Optimising TREATment for Severe Gram-Negative Bacterial Infections

Phase 4RecruitingNCT07004049

National University of Singapore600 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

600

Conditions

Bloodstream Infection Ventilator Associated Bacterial Pneumonia Hospital Acquired Bacterial Pneumonia

Interventions

Colistin/Polymyxin B + SulbactamDRUG

For carbapenem-resistant Acinetobacter infections in China, Malaysia, Thailand and Singapore

Colistin/Polymyxin B + Tigecycline/EravacyclineDRUG

For carbapenem-resistant Acintobacter, carbapenem-resistant Enterobacterales infections in China, Malaysia, Thailand and Singapore

Colistin/Polymyxin B + MeropenemDRUG

For carbapenem-resistant Pseudomonas aeruginosa, carbapenem-resistant Enterobacterales infections in China, Malaysia and Singapore

Ceftazidime-avibactam + SulbactamDRUG

For carbapenem-resistant Acinetobacter infections in China, Malaysia, Thailand, Singapore and Australia.

Ceftazidime-avibactam + FosfomycinDRUG

For carbapenem-resistant Pseudomonas aeruginosa, carbapenem-resistant Enterobacterales infections in Malaysia, Thailand and Singapore

Ceftazidime-avibactamDRUG

For carbapenem-resistant Pseudomonas aeruginosa, carbapenem-resistant Enterobacterales infections in China, Malaysia, Thailand, Singapore, Europe and Australia.

Ceftazidime-avibactam + AztreonamDRUG

For carbapenem-resistant Enterobacterales infections in China, Malaysia, Thailand, Singapore, Europe and Australia.

Ceftazidime-avibactam + Colistin/Polymyxin BDRUG

For carbapenem-resistant Pseudomonas aeruginosa in China, Malaysia, Thailand, Singapore and Europe.

High-dose meropenemDRUG

For carbapenem-resistant Enterobacterales infection in Europe

Meropenem + FosfomycinDRUG

For carbapenem-resistant Enterobacterales in Europe

Meropenem-vaborbactamDRUG

For carbapenem-resistant Enterobacterales infection in Europe

CefiderocolDRUG

For carbapenem-resistant Pseudomonas aeruginosa, carbapenem-resistant Enterobacterales infections in Europe and Australia.

Ceftolozane-tazobactamDRUG

For carbapenem-resistant Pseudomonas aeruginosa in Europe and Australia.

Ceftolozane-tazobactam + MeropenemDRUG

For carbapenem-resistant Pseudomonas aeruginosa in Europe.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (41)

Royal Brisbane and Women's Hospital

Brisbane, Queensland, Australia

NOT_YET_RECRUITING

Princess Alexandra Hospital

Brisbane, Australia

NOT_YET_RECRUITING

The First Affiliated Hospital, Zhejiang University School of Medicine

Hangzhou, China

NOT_YET_RECRUITING

The Second Affiliated Hospital, Xi'an Jiang Tong University

Xi'an, China

NOT_YET_RECRUITING

Outcomes

Primary Outcomes

Clinical outcome

28-day all-cause mortality after randomisation

Time frame: 28 days post-randomisation

Secondary Outcomes

Clinical outcome

All-cause mortality at 14, 60 and 90 days after randomisation

Time frame: 14, 60 and 90 days post-randomisation

Clinical outcome

Proportion of patients with infection relapse or reinfection within 90 days after randomisation

Time frame: 90 days post-randomisation

Clinical outcome

Length of mechanical ventilation in the intensive care within 28 days after randomisation

Time frame: 28 days post-randomisation

Clinical outcome

All cause re-admission into an acute care hospital within 90 days after randomisation

Time frame: 90 days post-randomisation

Clinical outcome

Proportion of patients that develop Kidney Disease Improving Global Outcomes (KDIGO) acute kidney injury within 28 days after randomisation

Time frame: 28 days post-randomisation

Clinical outcome

Proportion of patients that develop Clostridioides difficile or antibiotic-related diarrhea within 28 days after randomisation

Time frame: 28 days post-randomisation

Clinical outcome

Proportion of participants who have returned to their usual level of function at day 28 and 90 as determined by whether the modified functional bloodstream infection score (FBIS) remained the same or improved from baseline

Time frame: 28 and 90 days post-randomisation

Clinical outcome

Composite outcome measure defined by Desirability of Outcome Ranking (DOOR) at 28 days after randomisation

Time frame: 28 days post-randomisation

Clinical outcome

Sequential Organ Failure Assessment (SOFA) Score (0 to 24) improvement between baseline and 14 days after randomisation

Time frame: 14 days post-randomisation

Clinical outcome

Clinical response at 14 days after randomisation (Binary outcome: Improved or not improved, determined using 1. Temperature \< 38°C for 48hours, and 2. Systolic blood pressure \>90mmHg without inotropes)

Time frame: 14 days post-randomisation

Clinical outcome

Clinical cure at 14, 28 and 90 days after randomisation (binary outcome: cure or no cure, as defined in the INHALE trial for VAP/HAP and in Yahav et al. trial for BSI)

Time frame: 14, 28 and 90 days post-randomisation

Health economics outcomes

Length of continuous stay in the intensive care from the hospital which the participant was recruited within 28 days after randomisation

Time frame: 28 days post-randomisation

Health economics outcomes

Length of continuous stay in the hospital which the participant was recruited within 28 days after randomisation

Time frame: 28 days post-randomisation

Health economics outcomes

Days of antibiotic use within 28 days after randomisation

Time frame: 28 days post-randomisation

Health economics outcomes

Functional outcome at 28 and 90 days after randomisation (measured using EQ-5D-3L: https://euroqol.org/information-and-support/euroqol-instruments/eq-5d-3l/)

Time frame: 28 and 90 days post-randomisation

Optimising TREATment for Severe Gram-Negative Bacterial Infections

Overview

Conditions

Interventions

Eligibility

Locations (41)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts