. A study examining the use of cefiderocol in the setting of infections caused by carbapenem-resistant organisms is currently underway, as is a study of cefiderocol for hospital acquired pneumonia (ClinicalTrials.gov NCT02714595 & NCT03032380). Given the broad spectrum of activity against Gram-negative organisms, including those with resistant phenotypes, cefiderocol may be an ideal agent for empiric use in the setting of bloodstream infections acquired in the hospital or healthcare setting but as yet no clinical trial has examined this

Official Title
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Investigator Driven Randomized Controlled Trial of Cefiderocol Versus Standard Therapy for Healthcare Associated and Hospital Acquired Gram-negative Blood Stream Infection: Study Protocol (the GAME CHANGER Trial)

Conditions
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Bloodstream Infections

Intervention / Treatment
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* Drug: Cefiderocol
* Other: Best Available Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Bloodstream infection with a Gram-negative organism from at least one blood culture draw. Bacterial identification to species level will be performed using standard laboratory methods (e.g. MALDI-TOF) and susceptibility testing (e.g. Vitek2). The blood stream infection fulfils the criteria as a hospital acquired or healthcare associated infection as per the following definitions 1a Hospital acquired - Blood stream infection occurring greater than 48 hours after hospital admission, assessed as symptoms or signs of infection not present at time of hospital admission 1b Healthcare associated - Blood stream infection present at admission to hospital or within 48 hours of admission in patients that fulfil ANY of following criteria 2a Patient has an intravascular catheter/line that is the source of infection 2b Attended a hospital or haemodialysis clinic or received intravenous chemotherapy in the previous 30 days 2c were hospitalized in an acute care hospital for two or more days in the previous 90 days 2d resided in a nursing home or long-term care facility 2e received intravenous antibiotic therapy at home, wound care or specialized nursing care through a healthcare agency, family or friends; or had self-administered intravenous antibiotic medical therapy in the 30 days before the infection 1c OR patient meets the diagnosis of community acquired pneumonia where the Gram-negative organism isolated is considered or proven to be the causative agent of the pneumonia. No more than 36 hours has elapsed since the positive blood culture collection. Patient is aged 18 years and over (21 in Singapore) The patient or approved proxy is able to provide informed consent. Exclusion Criteria: Refractory shock or comorbid condition such that patient not expected to survive more than 7 days Patient with history of moderate to severe hypersensitivity reaction to a cephalosporin Patient with Gram-positive bacteraemia including a significant Gram-positive pathogen (a Gram-positive skin contaminant in one set of blood cultures may not regarded as significant). Where the bloodstream infection is thought to be related to a vascular catheter and the catheter is unable to be removed. Treatment is not with the intent to cure the infection (that is, palliative care is an exclusion). Known pregnancy or breast-feeding. Patient is receiving peritoneal dialysis

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cefiderocol<br>Participants will receive Cefiderocol 2 g administered intravenously over 3 hours, every 8 hours for up to 14 days | Drug: Cefiderocol<br>* 2 g intravenously over 3 hours every 8 hours for a period of 7 to 14 days (dosage adjustment is necessary based on renal function).<br>* Other names: S-649266;|
| Active Comparator: Best Available Therapy (BAT)<br>BAT will be chosen by the investigator and intravenously administered per country-specific guidelines | Other: Best Available Therapy<br>* Standard of care was determined by the investigator<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality at 14 days | To compare the 14-day mortality from day of randomisation of each regimen (cefiderocol versus standard of care therapy | 14 days post randomisation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality post blood stream infection of each regimen at longer time points | To compare the 30 and 90-day mortality from day of randomisation of each regimen (Cefiderocol versus standard of care therapy) | 30 & 90 days | 
| Functional outcome of patients treated with each regimen | Change of functional bacteremia outcome score from day of randomization to day 30. Functional Bacteremia Outcome Score (FBOS) 7 - Out of hospital; basically healthy; able to work or perform usual activities 6 - Out of hospital; moderate signs or symptoms of disease; unable to work or perform usual activities. 5 - Out of hospital; significant disability; requires a high level of care and assistance daily 4 - Hospitalised but not requiring ICU 3 - Hospitalised in ICU 2 - Accommodated in a long-term ventilator unit 1 - On palliative care in terminal phases of life (in hospital or at home) 0 - Dead | Day 30 | 
| Clinical and microbiologic success | Defined as survival PLUS resolution of fever and leucocytosis PLUS sterilisation of blood cultures | Day 14 | 
| Microbiologic resolution of infection | Defined as sterility of blood cultures collected on or before day 7 | on or before study day 7 | 
| Clostridium Difficile colitis | To compare the risk of Clostridium difficile colitis with each regime | 90 days post randomisation | 
| Microbiologic relapse | Defined as growth of a resistant Gram negative bacillus from any clinical specimen collected or a positive stool test (according to local lab diagnostic procedures) for C. difficile, from day 4 of study drug administration to day 30 and day 90 | 30 and 90 days post randomisation | 
| Total number of participants with any serious adverse events (SAEs), and the cumulative incidence of SAEs | To compare the safety profile between standard of care and Cefiderocol | At 30 and 90 days post randomisation | 
| Appropriateness of initial antibiotic therapy at enrolment (in vitro) | Defined as the organism isolated in blood culture testing susceptible to the antibiotic that the patient initially received. Susceptibility will be defined as per local laboratory protocol. | 14 days post randomisation | 
| Resource utilization required for the treatment of the study qualifying infection | To compare hospital length of stay (LOS), requirement of ICU admission and length of stay in ICU | 90 days post randomisation | 
| Risk of becoming colonised with a multidrug resistant organism | Colonisation with MRSA, VRE or a meropenem resistant Gram- negative organism (different from that in the original blood culture) during the 90 days from randomization | 90 days post randomisation |