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Ceftolozane-tazobactam Versus Meropenem for ESBL and AmpC-producing Enterobacterales Bloodstream Infection (MERINO III)

Primary Purpose

Bacteremia Caused by Gram-Negative Bacteria

Status
Withdrawn
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Ceftolozane-Tazobactam
Meropenem
Sponsored by
The University of Queensland
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Bacteremia Caused by Gram-Negative Bacteria

Eligibility Criteria

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

Inclusion Criteria:

  • Bloodstream infection defined as presence in at least one peripheral blood culture draw demonstrating Enterobacterales with proven non-susceptibility to third generation cephalosporins or cephalosporin susceptible species known to harbour chromosomal AmpC-beta-lactamases (Enterobacter spp., Klebsiella aerogenes, Citrobacter freundii, Morganella morganii, Providencia spp. or Serratia marcescens) during hospitalisation
  • Patient is aged 18 years and over (21 and over in Singapore)
  • The patient or approved proxy is able to provide informed consent
  • ≤72 hours has elapsed since the first positive qualifying (index) blood culture collection
  • Expected to receive IV therapy for ≥5 days

Exclusion Criteria:

  • Known hypersensitivity to a cephalosporin or a carbapenem, or anaphylaxis to beta-lactam antibiotics
  • Participant with significant polymicrobial bloodstream infection (i.e. not a contaminant)
  • Treatment is not with the intent to cure the infection (i.e. palliative intent) or the expected survival is ≤4 days
  • Participant is pregnant or breast-feeding (tested for in women of child-bearing age only)
  • Use of concomitant antimicrobials with known activity against Gram-negative bacilli (except trimethoprim/sulfamethoxazole for Pneumocystis prophylaxis and when adding metronidazole for suspected IAI) in the first 5 days post-randomisation
  • Participant with CrCl <15 mL/minute or on renal replacement therapy (in addition, participants will be withdrawn from the study if CrCl reaches this level)
  • Previously randomised in the MERINO-3 trial or concurrently enrolled in another therapeutic antibiotic clinical trial
  • Blood culture isolate with in-vitro resistance to either meropenem or ceftolozane-tazobactam (known either at time of enrolment or during the course of study treatment, in which case the participant will be withdrawn)

Sites / Locations

  • John Hunter Hospital
  • Royal Prince Alfred
  • Westmead Hospital
  • Woolongong Hospital
  • Royal Brisbane and Women's Hospital
  • Princess Alexandra Hospital
  • Peter MacCallum Cancer Centre
  • Alfred Hospital
  • Monash Medical Centre
  • Dandenong Hospital
  • Royal Perth Hospital
  • Sir Charles Gairdner
  • Fiona Stanley Hospital
  • Policlinico Sant'Orsola Malpighi
  • Dipartimento di Scienze Biomediche e Cliniche
  • Università di Pisa
  • Policlinico Umberto
  • Sanremo Hospital
  • King Fahad Specialist Hospital
  • King Abdulaziz Medical City - Jeddah
  • King Abdulaziz Medical City
  • National University Hospital
  • Singapore General Hospital
  • Tan Tock Seng Hospital
  • Bellvitge University Hospital
  • Hospital Clinic de Barcelona
  • Hospital del Mar
  • Hospital Sant Pau
  • Mutua Terrassa University Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Ceftolozane-tazobactam

Meropenem

Arm Description

Participants will receive ceftolozane-tazobactam 3 grams (comprising ceftolozane 2 grams and tazobactam 1 gram) administered, every 8 hours, three times a day, intravenously over 60 mins

Participants will receive meropenem 1 gram, every 8 hours, three times a day, intravenously over 30 mins.

Outcomes

Primary Outcome Measures

Mortality rate at 30 days
To compare the 30-day mortality from day of randomisation of each regimen

Secondary Outcome Measures

Mortality rate at 14 days
To compare the 14-day mortality from day of randomisation of each regimen
Clinical and microbiological success
Defined as survival PLUS resolution of fever (temperature <38 degrees Celsius) PLUS improved SOFA score (as compared to baseline) PLUS sterilisation of blood cultures at Day 5
Functional bacteraemia score (FBS)
To compare the functional bacteraemia score of patients treated with each regimen at baseline and Day 30 (scored 0-7, higher scores equal better outcomes)
Microbiological relapse
To compare the rates of relapse of bloodstream infection (microbiological failure) with each regimen at Day 30
Rates of new bloodstream infection
To compare the rates of new bloodstream infection (growth of a new organism from blood cultures - not a contaminant as determined by treating clinician) with each regimen
Length of in-patient hospital and ICU stay
To compare lengths of in-patient hospital and ICU stay with each regimen (not including in-patient rehabilitation, long term acute care or hospital in the home)
Serious adverse events
To compare the number of treatment emergent serious adverse events with each regimen
Clostridioides difficile infection
To compare rates of Clostridioides difficile infection with each regimen
Colonisation and/or infection with multi-resistant bacterial organisms
To compare rates of colonisation and/or infection with multi-resistant bacterial organisms (MROs) including those newly acquired
Desirability of Outcome Ranking (DOOR) with partial credit
To compare the Desirability of Outcome Ranking (DOOR) with partial credit with each regimen (scored 0-100, higher scores equal better outcomes)

Full Information

First Posted
December 16, 2019
Last Updated
May 17, 2022
Sponsor
The University of Queensland
Collaborators
Merck Sharp & Dohme LLC
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1. Study Identification

Unique Protocol Identification Number
NCT04238390
Brief Title
Ceftolozane-tazobactam Versus Meropenem for ESBL and AmpC-producing Enterobacterales Bloodstream Infection
Acronym
MERINO III
Official Title
A Multicentre, Parallel Group Open-label Randomised Controlled Non-Inferiority Phase 3 Trial, of Ceftolozane-tazobactam Versus Meropenem for Definitive Treatment of Bloodstream Infection Due to Extended-Spectrum Beta-Lactamase (ESBL) and AmpC-producing Enterobacterales
Study Type
Interventional

2. Study Status

Record Verification Date
October 2021
Overall Recruitment Status
Withdrawn
Why Stopped
The decision to withdraw the study was made due to delayed logistics of the supply chain of ceftolozane-tazobactam along with the immense complexities of conducting clinical research felt because of the COVID-19 pandemic.
Study Start Date
January 2022 (Anticipated)
Primary Completion Date
June 2024 (Anticipated)
Study Completion Date
December 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
The University of Queensland
Collaborators
Merck Sharp & Dohme LLC

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
The purpose of this study is to determine whether ceftolozane-tazobactam is as effective as meropenem with respect to 30 day mortality in the treatment of bloodstream infection due to third-generation cephalosporin non-susceptible Enterobacterales or a known chromosomal AmpC-producing Enterobacterales (Enterobacter spp., Citrobacter freundii, Morganella morganii, Providencia spp. or Serratia marcescens).
Detailed Description
Enterobacterales are common causes of bacteraemia, and may produce extended-spectrum beta-lactamases (ESBLs) or AmpC beta-lactamases. ESBL or AmpC producers are typically resistant to third generation cephalosporins such as ceftriaxone, but susceptible to carbapenems. In no study has the outcome of treatment for serious infections for ESBL producers been significantly surpassed by carbapenems. Despite the potential advantages of carbapenems for treatment of ceftriaxone non-susceptible organisms, widespread use of carbapenems may cause selection pressure leading to carbapenem-resistant organisms. This is a significant issue since carbapenem-resistant organisms are treated with last-line antibiotics such as colistin. Ceftolozane-tazobactam is a combination of a new beta-lactam antibiotic with an existing beta-lactamase inhibitor, tazobactam, and is active against ESBL and most AmpC producing organisms. In a large sample of ESBL- and AmpC-producing Enterobacterales isolates from urinary tract and intra-abdominal specimens, ceftolozane-tazobactam was susceptible in over 80%. It has been FDA approved for complicated urinary tract infections (cUTI) and complicated intra-abdominal infections (cIAI), and more recently for hospital-acquired and ventilator-associated pneumonia (HAP/VAP). In addition, a pooled analysis of phase 3 clinical trials has shown favourable clinical cure rates with ceftolozane-tazobactam for cUTI and cIAI caused by ESBL-producing Enterobacterales. Given the issues of carbapenem resistant organisms, there is a need for establishing the efficacy of an alternative to carbapenems for serious infections.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Bacteremia Caused by Gram-Negative Bacteria

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
0 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Ceftolozane-tazobactam
Arm Type
Experimental
Arm Description
Participants will receive ceftolozane-tazobactam 3 grams (comprising ceftolozane 2 grams and tazobactam 1 gram) administered, every 8 hours, three times a day, intravenously over 60 mins
Arm Title
Meropenem
Arm Type
Active Comparator
Arm Description
Participants will receive meropenem 1 gram, every 8 hours, three times a day, intravenously over 30 mins.
Intervention Type
Drug
Intervention Name(s)
Ceftolozane-Tazobactam
Intervention Description
Ceftolozane-tazobactam 3 grams (comprising ceftolozane 2 grams and tazobactam 1 gram) administered, every 8 hours, three times a day, intravenously over 60 mins. Dose adjusted for renal function.
Intervention Type
Drug
Intervention Name(s)
Meropenem
Intervention Description
Meropenem 1 gram, every 8 hours, three times a day, intravenously over 30 mins. Dose adjusted for renal function.
Primary Outcome Measure Information:
Title
Mortality rate at 30 days
Description
To compare the 30-day mortality from day of randomisation of each regimen
Time Frame
30 days post randomisation
Secondary Outcome Measure Information:
Title
Mortality rate at 14 days
Description
To compare the 14-day mortality from day of randomisation of each regimen
Time Frame
14 days post randomisation
Title
Clinical and microbiological success
Description
Defined as survival PLUS resolution of fever (temperature <38 degrees Celsius) PLUS improved SOFA score (as compared to baseline) PLUS sterilisation of blood cultures at Day 5
Time Frame
5 days post randomisation
Title
Functional bacteraemia score (FBS)
Description
To compare the functional bacteraemia score of patients treated with each regimen at baseline and Day 30 (scored 0-7, higher scores equal better outcomes)
Time Frame
0 and 30 days post randomisation
Title
Microbiological relapse
Description
To compare the rates of relapse of bloodstream infection (microbiological failure) with each regimen at Day 30
Time Frame
30 days post randomisation
Title
Rates of new bloodstream infection
Description
To compare the rates of new bloodstream infection (growth of a new organism from blood cultures - not a contaminant as determined by treating clinician) with each regimen
Time Frame
30 days post randomisation
Title
Length of in-patient hospital and ICU stay
Description
To compare lengths of in-patient hospital and ICU stay with each regimen (not including in-patient rehabilitation, long term acute care or hospital in the home)
Time Frame
30 days post randomisation
Title
Serious adverse events
Description
To compare the number of treatment emergent serious adverse events with each regimen
Time Frame
Day 1 to last dose plus 24 hours of treatment:
Title
Clostridioides difficile infection
Description
To compare rates of Clostridioides difficile infection with each regimen
Time Frame
30 days post randomisation
Title
Colonisation and/or infection with multi-resistant bacterial organisms
Description
To compare rates of colonisation and/or infection with multi-resistant bacterial organisms (MROs) including those newly acquired
Time Frame
30 days post randomisation
Title
Desirability of Outcome Ranking (DOOR) with partial credit
Description
To compare the Desirability of Outcome Ranking (DOOR) with partial credit with each regimen (scored 0-100, higher scores equal better outcomes)
Time Frame
30 days post randomisation

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Bloodstream infection defined as presence in at least one peripheral blood culture draw demonstrating Enterobacterales with proven non-susceptibility to third generation cephalosporins or cephalosporin susceptible species known to harbour chromosomal AmpC-beta-lactamases (Enterobacter spp., Klebsiella aerogenes, Citrobacter freundii, Morganella morganii, Providencia spp. or Serratia marcescens) during hospitalisation Patient is aged 18 years and over (21 and over in Singapore) The patient or approved proxy is able to provide informed consent ≤72 hours has elapsed since the first positive qualifying (index) blood culture collection Expected to receive IV therapy for ≥5 days Exclusion Criteria: Known hypersensitivity to a cephalosporin or a carbapenem, or anaphylaxis to beta-lactam antibiotics Participant with significant polymicrobial bloodstream infection (i.e. not a contaminant) Treatment is not with the intent to cure the infection (i.e. palliative intent) or the expected survival is ≤4 days Participant is pregnant or breast-feeding (tested for in women of child-bearing age only) Use of concomitant antimicrobials with known activity against Gram-negative bacilli (except trimethoprim/sulfamethoxazole for Pneumocystis prophylaxis and when adding metronidazole for suspected IAI) in the first 5 days post-randomisation Participant with CrCl <15 mL/minute or on renal replacement therapy (in addition, participants will be withdrawn from the study if CrCl reaches this level) Previously randomised in the MERINO-3 trial or concurrently enrolled in another therapeutic antibiotic clinical trial Blood culture isolate with in-vitro resistance to either meropenem or ceftolozane-tazobactam (known either at time of enrolment or during the course of study treatment, in which case the participant will be withdrawn)
Facility Information:
Facility Name
John Hunter Hospital
City
Newcastle
State/Province
New South Wales
ZIP/Postal Code
2305
Country
Australia
Facility Name
Royal Prince Alfred
City
Sydney
State/Province
New South Wales
ZIP/Postal Code
2050
Country
Australia
Facility Name
Westmead Hospital
City
Sydney
State/Province
New South Wales
ZIP/Postal Code
2145
Country
Australia
Facility Name
Woolongong Hospital
City
Wollongong
State/Province
New South Wales
ZIP/Postal Code
2500
Country
Australia
Facility Name
Royal Brisbane and Women's Hospital
City
Brisbane
State/Province
Queensland
ZIP/Postal Code
4029
Country
Australia
Facility Name
Princess Alexandra Hospital
City
Brisbane
State/Province
Queensland
ZIP/Postal Code
4102
Country
Australia
Facility Name
Peter MacCallum Cancer Centre
City
Melbourne
State/Province
Victoria
ZIP/Postal Code
3000
Country
Australia
Facility Name
Alfred Hospital
City
Melbourne
State/Province
Victoria
ZIP/Postal Code
3004
Country
Australia
Facility Name
Monash Medical Centre
City
Melbourne
State/Province
Victoria
ZIP/Postal Code
3168
Country
Australia
Facility Name
Dandenong Hospital
City
Melbourne
State/Province
Victoria
ZIP/Postal Code
3175
Country
Australia
Facility Name
Royal Perth Hospital
City
Perth
State/Province
Western Australia
ZIP/Postal Code
6000
Country
Australia
Facility Name
Sir Charles Gairdner
City
Perth
State/Province
Western Australia
ZIP/Postal Code
6009
Country
Australia
Facility Name
Fiona Stanley Hospital
City
Perth
State/Province
Western Australia
ZIP/Postal Code
6150
Country
Australia
Facility Name
Policlinico Sant'Orsola Malpighi
City
Bologna
Country
Italy
Facility Name
Dipartimento di Scienze Biomediche e Cliniche
City
Milan
Country
Italy
Facility Name
Università di Pisa
City
Pisa
Country
Italy
Facility Name
Policlinico Umberto
City
Roma
Country
Italy
Facility Name
Sanremo Hospital
City
Sanremo
Country
Italy
Facility Name
King Fahad Specialist Hospital
City
Dammam
Country
Saudi Arabia
Facility Name
King Abdulaziz Medical City - Jeddah
City
Jeddah
Country
Saudi Arabia
Facility Name
King Abdulaziz Medical City
City
Riyadh
ZIP/Postal Code
14611
Country
Saudi Arabia
Facility Name
National University Hospital
City
Singapore
ZIP/Postal Code
119074
Country
Singapore
Facility Name
Singapore General Hospital
City
Singapore
ZIP/Postal Code
169608
Country
Singapore
Facility Name
Tan Tock Seng Hospital
City
Singapore
ZIP/Postal Code
308433
Country
Singapore
Facility Name
Bellvitge University Hospital
City
Barcelona
Country
Spain
Facility Name
Hospital Clinic de Barcelona
City
Barcelona
Country
Spain
Facility Name
Hospital del Mar
City
Barcelona
Country
Spain
Facility Name
Hospital Sant Pau
City
Barcelona
Country
Spain
Facility Name
Mutua Terrassa University Hospital
City
Barcelona
Country
Spain

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
33888139
Citation
Stewart AG, Harris PNA, Chatfield MD, Littleford R, Paterson DL. Ceftolozane-tazobactam versus meropenem for definitive treatment of bloodstream infection due to extended-spectrum beta-lactamase (ESBL) and AmpC-producing Enterobacterales ("MERINO-3"): study protocol for a multicentre, open-label randomised non-inferiority trial. Trials. 2021 Apr 22;22(1):301. doi: 10.1186/s13063-021-05206-8.
Results Reference
derived

Learn more about this trial

Ceftolozane-tazobactam Versus Meropenem for ESBL and AmpC-producing Enterobacterales Bloodstream Infection

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