Clinical trial NCT07004049: Optimising TREATment for Severe Gram-Negative Bacterial Infections
Official title: TREAT-GNB [CR-GNB]
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Bloodstream Infection
Ventilator Associated Bacterial Pneumonia
Hospital Acquired Bacterial Pneumonia
Carbapenem Resistant Bacterial Infection
Multidrug Resistance
Lead sponsor: National University of Singapore
Sponsor class: OTHER
Collaborators: name: The University of Queensland
name: European Clinical Research Alliance for Infectious Diseases (ECRAID)
First posted: 2025-06-04
Enrollment: 600
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
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.
Primary purpose: TREATMENT

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.


Eligibility 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

Primary outcomes:
measure: Clinical outcome
timeFrame: 28 days post-randomisation
Secondary outcomes:
measure: Clinical outcome
timeFrame: 14, 60 and 90 days post-randomisation
measure: Clinical outcome
timeFrame: 90 days post-randomisation
measure: Clinical outcome
timeFrame: 28 days post-randomisation
measure: Clinical outcome
timeFrame: 90 days post-randomisation
measure: Clinical outcome
timeFrame: 28 days post-randomisation
measure: Clinical outcome
timeFrame: 28 days post-randomisation
measure: Clinical outcome
timeFrame: 28 and 90 days post-randomisation
measure: Clinical outcome
timeFrame: 28 days post-randomisation
measure: Clinical outcome
timeFrame: 14 days post-randomisation
measure: Clinical outcome
timeFrame: 14 days post-randomisation
measure: Clinical outcome
timeFrame: 14, 28 and 90 days post-randomisation
measure: Health economics outcomes
timeFrame: 28 days post-randomisation
measure: Health economics outcomes
timeFrame: 28 days post-randomisation
measure: Health economics outcomes
timeFrame: 28 days post-randomisation
measure: Health economics outcomes
timeFrame: 28 and 90 days post-randomisation
Other outcomes:
Locations:
city: Brisbane
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: Brisbane
country: Australia
facility: Princess Alexandra Hospital
city: Hangzhou
country: China
facility: The First Affiliated Hospital, Zhejiang University School of Medicine
city: Xi'an
country: China
facility: The Second Affiliated Hospital, Xi'an Jiang Tong University
city: Xuzhou
country: China
facility: Xuzhou First People's Hospital
city: Beirut
country: Lebanon
facility: American University of Beirut Medical Center
city: Kota Kinabalu
country: Malaysia
facility: Queen Elizabeth I
state: Sabah
city: Kota Kinabalu
country: Malaysia
facility: Queen Elizabeth II
state: Sabah
city: Miri
country: Malaysia
facility: Miri Sarawak Hospital
state: Sarawak
city: Ampang
country: Malaysia
facility: Ampang Hospital
state: Selangor
city: Sungai Buloh
country: Malaysia
facility: Hospital Sungai Buloh
state: Selangor
city: Doha
country: Qatar
facility: Hamad Medical Corporation
city: Riyadh
country: Saudi Arabia
facility: King Saud bin Abdulaziz University for Health Sciences
city: Singapore
country: Singapore
facility: National University Hospital
city: Johannesburg
country: South Africa
facility: Helen Joseph Hospital
city: Alicante
country: Spain
facility: Hospital General Universitario Dr. Balmis
city: Badajoz
country: Spain
facility: Hospital Universitario de Badajoz
city: Barakaldo
country: Spain
facility: Hospital Universitario de Cruces
city: Barcelona
country: Spain
facility: Hospital del Mar Barcelona
city: Barcelona
country: Spain
facility: Hospital Universitario Bellvitge
city: Córdoba
country: Spain
facility: Hospital Universitario Reina Sofía Córdoba
city: Granada
country: Spain
facility: Hospital Universitario San Cecilio
city: Granada
country: Spain
facility: Hospital Universitario Virgen de las Nieves
city: Madrid
country: Spain
facility: Hospital Clínico San Carlos
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañón
city: Madrid
country: Spain
facility: Hospital Universitario de La Princesa
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Málaga
country: Spain
facility: Hospital Regional Universitario de Málaga
city: Málaga
country: Spain
facility: Hospital Universitario Virgen de la Victoria
city: Pontevedra
country: Spain
facility: Hospital Álvaro Cunqueiro
city: San Sebastián
country: Spain
facility: Hospital Universitario de Donostia
city: Santander
country: Spain
facility: Hospital Universitario Marqués de Valdecilla
city: Seville
country: Spain
facility: Hospital Universitario Virgen Macarena
city: Seville
country: Spain
facility: Hospital Universitario Virgen de Valme
city: Seville
country: Spain
facility: Hospital Universitario Virgen del Rocío
city: Zaragoza
country: Spain
facility: Hospital Clínico Universitario Lozano Blesa
city: Bangkok
country: Thailand
facility: Phramongkutkloa Hospital
city: Bangkok
country: Thailand
facility: Rajavithi Hospital
city: Chiang Mai
country: Thailand
facility: Maharaj Nakorn Chiang Mai Hospital, Chiangmai University
city: Istanbul
country: Turkey
facility: İstanbul Medipol Üniversitesi
city: Dubai
country: United Arab Emirates
facility: Dubai Hospital
Study officials:
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.