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Bacteremia Caused by Gram-Negative BacteriaPhase 3MERINO IIINCT04238390

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

A Phase 3 study testing Ceftolozane-Tazobactam and Meropenem in people with Bacteremia Caused by Gram-Negative Bacteria, run by The University of Queensland at 29 sites in 5 countries.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Ceftolozane-Tazobactam and Meropenem
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
0 participants
Where
29 sitesin 5 countries
Study dates
Jan 2022to Dec 2024
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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)

Trial locations and contacts

29 sites in 5 countries.

29 sites in 5 countries

Australia13 sites

  • Royal Brisbane and Women's Hospital

    Brisbane, Queensland, 4029

  • Princess Alexandra Hospital

    Brisbane, Queensland, 4102

  • Peter MacCallum Cancer Centre

    Melbourne, Victoria, 3000

  • Alfred Hospital

    Melbourne, Victoria, 3004

  • Monash Medical Centre

    Melbourne, Victoria, 3168

  • Dandenong Hospital

    Melbourne, Victoria, 3175

  • John Hunter Hospital

    Newcastle, New South Wales, 2305

  • Royal Perth Hospital

    Perth, Western Australia, 6000

  • Sir Charles Gairdner

    Perth, Western Australia, 6009

  • Fiona Stanley Hospital

    Perth, Western Australia, 6150

  • Royal Prince Alfred

    Sydney, New South Wales, 2050

  • Westmead Hospital

    Sydney, New South Wales, 2145

  • Woolongong Hospital

    Wollongong, New South Wales, 2500

Other trials in Australia

Italy5 sites

  • Policlinico Sant'Orsola Malpighi

    Bologna

  • Dipartimento di Scienze Biomediche e Cliniche

    Milan

  • Università di Pisa

    Pisa

  • Policlinico Umberto

    Roma

  • Sanremo Hospital

    Sanremo

Other trials in Italy

Spain5 sites

  • Bellvitge University Hospital

    Barcelona

  • Hospital Clinic de Barcelona

    Barcelona

  • Hospital del Mar

    Barcelona

  • Hospital Sant Pau

    Barcelona

  • Mutua Terrassa University Hospital

    Barcelona

Other trials in Spain

Saudi Arabia3 sites

  • King Fahad Specialist Hospital

    Dammam

  • King Abdulaziz Medical City - Jeddah

    Jeddah

  • King Abdulaziz Medical City

    Riyadh, 14611

Other trials in Saudi Arabia

Singapore3 sites

  • National University Hospital

    Singapore, 119074

  • Singapore General Hospital

    Singapore, 169608

  • Tan Tock Seng Hospital

    Singapore, 308433

Other trials in Singapore

About this study

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

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).

Read the 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.

Being tested
Ceftolozane-Tazobactam, Meropenem

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Ceftolozane-TazobactamDrug

    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.

  • MeropenemDrug

    Meropenem 1 gram, every 8 hours, three times a day, intravenously over 30 mins. Dose adjusted for renal function.

Study groups in NCT04238390
Study groupRoleWhat they receive
Ceftolozane-tazobactamExperimentalParticipants 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
Receives: Drug: Ceftolozane-Tazobactam
MeropenemActive comparatorParticipants will receive meropenem 1 gram, every 8 hours, three times a day, intravenously over 30 mins.
Receives: Drug: Meropenem

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Mortality rate at 30 days

    To compare the 30-day mortality from day of randomisation of each regimen

    Measured: 30 days post randomisation

Secondary outcomes (10)

  1. Mortality rate at 14 days

    To compare the 14-day mortality from day of randomisation of each regimen

    Measured: 14 days post randomisation

  2. 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

    Measured: 5 days post randomisation

  3. 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)

    Measured: 0 and 30 days post randomisation

  4. Microbiological relapse

    To compare the rates of relapse of bloodstream infection (microbiological failure) with each regimen at Day 30

    Measured: 30 days post randomisation

  5. 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

    Measured: 30 days post randomisation

  6. 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)

    Measured: 30 days post randomisation

  7. Serious adverse events

    To compare the number of treatment emergent serious adverse events with each regimen

    Measured: Day 1 to last dose plus 24 hours of treatment:

  8. Clostridioides difficile infection

    To compare rates of Clostridioides difficile infection with each regimen

    Measured: 30 days post randomisation

  9. 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

    Measured: 30 days post randomisation

  10. 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)

    Measured: 30 days post randomisation

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted23 Jan 2020
  2. Study startJan 2022 (estimated)
  3. Primary completionJun 2024 (estimated)
  4. Study completionDec 2024 (estimated)

Why it 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.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04238390
Sponsor's protocol ID
UQCCR-DP-AS-2019-001
Acronym
MERINO III
Status last verified
Oct 2021
First submitted
16 Dec 2019
Last updated
19 May 2022
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 33888139

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Ceftolozane-Tazobactam and Meropenem in people with Bacteremia Caused by Gram-Negative Bacteria, run by The University of Queensland at 29 sites in 5 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: withdrawn, as of the sponsor's last update on 19 May 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 29 sites in Australia, Italy, Spain, Saudi Arabia, Singapore. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was withdrawn before enrolling participants, so there are no results.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Mortality rate at 30 days (time frame: 30 days post randomisation). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04238390, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 May 2022.

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