EaRly impAct theraPy With Ceftazidime-avibactam Via rapID Diagnostics (RAPID)

EaRly impAct theraPy With Ceftazidime-avibactam Via rapID Diagnostics Versus Standard of Care Antibiotics and Diagnostics in Patients With Bloodstream Infection, Hospital-acquired Pneumonia or Ventilator-associated Pneumonia Due to Pseudomonas Aeruginosa or Carbapenemase Producing Enterobacterales (RAPID)

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.

Study Overview

• Status: Recruiting
• Conditions: Hospital-acquired Pneumonia; Ventilator Associated Pneumonia; Healthcare Associated Infection; Blood Stream Infections; Carbapenem-Resistant Enterobacteriaceae Infection
• Intervention / Treatment: Diagnostic test: Rapid Diagnostics

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 Type: Interventional
• Enrollment (Estimated): 1900
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Kithalakshmi Vignesvaran; Phone Number: 90300178; Email: kitha@nus.edu.sg

Study Locations

• Malaysia
  • Kuala Lumpur, Malaysia, 50603
    • Not yet recruiting
    • University Malaya Medical Centre
    • Contact: Norhabibah; Email: nhabibahmohd11@gmail.com
    • Principal Investigator: Helmi Sulaiman, Dr
    • Sub-Investigator: Ong Hang Cheng, Dr
• Taiwan
  • Kaohsiung, Taiwan
    • Not yet recruiting
    • Kaohsiung Medical University Hospital
    • Contact: Hannah Yan-Zhen Hsu; Email: hannah.hsu530@gmail.com
    • Principal Investigator: Po-Liang Lu, Prof
    • Sub-Investigator: Shang-yi Lin, Dr
    • Sub-Investigator: Ya-Ting Chang, Dr
  • Xitun District
    • Taichung, Xitun District, Taiwan, 1650
      • Recruiting
      • Taichung Veterans General Hospital
      • Contact: Ying-Lan Li; Email: yinglanli.vghtc@gmail.com
      • Principal Investigator: Po-Yu Liu, Dr
      • Sub-Investigator: Chien-Hao Tseng, Dr
• Thailand
  • Ubon Ratchathani, Thailand, 34000
    • Not yet recruiting
    • Sunpasitthiprasong Hospital
    • Contact: Sornsuda Setaphan, Ms; Email: Sornsuda@tropmedres.ac
    • Principal Investigator: Suwatthiya Kitsaran, Dr
    • Sub-Investigator: Chamnan Parinya, Dr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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;

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Intervention; 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.	Diagnostic test: Rapid Diagnostics; 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 plus PanelPneumonia Panel 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.; Other Names: BioFire FilmArray BCID2; BioFire FilmArray Pneumonia Plus Panel; BioFire FilmArray Pneumonia Panel
No Intervention: Control; Patients randomised to the control arm, will have samples analysed by clinical microbiology laboratories using standard of care diagnostics. Antibiotics treatment will be administered as per usual institutional practice from hospital supplies.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite endpoint of all-cause mortality and/or no improvement in SOFA score at Day 14 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	14 days post index culture

Secondary Outcome Measures

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Genomics studies	Genotype of the infection causing bacterial isolate, as available through whole genome sequencing	Day 0

Collaborators and Investigators

• Sponsor: National University of Singapore
• Collaborators: Pfizer; Biomerieux inc
• Investigators: Principal Investigator: David Paterson, Professor, National University of Singapore

Study record dates

Study Major Dates

• Study Start (Actual): December 12, 2023
• Primary Completion (Estimated): October 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: July 31, 2023
• First Submitted That Met QC Criteria: July 31, 2023
• First Posted (Actual): August 7, 2023

Study Record Updates

• Last Update Posted (Estimated): March 6, 2024
• Last Update Submitted That Met QC Criteria: March 3, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: CRE; BCID2; rapid diagnostics; ceftazidime-avibactam; AMR; MDR; ASP; carbapenemase producing Enterobacterales; hospital-acquired; PN Plus
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Disease Attributes; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Iatrogenic Disease; Sepsis; Infections; Communicable Diseases; Healthcare-Associated Pneumonia; Pneumonia; Pneumonia, Ventilator-Associated; Cross Infection; Enterobacteriaceae Infections
• Other Study ID Numbers: ADVANCE-ID 22-002; 23-0135 (Other Grant/Funding Number: PFIZER INC); 225457/Z/22/Z (Other Grant/Funding Number: Wellcome Trust); 20535 (Other Identifier: BioMerieux)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No