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Trial registered on ANZCTR


Registration number
ACTRN12613000241730
Ethics application status
Approved
Date submitted
9/02/2013
Date registered
28/02/2013
Date last updated
20/09/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Sampling Antibiotics in Renal Replacement Therapy, A Multinational Prospective Pharmacokinetic Study.
Scientific title
Multi-national prospective pharmacokinetic study, improving antibiotic dosing in renal replacement therapy for the five most commonly prescribed antibiotics Piperacillin-Tazobactam, Meropenem, Vancomycin and Imipenem and Linezolid at selected sites.
Secondary ID [1] 281897 0
Nil
Universal Trial Number (UTN)
Trial acronym
SMARRT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute Renal Failure
Renal Replacement Therapy
288299 0
Condition category
Condition code
Renal and Urogenital 288642 288642 0 0
Other renal and urogenital disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
One of these study drugs (Piperacillin-Tazobactam, Meropenem, Vancomycin, Imipenem and Lizezolid) will be chosen, administered and dosed as per standard administration guidelines respective to the hospital. Participants will complete a full course of intravenous study drug for approx 7 days or as required by the site doctor to treat the associated infection. Study samples will be taken once on a dosing interval on days 1-2 and then again during a dosing interval between days 3-6. Serial samples of plasma, effluent and urine collections will be measured over either a 6, 8 or 12 hour study period to describe PK changes and potential resolution of infection as follows (assumes a 30-minute infusion for Meropenem or Piperacillin-Tazobactam and a 60-minute infusion for Vancomycin). Study samples will also be analysed to assess RRT clearance of drugs including sedatives and analgesics as well as micro nutrients (e.g. vitamin c , selenium).
Intervention code [1] 286465 0
Treatment: Drugs
Intervention code [2] 286630 0
Treatment: Other
Comparator / control treatment
N/A
Control group
Uncontrolled

Outcomes
Primary outcome [1] 288798 0
Description of pharmacokinetic parameters in various forms of renal replacement therapy
The parameters will be estimated by analysing antibiotic concentrations from blood samples using a robust population pharmacokinetic modelling.
Timepoint [1] 288798 0
3 years from first enrollment
Secondary outcome [1] 301014 0
28 day mortality
This outcome will be collected by trained research staff through revision of hospital records or when necessary, the death register for patients that has been discharged from hospital.
Timepoint [1] 301014 0
3 years after first enrollment

Eligibility
Key inclusion criteria
1. Age 18 years or older
2. Acute kidney injury requiring renal replacement therapy (defined according to published RIFLE, AKIN or KDIGO criteria)
3. Clinical indication for IV Piperacillin-Tazobactam, Meropenem or Vancomycin
4. Expected to be on filter for at least 4 days
5. Presence of intra-arterial line for blood sampling if renal replacement therapy filter port sampling not possible
6. Informed consent from patient or patient’s authorized representative
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Imminent death/not expected to survive etc.
2. Major bleeding or Haemoglobin <70g/L or platelets <20 x103/mm3.
3.Regular dosing with any of the 5 study antibiotics for greater than 36 hours, within the 7 days prior to enrolment
4. Unable to obtain consent

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Patients will be screened for potential eligibility by the ICU research coordinator (RC) or Principal Investigator (PI). If deemed eligible the patient will be provided with information about the study and the consent form, if they are unable to provide their own consent the patient’s authorized representative will be approached. The patient/authorized representative will be asked to consider participation in the study, ask any questions and inform the study team of their decision.

All five study drugs (Piperacillin-Tazobactam, Meropenem, Vancomycin, Imipenem and Linezolid) will be administered and dosed as per standard administration guidelines respective to the hospital.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
N/A
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
All patients will receive one or more of the five antibiotics stipulated but will undergo all the same interventions across the sampling period.
Phase
Phase 2
Type of endpoint(s)
Pharmacokinetics
Statistical methods / analysis
Problematic to all available single-centre pharmacokinetic studies in intensive care units is a lack of statistical power caused by a low throughput of patients per intensive care unit as well as extreme interpatient pharmacokinetic variability. For this reason, multiple intensive care units with experience in pharmacokinetic studies need to be coordinated to enroll patients to achieve acceptable statistical power. The significant variability of antibiotic exposures in intensive care units patients receiving renal replacement therapy is due to the complex interaction of multiple renal replacement therapy modalities and setting and patient factors. A robust analysis of a large data set of patients receiving different forms of renal replacement therapy and the associated clinical and pharmacokinetic changes over time will enable description of the pharmacokinetic distribution and variability in this patient population.

As the fundamental requirement in this study is to determine the distributions of pharmacokinetic parameters, the power analysis is aimed at establishing the confidence boundaries of individual pharmacokinetic parameters under different renal replacement therapy modalities and settings. To construct a 95% confidence boundary of clearance with standard deviation as high as 2.5 L/Hr with 80% power, we need 45 patients’ data for a particular renal replacement therapy modality. For the three modalities, we need a minimum of 150 patients per antibiotic. Our total sample is 450 patients to allow for potential attrition.

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,NT,QLD,SA,TAS,VIC
Recruitment hospital [1] 537 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [2] 538 0
Westmead Hospital - Westmead
Recruitment hospital [3] 539 0
Nepean Hospital - Kingswood
Recruitment hospital [4] 540 0
Royal Darwin Hospital - Tiwi
Recruitment hospital [5] 541 0
Royal Hobart Hospital - Hobart
Recruitment hospital [6] 542 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [7] 543 0
Gold Coast Hospital - Southport
Recruitment hospital [8] 544 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 6277 0
3084 - Rosanna
Recruitment postcode(s) [2] 6278 0
2145 - Westmead
Recruitment postcode(s) [3] 6279 0
2751 - Penrith
Recruitment postcode(s) [4] 6280 0
0810 - Tiwi
Recruitment postcode(s) [5] 6281 0
5011 - Woodville South
Recruitment postcode(s) [6] 6282 0
4029 - Royal Brisbane Hospital
Recruitment postcode(s) [7] 6283 0
4215 - Southport
Recruitment postcode(s) [8] 6284 0
7000 - Hobart
Recruitment outside Australia
Country [1] 4841 0
Hong Kong
State/province [1] 4841 0
Shatin
Country [2] 4842 0
Malaysia
State/province [2] 4842 0
Pahang
Country [3] 4843 0
Germany
State/province [3] 4843 0
Heidenheim
Country [4] 4844 0
Belgium
State/province [4] 4844 0
Brussels, Gent
Country [5] 4845 0
Portugal
State/province [5] 4845 0
Coimbra
Country [6] 4846 0
France
State/province [6] 4846 0
Cedex
Country [7] 4847 0
Greece
State/province [7] 4847 0
Athens
Country [8] 4848 0
Spain
State/province [8] 4848 0
Sabadell, Barcellona
Country [9] 4849 0
Ireland
State/province [9] 4849 0
Dublin
Country [10] 4850 0
United Kingdom
State/province [10] 4850 0
London

Funding & Sponsors
Funding source category [1] 286690 0
Government body
Name [1] 286690 0
National Health and Medical Research Council
Address [1] 286690 0
GPO Box 1421,
Canberra ACT 2601
Country [1] 286690 0
Australia
Primary sponsor type
Government body
Name
Nartional Health and Medical research Council
Address
GPO Box 1421,
Canberra ACT 2601
Country
Australia
Secondary sponsor category [1] 285459 0
None
Name [1] 285459 0
Address [1] 285459 0
Country [1] 285459 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 288753 0
Human Research Ethics Office Royal Brisbane and Women's Hopsital
Ethics committee address [1] 288753 0
Level 7
Block 7
Herston Rd
HERSTON, QLD, 4129
Ethics committee country [1] 288753 0
Australia
Date submitted for ethics approval [1] 288753 0
29/01/2013
Approval date [1] 288753 0
24/04/2013
Ethics approval number [1] 288753 0
HREC/13/QRBW/1

Summary
Brief summary
Inadequate antibiotic therapy is a critical determinant of survival in patients admitted to an Intensive Care Unit (ICU) with overwhelming infection requiring renal replacement therapy (RRT). Guidelines for effective dosing are not available because RRT can be vastly different between ICUs, resulting in significantly different antibiotic pharmacokinetics. Developing an evidence-based antibiotic dosing guideline is of global significance and should be considered a priority to improving clinical outcomes for patients requiring RRT that have infections.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 36870 0
Dr Jason Roberts
Address 36870 0
University of Queensland
Level 3 Ned Hanlon Building
Department of Intensive Care Medicine
Royal Brisbane and Women’s Hospital
Herston, Brisbane, QLD, 4029
AUSTRALIA
Country 36870 0
Australia
Phone 36870 0
+61 7 3646 4108
Fax 36870 0
+61 7 3646 3542
Email 36870 0
j.roberts2@uq.edu.au
Contact person for public queries
Name 36871 0
Ms Renae Deans
Address 36871 0
University of Queensland
Level 9, UQ Health Sciences Building
Royal Brisbane and Women’s Hospital
Herston, Brisbane, QLD, 4029
AUSTRALIA
Country 36871 0
Australia
Phone 36871 0
+61 410 560 503
Fax 36871 0
+61 7 3646 3542
Email 36871 0
r.deans@uq.edu.au
Contact person for scientific queries
Name 36872 0
Dr Jason Roberts
Address 36872 0
University of Queensland
Department of Intensive Care Medicine
Level 3 Ned Hanlon Building
Department of Intensive Care Medicine
Royal Brisbane and Women’s Hospital
Herston, Brisbane, QLD, 4029
AUSTRALIA
Country 36872 0
Australia
Phone 36872 0
+61 7 3646 4108
Fax 36872 0
+61 7 3646 3542
Email 36872 0
j.roberts2@uq.edu.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary