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Ceftazidime-Avibactam Use in Critically Ill Patients With Carbapenem-Resistant Enterobacteriaceae Infections (AVI-ICU)

Primary Purpose

Carbapenem-Resistant Enterobacteriaceae Infection

Status
Recruiting
Phase
Phase 3
Locations
Saudi Arabia
Study Type
Interventional
Intervention
Ceftazidime-avibactam
Colistin
Sponsored by
King Faisal Specialist Hospital & Research Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Carbapenem-Resistant Enterobacteriaceae Infection focused on measuring Carbapenem-Resistant Enterobacteriaceae, Critically ill, Ceftazidime-avibactam, Colistin

Eligibility Criteria

18 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Patients aged ≥ 18 years.
  2. Admitted to an intensive care unit (ICU).
  3. Patients with hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP), complicated urinary tract infection (cUTI), bacteremia, complicated intraabdominal infection (cIAI), and complicated skin and soft tissue infection (cSSTI).
  4. Confirmed infection with CRE, based on a culture and sensitivity obtained within the past 72 hours of study enrollment.
  5. Suspected CRE infection according to one of the following: (1) positive Xpert Carba-R test screening for blaKPC or blaOXA-48 or blaNDM or blaVIM or blaIMI assessed on the admission to the ICU, (2) positive culture for CRE obtained within 3 months from time of enrollment.

Exclusion Criteria:

  1. Acute Physiology and Chronic Health Evaluation II (APACHE II) score more than 30
  2. known significant hypersensitivity reaction to beta-lactam antibiotics or colistin
  3. Positive culture for Stenotrophomonas maltophilia or Acinetobacter baumannii within the current hospitalization.
  4. Patients received the study intervention or control for more than 24 hours before the intended randomization.
  5. Patient/substitute decision-maker or caring physician's refusal to enroll in the study.
  6. Patient with concomitant suspected or confirmed meningitis.
  7. Pregnancy.
  8. Cystic fibrosis.
  9. Patients with Do Not Attempt to Resuscitate (DNAR) code status.
  10. Prior knowledge that the index CRE pathogen was resistant to colistin (MIC >2 μg/ml) or ceftazidime-avibactam (MIC > 8 μg/ml) before randomization.
  11. Objective clinical evidence for any of the following infections that necessitate study therapy for >14 days: endovascular infection, including endocarditis, osteomyelitis, prosthetic joint infection, meningitis, and/or other central nervous system infections

Sites / Locations

  • King Faisal Specialist Hospital & Research CentreRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Ceftazidime-avibactam

Colistin

Arm Description

Ceftazidime-avibactam 2.5 grams intravenous (IV) every 8 hours infused over two hours for a duration of 7-14 days, with dose adjustment for renal impairment according to the FDA prescribing information. Patients who have a positive Xpert Carb-R screening test or culture for CRE with metallo-beta-lactamases will receive aztreonam added to ceftazidime-avibactam.

Colistin (9-million-unit loading dose IV followed with 9 million units IV daily divided into 3 doses), for 7 to 14 days. Patients with renal impairment will receive antibiotics with adjusted doses based on their glomerular filtration rate or the use and type of renal replacement therapy according to the 2019 International Consensus Guidelines for the Optimal Use of the Polymyxins.

Outcomes

Primary Outcome Measures

28-day mortality
Death

Secondary Outcome Measures

14-day mortality
Death
Number of patients with clinical success at end of therapy (EOT) at day 7-14 from randomization and test of cure (TOC) 7 days after completion of treatment
Defined as: 1- Alive, fever or hypothermia resolution, WBC counts normalization, hemodynamic stability with MAP ≥65 mmHg without vasopressors support. For HAP or VAP: 1+ improving respiratory status including improving PaO2/FiO2 ratio from baseline, decreasing FiO2 and PEEP or extubation or source control for empyema. For bloodstream infection: 1+ documented two negative blood cultures with source removal if applicable. For complicated intra-abdominal infection: 1+ resolution or decreasing size of intra-abdominal collections with source control if applicable. For complicated skin and soft tissue infection: 1+ resolution of signs and symptoms plus surgical drainage or debridement if applicable. For complicated urinary tract infection: 1+ resolution of signs and symptoms and source removal if applicable.
Number of patients with microbiological response at the EOT at days 7-14 from randomization and TOC 7 days after completion of treatment
Defined as: Eradication (successful microbiological response): Baseline pathogen no longer present in the culture(s) that indicated the use of study drugs. Presumed eradication (successful microbiological response): Patient deemed a clinical cure as assessed by the adjudication committee at EOT and TOC, and repeat culture that indicated enrollment in the study is not available. Persistence (failure of microbiological response): Presence of baseline pathogen in the culture that indicated the use of study drugs. Presumed persistence (failure of microbiological response): Patients deemed a clinical failure as assessed by the adjudication committee at EOT and TOC, and specimen is not available. Indeterminate: Any culture that cannot be classified into one of the above categories, or the patient was an indeterminate clinical response and no cultures were taken.
Time to weaning from mechanical ventilation at day 28
Number of days not receiving mechanical ventilation
Requirement for renal replacement therapy at day 28
New start of renal replacement therapy
Intensive care unit (ICU) length of stay, censored at 28 days
Duration of stay inside the ICU
Days alive and out of the ICU, censored at 28 days
Number of days alive and outside the ICU
Drug-related adverse events
Acute kidney injury, seizures, leukopenia, thrombocytopenia, allergic reaction, diarrhea, clostridium difficile infection.

Full Information

First Posted
February 17, 2022
Last Updated
June 20, 2022
Sponsor
King Faisal Specialist Hospital & Research Center
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1. Study Identification

Unique Protocol Identification Number
NCT05258851
Brief Title
Ceftazidime-Avibactam Use in Critically Ill Patients With Carbapenem-Resistant Enterobacteriaceae Infections
Acronym
AVI-ICU
Official Title
Ceftazidime-Avibactam Versus Colistin in Critically Ill Patients With Carbapenem-Resistant Enterobacteriaceae Infections (AVI-ICU): A Non-Inferiority Randomized Clinical Trial
Study Type
Interventional

2. Study Status

Record Verification Date
June 2022
Overall Recruitment Status
Recruiting
Study Start Date
June 1, 2022 (Actual)
Primary Completion Date
June 30, 2023 (Anticipated)
Study Completion Date
August 30, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
King Faisal Specialist Hospital & Research Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Carbapenem-Resistant Enterobacteriaceae (CRE) infections are a growing national and international challenge in healthcare settings. This is not only due to the rapid spread of resistance and paucity of options of targeted-antimicrobial agents, but also owing to the high mortality of patients infected with CRE reaching up to 50% as per the Centers of Disease Control and Prevention. Colistin-based combination regimens have been the mainstay for treating CRE-related infections. Ceftazidime-avibactam is a beta-lactamase inhibitor combination, a novel antibiotic, which recently showed a better clinical and microbiological cure against CRE along with the potential to reduce mortality and nephrotoxicity in comparison to colistin-based regimens in observational studies. However, randomized clinical trials are lacking. This non-inferiority randomized controlled study aims to assess the efficacy and safety of ceftazidime-avibactam-based regimens in critically ill patients with CRE infections in comparison to colistin-based regimens.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Carbapenem-Resistant Enterobacteriaceae Infection
Keywords
Carbapenem-Resistant Enterobacteriaceae, Critically ill, Ceftazidime-avibactam, Colistin

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Model Description
Open-label, multicenter, parallel-group, stratified, non-inferiority randomized controlled trial
Masking
Outcomes Assessor
Allocation
Randomized
Enrollment
168 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Ceftazidime-avibactam
Arm Type
Experimental
Arm Description
Ceftazidime-avibactam 2.5 grams intravenous (IV) every 8 hours infused over two hours for a duration of 7-14 days, with dose adjustment for renal impairment according to the FDA prescribing information. Patients who have a positive Xpert Carb-R screening test or culture for CRE with metallo-beta-lactamases will receive aztreonam added to ceftazidime-avibactam.
Arm Title
Colistin
Arm Type
Active Comparator
Arm Description
Colistin (9-million-unit loading dose IV followed with 9 million units IV daily divided into 3 doses), for 7 to 14 days. Patients with renal impairment will receive antibiotics with adjusted doses based on their glomerular filtration rate or the use and type of renal replacement therapy according to the 2019 International Consensus Guidelines for the Optimal Use of the Polymyxins.
Intervention Type
Drug
Intervention Name(s)
Ceftazidime-avibactam
Intervention Description
Experimental
Intervention Type
Drug
Intervention Name(s)
Colistin
Intervention Description
Control
Primary Outcome Measure Information:
Title
28-day mortality
Description
Death
Time Frame
28 days from randomization
Secondary Outcome Measure Information:
Title
14-day mortality
Description
Death
Time Frame
14 days from randomization
Title
Number of patients with clinical success at end of therapy (EOT) at day 7-14 from randomization and test of cure (TOC) 7 days after completion of treatment
Description
Defined as: 1- Alive, fever or hypothermia resolution, WBC counts normalization, hemodynamic stability with MAP ≥65 mmHg without vasopressors support. For HAP or VAP: 1+ improving respiratory status including improving PaO2/FiO2 ratio from baseline, decreasing FiO2 and PEEP or extubation or source control for empyema. For bloodstream infection: 1+ documented two negative blood cultures with source removal if applicable. For complicated intra-abdominal infection: 1+ resolution or decreasing size of intra-abdominal collections with source control if applicable. For complicated skin and soft tissue infection: 1+ resolution of signs and symptoms plus surgical drainage or debridement if applicable. For complicated urinary tract infection: 1+ resolution of signs and symptoms and source removal if applicable.
Time Frame
EOT at 7-14 days from randomization and TOC 7 days after completion of treatment
Title
Number of patients with microbiological response at the EOT at days 7-14 from randomization and TOC 7 days after completion of treatment
Description
Defined as: Eradication (successful microbiological response): Baseline pathogen no longer present in the culture(s) that indicated the use of study drugs. Presumed eradication (successful microbiological response): Patient deemed a clinical cure as assessed by the adjudication committee at EOT and TOC, and repeat culture that indicated enrollment in the study is not available. Persistence (failure of microbiological response): Presence of baseline pathogen in the culture that indicated the use of study drugs. Presumed persistence (failure of microbiological response): Patients deemed a clinical failure as assessed by the adjudication committee at EOT and TOC, and specimen is not available. Indeterminate: Any culture that cannot be classified into one of the above categories, or the patient was an indeterminate clinical response and no cultures were taken.
Time Frame
EOT at 7-14 days from randomization and TOC 7 days after completion of treatment
Title
Time to weaning from mechanical ventilation at day 28
Description
Number of days not receiving mechanical ventilation
Time Frame
28 days from randomization
Title
Requirement for renal replacement therapy at day 28
Description
New start of renal replacement therapy
Time Frame
28 days from randomization
Title
Intensive care unit (ICU) length of stay, censored at 28 days
Description
Duration of stay inside the ICU
Time Frame
28 days from randomization
Title
Days alive and out of the ICU, censored at 28 days
Description
Number of days alive and outside the ICU
Time Frame
28 days from randomization
Title
Drug-related adverse events
Description
Acute kidney injury, seizures, leukopenia, thrombocytopenia, allergic reaction, diarrhea, clostridium difficile infection.
Time Frame
28 days from randomization

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients aged ≥ 18 years. Admitted to an intensive care unit (ICU). Patients with hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP), complicated urinary tract infection (cUTI), bacteremia, complicated intraabdominal infection (cIAI), and complicated skin and soft tissue infection (cSSTI). Confirmed infection with CRE, based on a culture and sensitivity obtained within the past 72 hours of study enrollment. Suspected CRE infection according to one of the following: (1) positive Xpert Carba-R test screening for blaKPC or blaOXA-48 or blaNDM or blaVIM or blaIMI assessed on the admission to the ICU, (2) positive culture for CRE obtained within 3 months from time of enrollment. Exclusion Criteria: Acute Physiology and Chronic Health Evaluation II (APACHE II) score more than 30 known significant hypersensitivity reaction to beta-lactam antibiotics or colistin Positive culture for Stenotrophomonas maltophilia or Acinetobacter baumannii within the current hospitalization. Patients received the study intervention or control for more than 24 hours before the intended randomization. Patient/substitute decision-maker or caring physician's refusal to enroll in the study. Patient with concomitant suspected or confirmed meningitis. Pregnancy. Cystic fibrosis. Patients with Do Not Attempt to Resuscitate (DNAR) code status. Prior knowledge that the index CRE pathogen was resistant to colistin (MIC >2 μg/ml) or ceftazidime-avibactam (MIC > 8 μg/ml) before randomization. Objective clinical evidence for any of the following infections that necessitate study therapy for >14 days: endovascular infection, including endocarditis, osteomyelitis, prosthetic joint infection, meningitis, and/or other central nervous system infections
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Zainab Al Duhailib
Phone
+966-11-4647272
Ext
42817
Email
zalduhailib65@kfshrc.edu.sa
First Name & Middle Initial & Last Name or Official Title & Degree
Hakeam Hakeam
Phone
+966-11-4647272
Ext
48822
Email
hakeam@kfshrc.edu.sa
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Zainab Al Duhailib
Organizational Affiliation
King Faisal Specialist Hospital & Research Center
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Hakeam Hakeam
Organizational Affiliation
King Faisal Specialist Hospital & Research Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
King Faisal Specialist Hospital & Research Centre
City
Riyadh
Country
Saudi Arabia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Zainab Al Duhailib, MBBS, EDIC, MSc
First Name & Middle Initial & Last Name & Degree
Hakeam Hakeam, BCPS, MS Pharm

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Ceftazidime-Avibactam Use in Critically Ill Patients With Carbapenem-Resistant Enterobacteriaceae Infections

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