RCT Cefiderocol vs BAT for Treatment of Gram Negative BSI

NCT03869437 | Completed Phase 2 DMC

• 1 other identifier: GAME CHANGER
• Study Type: interventional
• Target: 513
• Locations: 6 countries
• Sites: 19

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.

Conditions

Bloodstream Infections

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (8)

• Mortality post blood stream infection of each regimen at longer time points

  30 and 90 days, from day of randomisation or "day 1"

• Clinical and microbiological failure at day 14

  Day 14, from day of randomisation or "day 1"

• Microbiological failure days 3 to 90 post randomisation

  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.

  Day 3 through to day 90

• Clostridioides difficile infection days 3 to 90 post randomisation.

  Day 3 through to day 90

Study Arms (2)

Cefiderocol

EXPERIMENTAL

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

Best Available Therapy (BAT)

ACTIVE COMPARATOR

BAT will be chosen by the investigator and intravenously administered per country-specific guidelines.

Other: Best Available Therapy

Interventions

Cefiderocol DRUG

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).

Also known as: S-649266

Cefiderocol

Best Available Therapy OTHER

Standard of care was determined by the investigator

Best Available Therapy (BAT)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• 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.
• 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
• No more than 48 hours has elapsed since the positive blood culture collection.
• Participant is aged 18 years and over (21 in Singapore)
• The participant or approved proxy is able to provide informed consent.

You may not qualify if:

• Refractory shock or comorbid condition such that patient not expected to survive more than 7 days.
• Participant with history of moderate to severe hypersensitivity reaction to a cephalosporin.
• 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).
• Where the bloodstream infection is thought to be related to a vascular catheter and the catheter is unable to be removed.
• Known pregnancy or breast-feeding.
• Participant is receiving peritoneal dialysis.
• Participant previously randomised in this trial.

Sponsors & Collaborators

• The University of Queensland: lead
• Shionogi: collaborator

Study Sites (19)

Westmead Hospital

Sydney, New South Wales, Australia

Location

Princess Alexandra Hospital

Brisbane, Queensland, Australia

Location

Royal Brisbane and Womens Hospital

Brisbane, Queensland, Australia

Location

The Prince Charles Hospital

Brisbane, Queensland, Australia

Location

Austin Hospital

Melbourne, Victoria, Australia

Location

Universiti Sains Malaysia

Kubang Kerian, Kelantan, Malaysia

Location

University of Malaya Medical Centre

Kuala Lumpur, Malaysia

Location

Changi General Hospital

Singapore, Singapore

Location

National University Hospital Singapore

Singapore, Singapore

Location

Singapore General Hospital

Singapore, Singapore

Location

Tan Tock Seng Hospital

Singapore, Singapore

Location

Taichung Veterans General Hospital

Taichung, Taiwan

Location

National Cheng Kung University Hospital

Tainan, Taiwan

Location

Tri-Service General Hospital

Taipei, Taiwan

Location

Chang Gung Memorial Hospital

Taoyuan District, Taiwan

Location

Ramathibodi Hospital

Bangkok, Thailand

Location

Siriraj Hospital

Bangkok, Thailand

Location

Khon Kaen University

Khon Kaen, Thailand

Location

Istanbul Medipol Üniversitesi

Istanbul, Turkey (Türkiye)

Location

Related Publications (2)

• Paterson DL, Sulaiman H, Liu PY, Chatfield MD, Yilmaz M, Salmuna ZN, Mazlan MZ, Anunnatsiri S, Sirijatuphat R, Chotiprasitsakul D, Lye DC, Somani J, Kalimuddin S, Aslan AT, Thamlikitkul V, Lee YT, Yang YS, Lin YT, Ramli WNW, Tseng CH, Archuleta S, Chan YFZ, Forde BM, Wright H, Stewart AG, Ramsay KA, Ling W, Rossi V, Harris-Brown TM, Harris PNA; GAME CHANGER Trial Investigators. Cefiderocol versus standard therapy for hospital-acquired and health-care-associated Gram-negative bacterial bloodstream infection (the GAME CHANGER trial): an open-label, parallel-group, randomised trial. Lancet Infect Dis. 2026 Feb;26(2):148-159. doi: 10.1016/S1473-3099(25)00469-4. Epub 2025 Oct 6.

  PMID: 41067237 DERIVED

• 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.

  PMID: 34876196 DERIVED

MeSH Terms

Conditions

Sepsis

Interventions

Cefiderocol

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Cephalosporins; beta-Lactams; Lactams; Amides; Organic Chemicals; Thiazines; Sulfur Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• David Paterson, Professor

  The Univeristy of Queensland

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 6, 2019
• First Posted: March 11, 2019
• Study Start: October 28, 2019
• Primary Completion: November 13, 2023
• Study Completion: January 29, 2024
• Last Updated: February 13, 2024

Record last verified: 2024-01

Locations

TW (4); MY (2); TH (3); SG (4); AU (5); TU (1)