Optimising TREATment for Severe Gram-Negative Bacterial Infections

Phase 4

Recruiting

• Conditions: Bloodstream Infection; Ventilator Associated Bacterial Pneumonia; Hospital Acquired Bacterial Pneumonia; Carbapenem Resistant Bacterial Infection; Multidrug Resistance
• Interventions: Drug: Ceftazidime-avibactam + Colistin/Polymyxin B; Drug: High-dose meropenem; Drug: Meropenem + Fosfomycin; Drug: Meropenem-vaborbactam; Drug: Ceftolozane-tazobactam; Drug: Ceftolozane-tazobactam + Meropenem; Drug: Cefiderocol; Drug: Colistin/Polymyxin B + Sulbactam; Drug: Colistin/Polymyxin B + Tigecycline/Eravacycline; Drug: Colistin/Polymyxin B + Meropenem; Drug: Ceftazidime-avibactam + Sulbactam; Drug: Ceftazidime-avibactam + Fosfomycin; Drug: Ceftazidime-avibactam; Drug: Ceftazidime-avibactam + Aztreonam

• Registration Number: NCT07004049
• Lead Sponsor: National University of Singapore

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2025-04-21
• Study First Submitted: 2025-04-29
• Status Verified: 2025-05
• Study First Submitted QC: 2025-05-26
• Last Update Submitted: 2025-05-26
• Study First Posted: 2025-06-04
• Last Update Posted: 2025-06-04
• Primary Completion: 2028-12-31
• Study Completion: 2028-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 600

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: FACTORIAL

Arm && Interventions

Group	Intervention	Description
Ceftazidime-avibactam + Colistin/Polymyxin B	Ceftazidime-avibactam + Colistin/Polymyxin B	-
High-dose meropenem	High-dose meropenem	-
Meropenem + Fosfomycin	Meropenem + Fosfomycin	-
Meropenem-vaborbactam	Meropenem-vaborbactam	-
Ceftolozane-tazobactam	Ceftolozane-tazobactam	-
Ceftolozane-tazobactam + Meropenem	Ceftolozane-tazobactam + Meropenem	-
Cefiderocol	Cefiderocol	-
Colistin/Polymyxin B + Sulbactam	Colistin/Polymyxin B + Sulbactam	-
Colistin/Polymyxin B + Tigecycline/Eravacycline	Colistin/Polymyxin B + Tigecycline/Eravacycline	-
Colistin/Polymyxin B + Meropenem	Colistin/Polymyxin B + Meropenem	-
Ceftazidime-avibactam + Sulbactam	Ceftazidime-avibactam + Sulbactam	-
Ceftazidime-avibactam + Fosfomycin	Ceftazidime-avibactam + Fosfomycin	-
Ceftazidime-avibactam	Ceftazidime-avibactam	-
Ceftazidime-avibactam + Aztreonam	Ceftazidime-avibactam + Aztreonam	-

Primary Outcome Measures

Name	Time	Method
Clinical outcome	28 days post-randomisation	28-day all-cause mortality after randomisation

Secondary Outcome Measures

Name	Time	Method
Clinical outcome	14, 28 and 90 days post-randomisation	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)
Health economics outcomes	28 and 90 days post-randomisation	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/)

Trial Locations

Locations (41)

Royal Brisbane and Women's Hospital; 🇦🇺 Brisbane, Queensland, Australia

Princess Alexandra Hospital; 🇦🇺 Brisbane, Australia

The First Affiliated Hospital, Zhejiang University School of Medicine; 🇨🇳 Hangzhou, China

The Second Affiliated Hospital, Xi'an Jiang Tong University; 🇨🇳 Xi'an, China

Xuzhou First People's Hospital; 🇨🇳 Xuzhou, China

American University of Beirut Medical Center; 🇱🇧 Beirut, Lebanon

Queen Elizabeth I; 🇲🇾 Kota Kinabalu, Sabah, Malaysia

Queen Elizabeth II; 🇲🇾 Kota Kinabalu, Sabah, Malaysia

Miri Sarawak Hospital; 🇲🇾 Miri, Sarawak, Malaysia

Ampang Hospital; 🇲🇾 Ampang, Selangor, Malaysia

Hospital Sungai Buloh; 🇲🇾 Sungai Buloh, Selangor, Malaysia

Hamad Medical Corporation; 🇶🇦 Doha, Qatar

King Saud bin Abdulaziz University for Health Sciences; 🇸🇦 Riyadh, Saudi Arabia

National University Hospital; 🇸🇬 Singapore, Singapore

Helen Joseph Hospital; 🇿🇦 Johannesburg, South Africa

Hospital General Universitario Dr. Balmis; 🇪🇸 Alicante, Spain

Hospital Universitario de Badajoz; 🇪🇸 Badajoz, Spain

Hospital Universitario de Cruces; 🇪🇸 Barakaldo, Spain

Hospital del Mar Barcelona; 🇪🇸 Barcelona, Spain

Hospital Universitario Bellvitge; 🇪🇸 Barcelona, Spain

Hospital Universitario Reina Sofía Córdoba; 🇪🇸 Córdoba, Spain

Hospital Universitario San Cecilio; 🇪🇸 Granada, Spain

Hospital Universitario Virgen de las Nieves; 🇪🇸 Granada, Spain

Hospital Clínico San Carlos; 🇪🇸 Madrid, Spain

Hospital General Universitario Gregorio Marañón; 🇪🇸 Madrid, Spain

Hospital Universitario de La Princesa; 🇪🇸 Madrid, Spain

Hospital Universitario La Paz; 🇪🇸 Madrid, Spain

Hospital Regional Universitario de Málaga; 🇪🇸 Málaga, Spain

Hospital Universitario Virgen de la Victoria; 🇪🇸 Málaga, Spain

Hospital Álvaro Cunqueiro; 🇪🇸 Pontevedra, Spain

Hospital Universitario de Donostia; 🇪🇸 San Sebastián, Spain

Hospital Universitario Marqués de Valdecilla; 🇪🇸 Santander, Spain

Hospital Universitario Virgen Macarena; 🇪🇸 Seville, Spain

Hospital Universitario Virgen de Valme; 🇪🇸 Seville, Spain

Hospital Universitario Virgen del Rocío; 🇪🇸 Seville, Spain

Hospital Clínico Universitario Lozano Blesa; 🇪🇸 Zaragoza, Spain

Phramongkutkloa Hospital; 🇹🇭 Bangkok, Thailand

Rajavithi Hospital; 🇹🇭 Bangkok, Thailand

Maharaj Nakorn Chiang Mai Hospital, Chiangmai University; 🇹🇭 Chiang Mai, Thailand

İstanbul Medipol Üniversitesi; 🇹🇷 Istanbul, Turkey

Dubai Hospital; 🇦🇪 Dubai, United Arab Emirates