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

NCT05258851 | Terminated Phase 3 DMC

• 1 other identifier: RAC#2211247
• Study Type: interventional
• Target: 29
• Locations: 1 country
• Sites: 1

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.

Conditions

Carbapenem-Resistant Enterobacteriaceae Infection

Keywords

Carbapenem-Resistant Enterobacteriaceae; Critically ill; Ceftazidime-avibactam; Colistin

Outcome Measures

Primary Outcomes (1)

• 28-day mortality

  Death

  28 days from randomization

Secondary Outcomes (8)

• 14-day mortality

  14 days from randomization

• 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

  EOT at 7-14 days from randomization and TOC 7 days after completion of treatment

• Number of patients with microbiological response at the EOT at days 7-14 from randomization and TOC 7 days after completion of treatment

  EOT at 7-14 days from randomization and TOC 7 days after completion of treatment

• Time to weaning from mechanical ventilation at day 28

  28 days from randomization

• Requirement for renal replacement therapy at day 28

  28 days from randomization

Study Arms (2)

Ceftazidime-avibactam

EXPERIMENTAL

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.

Drug: Ceftazidime-avibactam

Colistin

ACTIVE COMPARATOR

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.

Drug: Colistin

Interventions

Ceftazidime-avibactam DRUG

Experimental

Ceftazidime-avibactam

Colistin DRUG

Control

Colistin

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• King Faisal Specialist Hospital & Research Center: lead

Study Sites (1)

King Faisal Specialist Hospital & Research Centre

Riyadh, Saudi Arabia

Location

MeSH Terms

Conditions

Critical Illness

Interventions

avibactam, ceftazidime drug combination; Colistin

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Polymyxins; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Lipopeptides; Lipids; Antimicrobial Cationic Peptides; Peptides; Amino Acids, Peptides, and Proteins; Antimicrobial Peptides; Pore Forming Cytotoxic Proteins; Membrane Proteins; Proteins

Study Officials

• Zainab Al Duhailib

  King Faisal Specialist Hospital & Research Center

  PRINCIPAL INVESTIGATOR

• Hakeam Hakeam

  King Faisal Specialist Hospital & Research Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Critical Care Medicine Consultant

Model Details: Open-label, multicenter, parallel-group, stratified, non-inferiority randomized controlled trial

Study Record Dates

• First Submitted: February 17, 2022
• First Posted: February 28, 2022
• Study Start: June 1, 2022
• Primary Completion: April 12, 2023
• Study Completion: January 28, 2024
• Last Updated: June 14, 2024

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will not share

Locations

SA (1)