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Trial registered on ANZCTR


Trial ID
ACTRN12613000532707
Ethics application status
Approved
Date submitted
24/04/2013
Date registered
13/05/2013
Date last updated
15/05/2015
Type of registration
Prospectively registered

Titles & IDs
Public title
Pilot Randomized Control Trial of Meropenem vs. Piperacillin-Tazobactam for definitive treatment of bloodstream infections due to ceftriaxone non-susceptible Escherichia Coli and Klebsiella spp.
Scientific title
Pilot Randomized Control Trial of Meropenem vs. Piperacillin-Tazobactam for definitive treatment of bloodstream infections due to ceftriaxone non-susceptible Escherichia Coli and Klebsiella spp.
Secondary ID [1] 281961 0
Nil
Universal Trial Number (UTN)
Trial acronym
MERINO
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Participants who have had an identified Escherichia Coli or Klebsiella spp. bloodstream infection that is found non-susceptible to Ceftriaxone. 288383 0
Condition category
Condition code
Infection 288729 288729 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Recruited participants will randomly be assigned to either receive the study drugs of Meropenem or Piperacillin-Tazobactam in a 1:1 ratio according to a randomisation list prepared in advance. The intervention treatment for this study is the administration of the drug Piperacillin-Tazobactam 4.5 grams administered every 6 hours intravenously over a 30 minute period. The duration of treatment with this drug will be for a minimum of 4 days and a maximum of 14 days. The duration of the therapy will be determined by the treating clinician.
Intervention code [1] 286528 0
Treatment: Drugs
Comparator / control treatment
The control treatment for this study is the administration of the drug Meropenem 1 gram to be administered every 8 hours intravenously over a 30 minute period. The duration of treatment with this drug will be for a minimun of 4 days and a maximum of 14 days. The duration of the therapy will be determined by the treating clinician.
Control group
Active

Outcomes
Primary outcome [1] 288873 0
1. The primary outcome for the trial is the occurence and confirmation of mortality at 30 days after the first positive blood culture.
Timepoint [1] 288873 0
30 days post first positive blood culture.
Secondary outcome [1] 301210 0
1. Time to clinical and microbiologic resolution
Timepoint [1] 301210 0
Number of days from initiation of study drug to resolution of SIRS PLUS sterilisation of blood cultures.
Secondary outcome [2] 301211 0
2. Clinical and microbiologic success
Timepoint [2] 301211 0
Survival at day four after the initation of study drug PLUS resolution of SIRS on or before day four PLUS sterilisation of blood cultures on or before day four.
Secondary outcome [3] 301212 0
3. Microbiologic resolution of infection
Timepoint [3] 301212 0
Sterility of blood cultures on 3rd day post initial recruitment.
Secondary outcome [4] 301213 0
4. Microbiologic relapse
Timepoint [4] 301213 0
Growth of the same organism as in the original blood culture after the end of the period of study drug administration, before 30 days after the first positive blood culture was drawn.

Eligibility
Key inclusion criteria
1. Bloodstream infection with Escherichia coli or Klebsiella spp., as defined by at least one positive blood culture from a peripheral blood draw.
2. Bacteria confirmed as ceftriaxone non-susceptible, Piperacillin-Tazobactam susceptible and Meropenem susceptible by use of EUCAST definitions (www.eucast.org).
3. No more than 72 hours since the first positive blood culture was collected for this infection.
4. Patient or their ethics committee approved proxy able to give written informed consent.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Patient not expected to survive more than 4 days.
2. Patient allergic to a penicillin or a carbapenem.
3. Patient with significant polymicrobial bacteraemia (that is, a Gram positive skin containment in one set of blood cultures is not regarded as significant polymicrobial bacteraemia).
4. Treatment is not with the intent to cure the infection (that is, palliative care is an exclusion).

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Subjects who meet the inclusion criteria will be approached by the study team and given clear concise information about the trial in the form of verbal communication and a patient information form. Once the subject or their ethics committee approved proxy give written informed consent, they will be randomly assigned to receive either the study drugs of meropenem or piperacillin-tazobactam. Patients will be randomly assigned to either Meropeneum or Pipercillin-Tazobactam in a 1:1 ratio according to the randomisation list prepared in advance.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Recruited subjects will be randomly assigned to receive either meropenem or piperacillin/tazobactam in a 1:1 ratio according to a randomisation list prepared in advance (the radomisation list will be centrally radomised by a computer). Random sequence will be generated using random permuted blocks of unequal length. Four strata will be used. Subjects will be stratified according to the bacterial genus identified in the blood culture and the likelihood of death, as defined by the following high-risk features-any of: a) likely source of infection other than urinary or biliary tract, b) Pitt score greater than 4, c) presentation with severe sepsis or shock.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint(s)
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,VIC
Recruitment hospital [1] 925 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [2] 926 0
Westmead Hospital - Westmead
Recruitment hospital [3] 927 0
The Alfred - Prahran
Recruitment hospital [4] 928 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [5] 929 0
Dandenong Hospital - Dandenong
Recruitment hospital [6] 931 0
Wollongong Hospital - Wollongong
Recruitment hospital [7] 932 0
Barwon Health - Geelong Hospital campus - Geelong
Recruitment hospital [8] 2679 0
Peter MacCallum Cancer Institute - East Melbourne
Recruitment hospital [9] 2680 0
Princess Alexandra Hospital - Woolloongabba
Recruitment postcode(s) [1] 6773 0
4029 - Royal Brisbane Hospital
Recruitment postcode(s) [2] 6774 0
2145 - Wentworthville
Recruitment postcode(s) [3] 6775 0
3181 - Prahran
Recruitment postcode(s) [4] 6776 0
3168 - Clayton
Recruitment postcode(s) [5] 6777 0
2050 - Camperdown
Recruitment postcode(s) [6] 6778 0
2500 - Wollongong
Recruitment postcode(s) [7] 6779 0
3220 - Geelong
Recruitment postcode(s) [8] 8363 0
4102 - Woolloongabba
Recruitment postcode(s) [9] 8364 0
3002 - East Melbourne
Recruitment outside Australia
Country [1] 4867 0
New Zealand
State/province [1] 4867 0
Auckland
Country [2] 6177 0
Singapore
State/province [2] 6177 0
Singapore

Funding & Sponsors
Funding source category [1] 287149 0
Other Collaborative groups
Name [1] 287149 0
Australian Society for Infectious Diseases
Address [1] 287149 0
Suite 405, Level 4
5 Hunter Street
Sydney NSW 2000
Country [1] 287149 0
Australia
Funding source category [2] 287150 0
Other Collaborative groups
Name [2] 287150 0
Australian Society for Antimicrobials
Address [2] 287150 0
PO Box 8266
Angelo St, South Perth
Western Australia 6151
Country [2] 287150 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Society of Infectious Diseases Clinical Research Network
Address
Suite 405, Level 4
5 Hunter Street
Sydney NSW 2000
Country
Australia
Secondary sponsor category [1] 285916 0
University
Name [1] 285916 0
University of Queensland Centre for Clinical Research
Address [1] 285916 0
Building 71/918 RBWH
Herston Rd
Herston QLD 4006
Country [1] 285916 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289085 0
Royal Brisbane and Women's Hospital Human Research Ethics Committee
Ethics committee address [1] 289085 0
RBWH Human Research Ethics Committee
Butterfield Street
Herston QLD 4029
Ethics committee country [1] 289085 0
Australia
Date submitted for ethics approval [1] 289085 0
26/11/2012
Approval date [1] 289085 0
26/03/2013
Ethics approval number [1] 289085 0
HREC/12/QRBW/440

Summary
Brief summary
Escherichia coli (“E. coli”) and Klebsiella are bacteria which are common causes of infections in your blood stream. Patients with bloodstream infections due to either E. coli or Klebsiella, can commonly be treated with antibiotics called third generation cephalosporins, such as the antibiotic ceftriaxone. When the blood stream infection is resistant to these antibiotics, the antibiotics meropenem and piperacillin/tazobactam have been shown to be effective alternatives for treatment.
The purpose of this study is to work out whether these two other antibiotics, meropenem and piperacillin/tazobactam, are equally effective in the treatment of these antibiotic resistant bloodstream infections. These antibiotics have never been compared “head to head” in order to establish the best available treatment for these serious infections. This research project has been designed to make sure the researchers interpret the results in a fair and appropriate way and avoids study doctors or participants jumping to conclusions.
Trial website
Trial related presentations / publications
none for pilot phase
Public notes

Contacts
Principal investigator
Name 37882 0
Prof David L. Paterson
Address 37882 0
University of Queensland Centre for Clinical Research
Level 8, 71/918 Royal Brisbane and Womens Hospital
Herston Road
Herston QLD 4029
Country 37882 0
Australia
Phone 37882 0
+61 7 3346 6074
Fax 37882 0
+61 7 3346 5598
Email 37882 0
david.antibiotics@gmail.com
Contact person for public queries
Name 37883 0
Prof David L. Paterson
Address 37883 0
University of Queensland Centre for Clinical Research
Level 8, 71/918 Royal Brisbane and Womens Hospital
Herston Road
Herston QLD 4029
Country 37883 0
Australia
Phone 37883 0
+61 7 3346 6074
Fax 37883 0
+61 7 3346 5598
Email 37883 0
david.antibiotics@gmail.com
Contact person for scientific queries
Name 37884 0
Prof David L. Paterson
Address 37884 0
University of Queensland Centre for Clinical Research
Level 8, 71/918 Royal Brisbane and Womens Hospital
Herston Road
Herston QLD 4029
Country 37884 0
Australia
Phone 37884 0
+61 7 3346 6074
Fax 37884 0
+61 7 3346 5598
Email 37884 0
david.antibiotics@gmail.com