Clinical trial NCT03869437: RCT Cefiderocol vs BAT for Treatment of Gram Negative BSI
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Bloodstream Infections
Lead sponsor: The University of Queensland
Sponsor class: OTHER
Collaborators: name: Shionogi
First posted: 2019-03-11
Enrollment: 513
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. 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).
2. The blood stream infection fulfils the criteria as a hospital acquired or healthcare associated infection as per the following definitions:

   1. 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.
   2. Healthcare associated - Blood stream infection present at admission to hospital or within 48 hours of admission in patients that fulfil ANY of following criteria:

   i. Participant has an intravascular catheter/line that is the source of infection ii. Attended a hospital or haemodialysis clinic or received intravenous chemotherapy in the previous 30 days iii. were hospitalized in an acute care hospital for two or more days in the previous 90 days iv. resided in a nursing home or long-term care facility v. 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
3. No more than 48 hours has elapsed since the positive blood culture collection.
4. Participant is aged 18 years and over (21 in Singapore)
5. The participant or approved proxy is able to provide informed consent.

Exclusion Criteria:

1. Refractory shock or comorbid condition such that patient not expected to survive more than 7 days.
2. Participant with history of moderate to severe hypersensitivity reaction to a cephalosporin.
3. Participant with significant polymicrobial bacteraemia including a significant Gram-positive pathogen (that is, a Gram-positive skin contaminant in one set of blood cultures is not regarded as significant polymicrobial bacteraemia).
4. Where the bloodstream infection is thought to be related to a vascular catheter and the catheter is unable to be removed.
5. Treatment is not with the intent to cure the infection (that is, palliative care is an exclusion).
6. Known pregnancy or breast-feeding.
7. Participant is receiving peritoneal dialysis.
8. Participant previously randomised in this trial.

Primary outcomes:
measure: Mortality at 14 days
timeFrame: 14 days post date of randomisation
Secondary outcomes:
measure: Mortality post blood stream infection of each regimen at longer time points
timeFrame: 30 and 90 days, from day of randomisation or "day 1"
measure: Clinical and microbiological failure at day 14
timeFrame: Day 14, from day of randomisation or "day 1"
measure: Microbiological failure days 3 to 90 post randomisation
timeFrame: Day 3 through to day 90
measure: Colonisation or infection with methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), carbapenem-resistant Gram-negative bacilli or Candida bloodstream infection.
timeFrame: Day 3 through to day 90
measure: Clostridioides diﬃcile infection days 3 to 90 post randomisation.
timeFrame: Day 3 through to day 90
measure: Improvement in functional status at day 30 post randomisation compared to baseline.
timeFrame: Day 30, from day of randomisation or "day 1"
measure: Time to hospital discharge.
timeFrame: From day of randomisation or "day 1" through to day 90
measure: Treatment emergent SAEs (Serious Adverse Events)
timeFrame: From day of randomisation or "day 1" through to 5 days post end of study treatment.
Other outcomes:
Locations:
city: Sydney
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Brisbane
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Brisbane
country: Australia
facility: Royal Brisbane and Womens Hospital
state: Queensland
city: Brisbane
country: Australia
facility: The Prince Charles Hospital
state: Queensland
city: Melbourne
country: Australia
facility: Austin Hospital
state: Victoria
city: Kubang Kerian
country: Malaysia
facility: Universiti Sains Malaysia
state: Kelantan
city: Kuala Lumpur
country: Malaysia
facility: University of Malaya Medical Centre
city: Singapore
country: Singapore
facility: Changi General Hospital
city: Singapore
country: Singapore
facility: National University Hospital Singapore
city: Singapore
country: Singapore
facility: Singapore General Hospital
city: Singapore
country: Singapore
facility: Tan Tock Seng Hospital
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital
city: Taipei
country: Taiwan
facility: Tri-Service General Hospital
city: Taoyuan
country: Taiwan
facility: Chang Gung Memorial Hospital
city: Bangkok
country: Thailand
facility: Ramathibodi Hospital
city: Bangkok
country: Thailand
facility: Siriraj Hospital
city: Khon Kaen
country: Thailand
facility: Khon Kaen University
city: Istanbul
country: Turkey
facility: Istanbul Medipol Üniversitesi
Study officials:
affiliation: The Univeristy of Queensland
name: David Paterson, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Wright H, Harris PNA, Chatfield MD, Lye D, Henderson A, Harris-Brown T, Donaldson A, Paterson DL. Investigator-Driven Randomised Controlled Trial of Cefiderocol versus Standard Therapy for Healthcare-Associated and Hospital-Acquired Gram-negative Bloodstream Infection: Study protocol (the GAME CHANGER trial): study protocol for an open-label, randomised controlled trial. Trials. 2021 Dec 7;22(1):889. doi: 10.1186/s13063-021-05870-w.