Optimising TREATment for Severe Gram-Negative Bacterial Infections (TREAT-GNB)

National University of Singapore

Status and phase: Enrolling; Phase 4

Conditions: Bloodstream Infection; Ventilator Associated Bacterial Pneumonia; Carbapenem Resistant Bacterial Infection; Hospital Acquired Bacterial Pneumonia; Multidrug Resistance

Treatments: Drug: Ceftazidime-avibactam; Drug: Cefiderocol; Drug: Meropenem + Fosfomycin; Drug: Meropenem-vaborbactam; Drug: Ceftazidime-avibactam + Sulbactam; Drug: Colistin/Polymyxin B + Sulbactam; Drug: Ceftazidime-avibactam + Aztreonam; Drug: Ceftazidime-avibactam + Colistin/Polymyxin B; Drug: Ceftolozane-tazobactam + Meropenem; Drug: Colistin/Polymyxin B + Meropenem; Drug: Ceftazidime-avibactam + Fosfomycin; Drug: High-dose meropenem; Drug: Ceftolozane-tazobactam; Drug: Colistin/Polymyxin B + Tigecycline/Eravacycline

Study type: Interventional

Funder types: Other

Identifiers

NCT07004049

ADVANCE-ID 24003

Details and patient eligibility

About

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.

Enrollment: 600 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Factorial Assignment

Masking: None (Open label)

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600 participants in 14 patient groups

Colistin/Polymyxin B + Sulbactam

Active Comparator group

Treatment:

Drug: Colistin/Polymyxin B + Sulbactam

Colistin/Polymyxin B + Tigecycline/Eravacycline

Active Comparator group

Treatment:

Drug: Colistin/Polymyxin B + Tigecycline/Eravacycline

Colistin/Polymyxin B + Meropenem

Active Comparator group

Treatment:

Drug: Colistin/Polymyxin B + Meropenem

Ceftazidime-avibactam + Sulbactam

Active Comparator group

Treatment:

Drug: Ceftazidime-avibactam + Sulbactam

Ceftazidime-avibactam + Fosfomycin

Active Comparator group

Treatment:

Drug: Ceftazidime-avibactam + Fosfomycin

Ceftazidime-avibactam

Active Comparator group

Treatment:

Drug: Ceftazidime-avibactam

Ceftazidime-avibactam + Aztreonam

Active Comparator group

Treatment:

Drug: Ceftazidime-avibactam + Aztreonam

Ceftazidime-avibactam + Colistin/Polymyxin B

Active Comparator group

Treatment:

Drug: Ceftazidime-avibactam + Colistin/Polymyxin B

High-dose meropenem

Active Comparator group

Treatment:

Drug: High-dose meropenem

Meropenem + Fosfomycin

Active Comparator group

Treatment:

Drug: Meropenem + Fosfomycin

Meropenem-vaborbactam

Active Comparator group

Treatment:

Drug: Meropenem-vaborbactam

Cefiderocol

Active Comparator group

Treatment:

Drug: Cefiderocol

Ceftolozane-tazobactam

Active Comparator group

Treatment:

Drug: Ceftolozane-tazobactam

Ceftolozane-tazobactam + Meropenem

Active Comparator group

Treatment:

Drug: Ceftolozane-tazobactam + Meropenem