Optimising TREATment for Severe Gram-Negative Bacterial Infections

NCT07004049 | Recruiting Phase 4

• 1 other identifier: ADVANCE-ID 24003
• Study Type: interventional
• Target: 600
• Locations: 12 countries
• Sites: 41

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.

Conditions

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

Outcome Measures

Primary Outcomes (1)

• Clinical outcome

  28-day all-cause mortality after randomisation

  28 days post-randomisation

Secondary Outcomes (15)

• Clinical outcome

  14, 60 and 90 days post-randomisation

• Clinical outcome

  90 days post-randomisation

• Clinical outcome

  28 days post-randomisation

• Clinical outcome

  90 days post-randomisation

• Clinical outcome

  28 days post-randomisation

Study Arms (14)

Colistin/Polymyxin B + Sulbactam

ACTIVE COMPARATOR

Drug: Colistin/Polymyxin B + Sulbactam

Colistin/Polymyxin B + Tigecycline/Eravacycline

ACTIVE COMPARATOR

Drug: Colistin/Polymyxin B + Tigecycline/Eravacycline

Colistin/Polymyxin B + Meropenem

ACTIVE COMPARATOR

Drug: Colistin/Polymyxin B + Meropenem

Ceftazidime-avibactam + Sulbactam

ACTIVE COMPARATOR

Drug: Ceftazidime-avibactam + Sulbactam

Ceftazidime-avibactam + Fosfomycin

ACTIVE COMPARATOR

Drug: Ceftazidime-avibactam + Fosfomycin

Ceftazidime-avibactam

ACTIVE COMPARATOR

Drug: Ceftazidime-avibactam

Ceftazidime-avibactam + Aztreonam

ACTIVE COMPARATOR

Drug: Ceftazidime-avibactam + Aztreonam

Ceftazidime-avibactam + Colistin/Polymyxin B

ACTIVE COMPARATOR

Drug: Ceftazidime-avibactam + Colistin/Polymyxin B

High-dose meropenem

ACTIVE COMPARATOR

Drug: High-dose meropenem

Meropenem + Fosfomycin

ACTIVE COMPARATOR

Drug: Meropenem + Fosfomycin

Meropenem-vaborbactam

ACTIVE COMPARATOR

Drug: Meropenem-vaborbactam

Cefiderocol

ACTIVE COMPARATOR

Drug: Cefiderocol

Ceftolozane-tazobactam

ACTIVE COMPARATOR

Drug: Ceftolozane-tazobactam

Ceftolozane-tazobactam + Meropenem

ACTIVE COMPARATOR

Drug: Ceftolozane-tazobactam + Meropenem

Interventions

Colistin/Polymyxin B + Sulbactam DRUG

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

Colistin/Polymyxin B + Sulbactam

Colistin/Polymyxin B + Tigecycline/Eravacycline DRUG

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

Colistin/Polymyxin B + Tigecycline/Eravacycline

Colistin/Polymyxin B + Meropenem DRUG

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

Colistin/Polymyxin B + Meropenem

Ceftazidime-avibactam + Sulbactam DRUG

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

Ceftazidime-avibactam + Sulbactam

Ceftazidime-avibactam + Fosfomycin DRUG

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

Ceftazidime-avibactam + Fosfomycin

Ceftazidime-avibactam DRUG

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

Ceftazidime-avibactam

Ceftazidime-avibactam + Aztreonam DRUG

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

Ceftazidime-avibactam + Aztreonam

Ceftazidime-avibactam + Colistin/Polymyxin B DRUG

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

Ceftazidime-avibactam + Colistin/Polymyxin B

High-dose meropenem DRUG

For carbapenem-resistant Enterobacterales infection in Europe

High-dose meropenem

Meropenem + Fosfomycin DRUG

For carbapenem-resistant Enterobacterales in Europe

Meropenem + Fosfomycin

Meropenem-vaborbactam DRUG

For carbapenem-resistant Enterobacterales infection in Europe

Meropenem-vaborbactam

Cefiderocol DRUG

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

Cefiderocol

Ceftolozane-tazobactam DRUG

For carbapenem-resistant Pseudomonas aeruginosa in Europe and Australia.

Ceftolozane-tazobactam

Ceftolozane-tazobactam + Meropenem DRUG

For carbapenem-resistant Pseudomonas aeruginosa in Europe.

Ceftolozane-tazobactam + Meropenem

Eligibility Criteria

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

You may qualify if:

• A: Bloodstream infections
• a) Suitable for at least 2 antibiotic regimens in the site randomisation list
• Growth of Gram-negative bacilli identified from blood culture(s)
• Receiving or planning to receive intravenous antibiotics
• Expected time from blood culture sampling to randomisation is ≤ 96 hours.
• 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:
• temperature \> 38 °C
• 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)
• 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:
• \) 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:
• new onset of purulent sputum, or change in character of sputum, or increased respiratory secretions, or increased in suctioning requirements
• new onset or worsening tachypnoea or dyspnoea
• rales or bronchial breath sounds
• 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

You may not qualify if:

• Treating team deems enrolment in the study is not in the best interest of the patient
• Patient is on end-of-life care
• Patient is incarcerated in a correctional facility
• Participation in any interventional study activities outlined in the TREAT-GNB study within the last 90 days
• Pregnant women and children
• Polymicrobial bloodstream infection

Sponsors & Collaborators

• National University of Singapore: lead
• The University of Queensland: collaborator
• European Clinical Research Alliance for Infectious Diseases (ECRAID): collaborator

Study Sites (41)

Royal Brisbane and Women's Hospital

Brisbane, Queensland, 4006, Australia

NOT YET RECRUITING

Princess Alexandra Hospital

Brisbane, Australia

NOT YET RECRUITING

The First Affiliated Hospital, Zhejiang University School of Medicine

Hangzhou, 310058, China

NOT YET RECRUITING

The Second Affiliated Hospital, Xi'an Jiang Tong University

Xi'an, 710006, China

NOT YET RECRUITING

Xuzhou First People's Hospital

Xuzhou, 221002, China

NOT YET RECRUITING

American University of Beirut Medical Center

Beirut, Lebanon

NOT YET RECRUITING

Queen Elizabeth I

Kota Kinabalu, Sabah, 88200, Malaysia

NOT YET RECRUITING

Queen Elizabeth II

Kota Kinabalu, Sabah, 88300, Malaysia

NOT YET RECRUITING

Miri Sarawak Hospital

Miri, Sarawak, 98000, Malaysia

NOT YET RECRUITING

Ampang Hospital

Ampang, Selangor, 68000, Malaysia

NOT YET RECRUITING

Hospital Sungai Buloh

Sungai Buloh, Selangor, 47000, Malaysia

NOT YET RECRUITING

Hamad Medical Corporation

Doha, Qatar

NOT YET RECRUITING

King Saud bin Abdulaziz University for Health Sciences

Riyadh, Saudi Arabia

NOT YET RECRUITING

National University Hospital

Singapore, Singapore, 119074, Singapore

RECRUITING

Helen Joseph Hospital

Johannesburg, South Africa

NOT YET RECRUITING

Hospital General Universitario Dr. Balmis

Alicante, Spain

NOT YET RECRUITING

Hospital Universitario de Badajoz

Badajoz, Spain

NOT YET RECRUITING

Hospital Universitario de Cruces

Barakaldo, Spain

NOT YET RECRUITING

Hospital del Mar Barcelona

Barcelona, 08003, Spain

NOT YET RECRUITING

Hospital Universitario Bellvitge

Barcelona, Spain

NOT YET RECRUITING

Hospital Universitario Reina Sofía Córdoba

Córdoba, Spain

NOT YET RECRUITING

Hospital Universitario San Cecilio

Granada, Spain

NOT YET RECRUITING

Hospital Universitario Virgen de las Nieves

Granada, Spain

NOT YET RECRUITING

Hospital Clínico San Carlos

Madrid, Spain

NOT YET RECRUITING

Hospital General Universitario Gregorio Marañón

Madrid, Spain

NOT YET RECRUITING

Hospital Universitario de La Princesa

Madrid, Spain

NOT YET RECRUITING

Hospital Universitario La Paz

Madrid, Spain

NOT YET RECRUITING

Hospital Regional Universitario de Málaga

Málaga, Spain

NOT YET RECRUITING

Hospital Universitario Virgen de la Victoria

Málaga, Spain

NOT YET RECRUITING

Hospital Álvaro Cunqueiro

Pontevedra, Spain

NOT YET RECRUITING

Hospital Universitario de Donostia

San Sebastián, Spain

NOT YET RECRUITING

Hospital Universitario Marqués de Valdecilla

Santander, Spain

NOT YET RECRUITING

Hospital Universitario Virgen Macarena

Seville, 41009, Spain

NOT YET RECRUITING

Hospital Universitario Virgen de Valme

Seville, Spain

NOT YET RECRUITING

Hospital Universitario Virgen del Rocío

Seville, Spain

NOT YET RECRUITING

Hospital Clínico Universitario Lozano Blesa

Zaragoza, Spain

NOT YET RECRUITING

Phramongkutkloa Hospital

Bangkok, 10400, Thailand

NOT YET RECRUITING

Rajavithi Hospital

Bangkok, 10400, Thailand

NOT YET RECRUITING

Maharaj Nakorn Chiang Mai Hospital, Chiangmai University

Chiang Mai, 50200, Thailand

NOT YET RECRUITING

İstanbul Medipol Üniversitesi

Istanbul, Turkey (Türkiye)

NOT YET RECRUITING

Dubai Hospital

Dubai, United Arab Emirates

NOT YET RECRUITING

Related Publications (5)

• Niederman MS, Alder J, Bassetti M, Boateng F, Cao B, Corkery K, Dhand R, Kaye KS, Lawatscheck R, McLeroth P, Nicolau DP, Wang C, Wood GC, Wunderink RG, Chastre J. Inhaled amikacin adjunctive to intravenous standard-of-care antibiotics in mechanically ventilated patients with Gram-negative pneumonia (INHALE): a double-blind, randomised, placebo-controlled, phase 3, superiority trial. Lancet Infect Dis. 2020 Mar;20(3):330-340. doi: 10.1016/S1473-3099(19)30574-2. Epub 2019 Dec 19.

  PMID: 31866328 BACKGROUND

• Yahav D, Franceschini E, Koppel F, Turjeman A, Babich T, Bitterman R, Neuberger A, Ghanem-Zoubi N, Santoro A, Eliakim-Raz N, Pertzov B, Steinmetz T, Stern A, Dickstein Y, Maroun E, Zayyad H, Bishara J, Alon D, Edel Y, Goldberg E, Venturelli C, Mussini C, Leibovici L, Paul M; Bacteremia Duration Study Group. Seven Versus 14 Days of Antibiotic Therapy for Uncomplicated Gram-negative Bacteremia: A Noninferiority Randomized Controlled Trial. Clin Infect Dis. 2019 Sep 13;69(7):1091-1098. doi: 10.1093/cid/ciy1054.

  PMID: 30535100 BACKGROUND

• McNamara JF, Harris PNA, Chatfield MD, Lorenc P, Paterson DL. Measuring patient-centred long-term outcome following a bloodstream infection: a pilot study. Clin Microbiol Infect. 2020 Feb;26(2):257.e1-257.e4. doi: 10.1016/j.cmi.2019.10.011. Epub 2019 Oct 23.

  PMID: 31654791 BACKGROUND

• Evans SR, Rubin D, Follmann D, Pennello G, Huskins WC, Powers JH, Schoenfeld D, Chuang-Stein C, Cosgrove SE, Fowler VG Jr, Lautenbach E, Chambers HF. Desirability of Outcome Ranking (DOOR) and Response Adjusted for Duration of Antibiotic Risk (RADAR). Clin Infect Dis. 2015 Sep 1;61(5):800-6. doi: 10.1093/cid/civ495. Epub 2015 Jun 25.

  PMID: 26113652 BACKGROUND

• Walker AS, White IR, Turner RM, Hsu LY, Yeo TW, White NJ, Sharland M, Thwaites GE. Personalised randomised controlled trial designs-a new paradigm to define optimal treatments for carbapenem-resistant infections. Lancet Infect Dis. 2021 Jun;21(6):e175-e181. doi: 10.1016/S1473-3099(20)30791-X. Epub 2021 Apr 21.

  PMID: 33894130 BACKGROUND

MeSH Terms

Conditions

Sepsis

Interventions

Colistin; Polymyxin B; Sulbactam; Meropenem; avibactam, ceftazidime drug combination; Fosfomycin; Aztreonam; meropenem and vaborbactam; Cefiderocol; ceftolozane, tazobactam drug combination

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Polymyxins; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Lipopeptides; Lipids; Antimicrobial Cationic Peptides; Peptides; Amino Acids, Peptides, and Proteins; Antimicrobial Peptides; Pore Forming Cytotoxic Proteins; Membrane Proteins; Proteins; Penicillins; beta-Lactams; Lactams; Amides; Organic Chemicals; Sulfur Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Thienamycins; Carbapenems; Organophosphonates; Organophosphorus Compounds; Monobactams; Heterocyclic Compounds, 1-Ring; Cephalosporins; Thiazines

Central Study Contacts

Yin Mo, MBBS, PhD

CONTACT

+65 65164988; mdcmy@nus.edu.sg

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Consultant / Adjunct Assistant Professor

Model Details: 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.

Study Record Dates

• First Submitted: April 29, 2025
• First Posted: June 4, 2025
• Study Start: April 21, 2025
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): December 31, 2028
• Last Updated: June 4, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will share

Locations

TH (3); TU (1); CN (3); ZA (1); AU (2); ES (21); SA (1); AE (1); QA (1); LE (1); MY (5); SG (1)