Bloodstream Infection, Ventilator Associated Bacterial Pneumonia, Hospital Acquired Bacterial Pneumonia, Carbapenem Resistant Bacterial Infection, Multidrug Resistance
Conditions
Brief summary
TREAT-GNB is an innovative trial to expedite the evaluation of various antibiotic choices and treatment strategies for severe multidrug-resistant Gram-negative bacterial infections, specifically bloodstream and lower respiratory tract infections. This approach combines platform trial elements with adaptive clinical designs to streamline the evaluation of various treatment options and optimise resource utilisation. The overall aim of the TREAT-GNB platform trial is to identify interventions that improve survival in patients with severe infections due to Gram-negative bacteria. In the CR-GNB silo of TREAT-GNB, the primary objective is to quantify the effect on all-cause mortality at 28 days of a range of interventions in patients with bloodstream infections, ventilator-associated pneumonia, and hospital-acquired pneumonia caused by CR-GNB.
Interventions
DRUGColistin/Polymyxin B + Sulbactam
For carbapenem-resistant Acinetobacter infections in China, Malaysia, Thailand and Singapore
DRUGColistin/Polymyxin B + Tigecycline/Eravacycline
For carbapenem-resistant Acintobacter, carbapenem-resistant Enterobacterales infections in China, Malaysia, Thailand and Singapore
DRUGColistin/Polymyxin B + Meropenem
For carbapenem-resistant Pseudomonas aeruginosa, carbapenem-resistant Enterobacterales infections in China, Malaysia and Singapore
DRUGCeftazidime-avibactam + Sulbactam
For carbapenem-resistant Acinetobacter infections in China, Malaysia, Thailand, Singapore and Australia.
DRUGCeftazidime-avibactam + Fosfomycin
For carbapenem-resistant Pseudomonas aeruginosa, carbapenem-resistant Enterobacterales infections in Malaysia, Thailand and Singapore
For carbapenem-resistant Pseudomonas aeruginosa, carbapenem-resistant Enterobacterales infections in China, Malaysia, Thailand, Singapore, Europe and Australia.
For carbapenem-resistant Enterobacterales infections in China, Malaysia, Thailand, Singapore, Europe and Australia.
DRUGCeftazidime-avibactam + Colistin/Polymyxin B
For carbapenem-resistant Pseudomonas aeruginosa in China, Malaysia, Thailand, Singapore and Europe.
DRUGHigh-dose meropenem
For carbapenem-resistant Enterobacterales infection in Europe
DRUGMeropenem + Fosfomycin
For carbapenem-resistant Enterobacterales in Europe
For carbapenem-resistant Enterobacterales infection in Europe
DRUGCefiderocol
For carbapenem-resistant Pseudomonas aeruginosa, carbapenem-resistant Enterobacterales infections in Europe and Australia.
For carbapenem-resistant Pseudomonas aeruginosa in Europe and Australia.
DRUGCeftolozane-tazobactam + Meropenem
For carbapenem-resistant Pseudomonas aeruginosa in Europe.
Sponsors
The University of Queensland
European Clinical Research Alliance for Infectious Diseases (ECRAID)
National University of Singapore
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
The backbone domain is a multi-arm antibiotic treatment intervention with a personalisable randomisation list. It adopts the Personalised Randomised Controlled Trial (PRACTical) design, which allows each participant to be randomised between a personalised randomisation list of treatments that are suitable for them. Each patient randomisation list (personalised randomisation list) may be tailored based on their kidney function, pathogen genotype, pathogen antibiotic susceptibility and physician preference. Potential participants may be enrolled and randomised if they are eligible for at least two antibiotic options in the site randomisation list.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
A: Bloodstream infections a) Suitable for at least 2 antibiotic regimens in the site randomisation list 1. Growth of Gram-negative bacilli identified from blood culture(s) 2. Receiving or planning to receive intravenous antibiotics 3. Expected time from blood culture sampling to randomisation is ≤ 96 hours. OR B: Ventilator-associated pneumonia / hospital-acquired pneumonia a) Suitable for at least 2 antibiotic regimens in the site randomisation list b) Infection syndrome definitions\^( (US Centers for Disease Control and Prevention National Healthcare Safety Network)3: i) At least one of the following: 1. temperature \> 38 °C 2. white blood cell count ≥ 12,000 cells/mm3 (12 x 109/L, 12 x 103/µL) or ≤ 4,000 cells/mm3 (4 x 109/L, 4 x 103/µL) 3. altered mental status with no other causes in \> 70 years old; AND ii) Two or more chest imaging tests demonstrating at least one of the following: 1\) new and progressive OR progressive and persistent infiltrate 2) new and persistent OR progressive and persistent consolidation 3) new and persistent OR progressive and persistent cavitation; AND iii) At least two of the following: 1. new onset of purulent sputum, or change in character of sputum, or increased respiratory secretions, or increased in suctioning requirements 2. new onset or worsening tachypnoea or dyspnoea 3. rales or bronchial breath sounds 4. worsening gas exchange defined by oxygen desaturations (e.g., PaO2/FiO2 \< 240), increased oxygen requirements or increased ventilation demand. c) Hospital admission \> 48 hours d) Predominant growth of Gram-negative bacilli identified from respiratory tract specimen(s)\*; e) Receiving or planning to receive intravenous antibiotics f) Expected time from respiratory culture sampling to randomisation is ≤ 96 hours AND C: CR-GNB antibiotic backbone domain a) Gram-negative bacilli belonging to Acinetobacter baumannii-calcoaceticus complex, Pseudomonas aeruginosa or Enterobacterales b) Carbapenem resistance in isolate detected - i) Phenotypically via conventional microbiology testing: meropenem / imipenem / ertapenem resistance; OR ii) Genotypically via PCR or next generation sequencing: presence of genes associated with carbapenemase production (eg. blaNDM, blaKPC, blaIMP, blaIMI, blaVIM, blaOXA-48-like).
Exclusion criteria
1. Treating team deems enrolment in the study is not in the best interest of the patient 2. Patient is on end-of-life care 3. Patient is incarcerated in a correctional facility 4. Participation in any interventional study activities outlined in the TREAT-GNB study within the last 90 days 5. Pregnant women and children OR 6. Polymicrobial bloodstream infection
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical outcome | 28 days post-randomisation | 28-day all-cause mortality after randomisation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical outcome | 14, 60 and 90 days post-randomisation | All-cause mortality at 14, 60 and 90 days after randomisation |
| Health economics outcomes | 28 days post-randomisation | Length of continuous stay in the intensive care from the hospital which the participant was recruited within 28 days after randomisation |
Countries
Australia, China, Lebanon, Malaysia, Qatar, Saudi Arabia, Singapore, South Africa, Spain, Thailand, Turkey (Türkiye), United Arab Emirates
Contacts
Primary ContactYin Mo, MBBS, PhD
Outcome results
None listed