Optimising TREATment for Severe Gram-Negative Bacterial Infections

Official title

TREAT-GNB [CR-GNB]

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.

Interventions

• Drug Colistin/Polymyxin B + Sulbactam
  For carbapenem-resistant Acinetobacter infections in China, Malaysia, Thailand and Singapore
• Drug Colistin/Polymyxin B + Tigecycline/Eravacycline
  For carbapenem-resistant Acintobacter, carbapenem-resistant Enterobacterales infections in China, Malaysia, Thailand and Singapore
• Drug Colistin/Polymyxin B + Meropenem
  For carbapenem-resistant Pseudomonas aeruginosa, carbapenem-resistant Enterobacterales infections in China, Malaysia and Singapore
• Drug Ceftazidime-avibactam + Sulbactam
  For carbapenem-resistant Acinetobacter infections in China, Malaysia, Thailand, Singapore and Australia.
• Drug Ceftazidime-avibactam + Fosfomycin
  For carbapenem-resistant Pseudomonas aeruginosa, carbapenem-resistant Enterobacterales infections in Malaysia, Thailand and Singapore
• Drug Ceftazidime-avibactam
  For carbapenem-resistant Pseudomonas aeruginosa, carbapenem-resistant Enterobacterales infections in China, Malaysia, Thailand, Singapore, Europe and Australia.
• Drug Ceftazidime-avibactam + Aztreonam
  For carbapenem-resistant Enterobacterales infections in China, Malaysia, Thailand, Singapore, Europe and Australia.
• Drug Ceftazidime-avibactam + Colistin/Polymyxin B
  For carbapenem-resistant Pseudomonas aeruginosa in China, Malaysia, Thailand, Singapore and Europe.
• Drug High-dose meropenem
  For carbapenem-resistant Enterobacterales infection in Europe
• Drug Meropenem + Fosfomycin
  For carbapenem-resistant Enterobacterales in Europe

Primary outcome measures

• Clinical outcome [Time frame: 28 days post-randomisation]

Secondary outcome measures (12)

• Clinical outcome [Time frame: 14, 60 and 90 days post-randomisation]
• Clinical outcome [Time frame: 90 days post-randomisation]
• Clinical outcome [Time frame: 28 days post-randomisation]
• Clinical outcome [Time frame: 90 days post-randomisation]
• Clinical outcome [Time frame: 28 days post-randomisation]
• Clinical outcome [Time frame: 28 days post-randomisation]
• Clinical outcome [Time frame: 28 and 90 days post-randomisation]
• Clinical outcome [Time frame: 28 days post-randomisation]
• Clinical outcome [Time frame: 14 days post-randomisation]
• Clinical outcome [Time frame: 14 days post-randomisation]
• Clinical outcome [Time frame: 14, 28 and 90 days post-randomisation]
• Health economics outcomes [Time frame: 28 days post-randomisation]

Eligibility criteria

Inclusion criteria

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.

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:

• 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:

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:

• 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

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

• 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

OR

• Polymicrobial bloodstream infection

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Factorial

Masking

Open label

Primary purpose

Treatment

Study locations

Spain · 21 centers

• Hospital General Universitario Dr. Balmis — Alicante
• Hospital Universitario de Badajoz — Badajoz
• Hospital Universitario de Cruces — Barakaldo
• Hospital del Mar Barcelona — Barcelona
• Hospital Universitario Bellvitge — Barcelona
• Hospital Universitario Reina Sofía Córdoba — Córdoba
• Hospital Universitario San Cecilio — Granada
• Hospital Universitario Virgen de las Nieves — Granada
• … and 13 more centers

Malaysia · 5 centers

• Queen Elizabeth I — Kota Kinabalu
• Queen Elizabeth II — Kota Kinabalu
• Miri Sarawak Hospital — Miri
• Ampang Hospital — Ampang
• Hospital Sungai Buloh — Sungai Buloh

China · 3 centers

• The First Affiliated Hospital, Zhejiang University School of Medicine — Hangzhou
• The Second Affiliated Hospital, Xi'an Jiang Tong University — Xi'an
• Xuzhou First People's Hospital — Xuzhou

Thailand · 3 centers

• Phramongkutkloa Hospital — Bangkok
• Rajavithi Hospital — Bangkok
• Maharaj Nakorn Chiang Mai Hospital, Chiangmai University — Chiang Mai

Australia · 2 centers

• Royal Brisbane and Women's Hospital — Brisbane
• Princess Alexandra Hospital — Brisbane

Lebanon · 1 center

• American University of Beirut Medical Center — Beirut

Qatar · 1 center

• Hamad Medical Corporation — Doha

Saudi Arabia · 1 center

• King Saud bin Abdulaziz University for Health Sciences — Riyadh

Singapore · 1 center

• National University Hospital — Singapore

South Africa · 1 center

• Helen Joseph Hospital — Johannesburg

Turkey (Türkiye) · 1 center

• İstanbul Medipol Üniversitesi — Istanbul

United Arab Emirates · 1 center

• Dubai Hospital — Dubai

Publications

• 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 PMID 31866328
• 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 No PMID 30535100
• 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
• 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
• 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

Identifiers

NCT: NCT07004049 · ADVANCE-ID 24003

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗