RCT Cefiderocol vs BAT for Treatment of Gram Negative BSI (GAMECHANGER)

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)

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.

Study Overview

• Status: Completed
• Conditions: Bloodstream Infections
• Intervention / Treatment: Other: Best Available Therapy; Drug: Cefiderocol

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.

• Study Type: Interventional
• Enrollment (Actual): 513
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia
      • Westmead Hospital
  • Queensland
    • Brisbane, Queensland, Australia
      • Princess Alexandra Hospital
    • Brisbane, Queensland, Australia
      • The Prince Charles Hospital
    • Brisbane, Queensland, Australia
      • Royal Brisbane and Womens Hospital
  • Victoria
    • Melbourne, Victoria, Australia
      • Austin Hospital
• Malaysia
  • Kuala Lumpur, Malaysia
    • University of Malaya Medical Centre
  • Kelantan
    • Kubang Kerian, Kelantan, Malaysia
      • Universiti Sains Malaysia
• Singapore
  • Singapore, Singapore
    • Singapore General Hospital
  • Singapore, Singapore
    • Tan Tock Seng Hospital
  • Singapore, Singapore
    • Changi General Hospital
  • Singapore, Singapore
    • National University Hospital Singapore
• Taiwan
  • Taichung, Taiwan
    • Taichung Veterans General Hospital
  • Tainan, Taiwan
    • National Cheng Kung University Hospital
  • Taipei, Taiwan
    • Tri-Service General Hospital
  • Taoyuan, Taiwan
    • Chang Gung Memorial Hospital
• Thailand
  • Bangkok, Thailand
    • Siriraj Hospital
  • Bangkok, Thailand
    • Ramathibodi Hospital
  • Khon Kaen, Thailand
    • Khon Kaen University
• Turkey
  • Istanbul, Turkey
    • İstanbul Medipol Üniversitesi

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cefiderocol; Participants will receive Cefiderocol 2 grams administered intravenously over 3 hours, every 8 hours for a minium of 5 days and a maximun of 14 days.	Drug: Cefiderocol; 2 grams intravenously administered over 3 hours every 8 hours for a period of 5 to 14 days (dosage adjustment is necessary based on renal function).; Other Names: S-649266
Active Comparator: Best Available Therapy (BAT); BAT will be chosen by the investigator and intravenously administered per country-specific guidelines.	Other: Best Available Therapy; Standard of care was determined by the investigator

What is the study measuring?

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). If the primary objective meets the criteria for non-inferiority (with a margin of 10% for the difference in proportions), superiority will be examined.	14 days post date of randomisation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality post blood stream infection of each regimen at longer time points	If a date of death is recorded on or before our calculation of Day 14, the participant will be classed as dead, otherwise considered to be alive. Similar for Day 30. Where possible this rule will also be applied for Day 90 vital status. If the Day 90 follow-up actually occurred on day 85 to 89 and the participant was alive we will assume the participant was alive at day 90.	30 and 90 days, from day of randomisation or "day 1"
Clinical and microbiological failure at day 14	Defined as composite of: Death; Still in hospital and clinical failure, as defined byIf baseline SOFA ≥3, D(day)14 SOFA not improved by ≥30%If baseline SOFA <3, D14 SOFA worse; Microbiological failure (GNB Growth in blood of same species as index GNB from days 3-14) The SOFA score we will calculate is a slight modification of the original SOFA score. It will be used for ICU and non-ICU participants. The sole modification is that the respiratory component will be scored as in the modified SOFA: 0 (if SaO2/FiO2 >400); 1 (if SaO2/FiO2 315-400); 2 (if SaO2/FiO2 235-314); 3 (if SaO2/FiO2 150-234); 4 (if SaO2/FiO2 <150)	Day 14, from day of randomisation or "day 1"
Microbiological failure days 3 to 90 post randomisation	Defined as growth in blood cultures of the same GNB as the index blood culture(s), from day 3 up to day 90.	Day 3 through to day 90
Colonisation or infection with methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), carbapenem-resistant Gram-negative bacilli or Candida bloodstream infection.	Defined as the presence of MRSA, VRE or carbapenem-resistant Gram-negative bacilli (of a different species from primary BSI organism) on culture +/- molecular test of clinical samples or screening swabs, or Candida species grown in blood cultures from day 3 up to day 90.	Day 3 through to day 90
Clostridioides difficile infection days 3 to 90 post randomisation.	Defined as presence of a compatible clinical illness with a positive laboratory stool test for C. difficile (as per local diagnostic protocol / method).	Day 3 through to day 90
Improvement in functional status at day 30 post randomisation compared to baseline.	Functional status will be measured according to a score ranging from 0 (dead) to 7 (out of hospital, healthy, able to complete daily actvities). This score is based on the Functional Bloodstream Infection Score (FBIS) [McNamara et al. Clin Microbiol Infect. 2020 Feb;26(2):257.e1-257].	Day 30, from day of randomisation or "day 1"
Time to hospital discharge.	Defined as to the day of first discharge alive (e.g. Day 2 is the day after randomisation). However, if a participant dies in the 3 days following first hospital discharge, we will consider that participant as not having a discharge alive.	From day of randomisation or "day 1" through to day 90
Treatment emergent SAEs (Serious Adverse Events)	Defined as a serious adverse event possibly, probably or definitely related to the randomised drug treatment.	From day of randomisation or "day 1" through to 5 days post end of study treatment.

Collaborators and Investigators

• Sponsor: The University of Queensland
• Collaborators: Shionogi
• Investigators: Principal Investigator: David Paterson, Professor, The Univeristy of Queensland

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): October 28, 2019
• Primary Completion (Actual): November 13, 2023
• Study Completion (Actual): January 29, 2024

Study Registration Dates

• First Submitted: February 6, 2019
• First Submitted That Met QC Criteria: March 7, 2019
• First Posted (Actual): March 11, 2019

Study Record Updates

• Last Update Posted (Estimated): February 13, 2024
• Last Update Submitted That Met QC Criteria: February 11, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Infections
• Other Study ID Numbers: GAME CHANGER

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No