EaRly impAct theraPy With Ceftazidime-avibactam Via rapID Diagnostics

Phase 4

Recruiting

• Conditions: Hospital-acquired Pneumonia; Blood Stream Infections; Ventilator Associated Pneumonia; Healthcare Associated Infection; Carbapenem-Resistant Enterobacteriaceae Infection
• Interventions: Diagnostic Test: Rapid Diagnostics

• Registration Number: NCT05979545
• Lead Sponsor: National University of Singapore

Brief Summary

The goal of this clinical trial is to propose a seamless intervention linking rapid bacterial isolate identification and antibiotic resistance gene detection and targeted antibiotic prescription to minimise time between infection onset and appropriate treatment in patients with Pseudomonas aeruginosa or carbapenemase producing Enterobacterales infections. This is an investigator initiated trial.

The primary hypothesis is that these interventions will lead to improved clinical outcomes amongst patients with hospital-acquired bloodstream infection, hospital-acquired pneumonia or ventilator-associated pneumonia due to carbapenem non-susceptible Pseudomonas aeruginosa or Enterobacterales, compared to standard antibiotic susceptibility testing.

Patients will be randomised to either a control or intervention arm. Patients randomised to the intervention arm will have relevant specimens analysed by rapid microbiological diagnostics and will have early availability of ceftazidime-avibactam if appropriate. Patients randomised to the control arm, will have samples analysed by clinical microbiology laboratories using standard of care diagnostics. Antibiotics will be available to these patients as per usual institutional practice.

Detailed Description

This is an open-label, multinational, randomised, superiority trial. Patients will be randomised to control and intervention arms.

Patients randomised to the intervention arm, will have the BioFire Blood Culture Identification 2 Panel (BCID2) used for positive blood cultures and/or the BioFire FilmArray Pneumonia or Pneumonia plus Panel for respiratory tract specimens if having hospital-acquired pneumonia or ventilator-associated pneumonia. Standard of care diagnostics will also be used. Antibiotic guidelines will be provided to clinicians to aid interpretation of test results and treatment prescription. Ceftazidime-avibactam will be available for targeted use in patients with Pseudomonas aeruginosa or carbapenemase producing Enterobacterales.

Patients randomised to the control arm, will have samples analysed by clinical microbiology laboratories using standard of care diagnostics. Antibiotics will be available to these patients as per usual institutional practice.

The main population that will be recruited in the study will be hospitalised patients with bloodstream infections, hospital-acquired pneumonia or ventilator-associated pneumonia due to Pseudomonas aeruginosa or carbapenemase producing Enterobacterales treated with ceftazidime-avibactam, while the secondary population recruited will be those with multidrug resistant (MDR) Gram-negative bacilli. The enrolment criteria are based on the US Centers for Disease Control and Prevention criteria for healthcare-associated infection surveillance.

Clinical and mortality outcomes will be assessed for 60 days post infection. The infection causing bacterial isolates will be collected for genotypic description via whole genome sequencing. The total target sample size is 1900 participants in the main population over 20 study sites.

Study Timeline

• Study First Submitted: 2023-07-31
• Study First Submitted QC: 2023-07-31
• Study First Posted: 2023-08-07
• Study Start: 2023-12-12
• Status Verified: 2024-03
• Last Update Submitted: 2024-03-03
• Last Update Posted: 2024-03-06
• Primary Completion: 2026-10-31
• Study Completion: 2026-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 1900

Inclusion Criteria

1. patient developed clinical symptoms compatible with bloodstream infection, hospital-acquired or ventilator-associated pneumonia (hospital-acquired and ventilator-associated pneumonia should fulfil US CDC NHSN criteria) AND,
2. an appropriate specimen has been received by the participating laboratory - that is, a blood culture bottle showing Gram negative bacilli or a respiratory sample collected for clinical purposes showing Gram negative bacilli on Gram stain;

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Exclusion Criteria

1. Refractory shock or comorbid condition such that patient not expected to survive more than 48 hours; OR,
2. where the bloodstream infection is thought to be related to a vascular catheter and the catheter is unable to be removed; OR,
3. treatment is not with the intent to cure the infection; OR,
4. patient is incarcerated in a correctional facility; OR,
5. patients previously randomised in this trial within the last 60 days.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Intervention	Rapid Diagnostics	Samples from patients randomised to the intervention arm will undergo the BioFire FilmArray systems. Patients will be then administered with the study drug, ceftazidime-avibactam when Pseudomonas aeruginosa or carbapenemase producing Enterobacterales detected.

Primary Outcome Measures

Name	Time	Method
Composite endpoint of all-cause mortality and/or no improvement in SOFA score at Day 14 post index culture	14 days post index culture	Patient has died within 14 days from collection of index microbiology culture from any cause or SOFA score has not improved at Day 14 compared with baseline score on day of collection of index microbiology culture

Secondary Outcome Measures

Name	Time	Method
Clinical response	Day 7 and Day 14 post index culture	Clinical response at Day 7 and Day 14 post index culture, as determined retrospectively by an adjudication committee
Implementation cost-Health Economics	60 days since enrolment	Hospital and ICU level length of stay in the 60 days from randomisation
All-cause mortality	Day 14, Day 28, and Day 60 post index culture	All-cause mortality at Day 14, Day 28, and Day 60 post index culture
Composite outcome	Day 28 from index microbiology culture sample	Composite outcome measure defined by Desirability of Outcome Ranking (DOOR) at Day 28 from index culture sample
Functional outcome	Day 14, Day 28 and Day 60 from collection of index culture	Functional outcome at Day 14, Day 28 and Day 60 from collection of index culture

Trial Locations

Locations (4)

University Malaya Medical Centre; 🇲🇾 Kuala Lumpur, Malaysia

Taichung Veterans General Hospital; 🇨🇳 Taichung, Xitun District, Taiwan

Kaohsiung Medical University Hospital; 🇨🇳 Kaohsiung, Taiwan

Sunpasitthiprasong Hospital; 🇹🇭 Ubon Ratchathani, Thailand