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Trial registered on ANZCTR


Registration number
ACTRN12611000195954
Ethics application status
Approved
Date submitted
17/02/2011
Date registered
18/02/2011
Date last updated
9/07/2013
Type of registration
Prospectively registered

Titles & IDs
Public title
Optimise Dosing of Doripenem in critically ill patients receiving a form of dialysis called Continuous Veno-Venous Haemodialfiltration
Scientific title
Pharmacokinetics of Doripenem in Critically Ill Patients receiving Continuous Veno-Venous Haemodialfiltration
Secondary ID [1] 259633 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Infection 261199 0
Critical Illness 261200 0
Acute Kidney Injury 261201 0
Condition category
Condition code
Infection 259349 259349 0 0
Studies of infection and infectious agents
Renal and Urogenital 259353 259353 0 0
Other renal and urogenital disorders

Intervention/exposure
Study type
Observational
Patient registry
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
Observational pharmacokinetic study - blood and dialysate sampling in critically ill patients.

This project will run for 18 months.

For each patient, drug dosing will be at the discretion of the clinician. Doses will be reconstituted in 10ml of diluent and given as intermittent infusion in 50ml over 60 minutes.

Sample collection
All patients will be sampled on 2 separate doses between DAY 1 and DAY 5 of treatment.
1. Plasma sample (3mls of blood for each sample)
Samples will be collected pre and post filter at the following time points (0, 15, 30, 45, 60, 90, 120, 180 and 480 minutes). (Total blood removed during both days of sampling =54ml)

2. Filtrate/dialysate samples
A new dialysate bag and filter will be placed at the start of dosing. If the filter is more than 12 hours old the filter will be changed by an ICU nurse using Aseptic technique. If the filter is less than 12 hours old it will be considered new and will not be changed.
An aliquot (5ml) of the dialysis effluent will be taken from each bag of dialysis effluent collected throughout the study period to determine the amount of drug cleared by CVVHDF. The total volume of each bag of dialysis effluent sampled will be recorded.
Small samples (5ml) of dialysis effluent will also be collected at the following time points 60, 120 and 180 minutes to enable the calculation of the sieving coefficient.
Sieving coefficient = (Concentration of drug in effluent)/ (Concentration of drug in plasma)

3. Urine specimens
Urine samples will be collected during the study period (if there is urine output) and will be used to calculate residual renal function (8 hour urinary creatinine clearance- to compare with other measures of renal function)
All the collected blood samples will be centrifuged and stored at -80oC until assay.

Other investigations
Total Body Bioelectrical Impedance
Total body bioelectrical impedance will be performed by experienced clinicians. This is a non-invasive process requiring connection of leads (similar to an echocardiogram) that measure resistance of electrical impulses throughout the body. The greater the resistance, the larger the volume of distribution and as such this method will be used for detecting altered fluid status.

Data collection
For each patient various de-identified clinical and demographic data will be collected:
Patient demographics- Age, gender, weight, height
Clinical details- Admission diagnosis, other concomitant drugs, allergies
Physiological variables- temperature, mean arterial pressure, heart rate, respiratory rate
Results of routine tests performed as standard ICU policy-biochemistry, microbiology studies, liver function tests, arterial blood gases, coagulation studies
Disease Severity Scores – Sequential Organ Failure Assessment (SOFA) score & Acute Physiology and Chronic Health Evaluation II (APACHE II) score
CVVHDF settings- blood flow rate, dialysate & filtrate flow rate, type of filter membrane & surface area of filter membrane, age of filter (times of all filter changes to be recorded), type of anticoagulation used
Intervention code [1] 258065 0
Not applicable
Comparator / control treatment
Nil
Control group
Uncontrolled

Outcomes
Primary outcome [1] 262159 0
Determination of pharmacokinetic parameters (volume of distribution and clearance).

Outcome will be determined using pharmacokinetic analysis of doripenem concentrations in serial blood samples
Timepoint [1] 262159 0
One 8-hour dosing interval between day 2 and 5 of the antibiotic course
Primary outcome [2] 262160 0
Development of doripenem dose schedule in continuous venovenous haemodialfiltration

Pharmacokinetic analysis of data will procure a population pharmacokinetic model. Within the software NONMEM (Globomax), we will then perform Monte Carlo Simulations of different doses to confirm which doses of doripenem should be administered to ensure therapeutic antibiotic concentrations.
Timepoint [2] 262160 0
End of patient enrolment
Secondary outcome [1] 273242 0
Identification of covariates predictive of altered pharmacokinetics.

Covariates will be asssessed for statistical significance using a statistical package (SPSS, version 17.0) and subsequently interpreted for clinical relevance by an intensive care physician
Timepoint [1] 273242 0
End of patient enrolment

Eligibility
Key inclusion criteria
- Critical illness
- Acute kidney injury
- Receiving continuous venovenous haemodialfiltration
- Clinical indication for doripenem
Minimum age
18 Years
Maximum age
90 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Pregnancy
- Allergy to doripenem

Study design
Purpose
Screening
Duration
Cross-sectional
Selection
Convenience sample
Timing
Prospective
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)

Funding & Sponsors
Funding source category [1] 258529 0
Commercial sector/Industry
Name [1] 258529 0
Janssen-Cilag Pty Ltd
Address [1] 258529 0
1-5 Khartoum Rd
North Ryde
NSW 2113
Country [1] 258529 0
Australia
Primary sponsor type
Hospital
Name
Royal Brisbane and Women's Hospital
Address
Department of Intensive Care Medicine
Level 3 Ned Hanlon Building
Royal Brisbane and Women's Hospital
Butterfield St
Herston QLD 4029
Country
Australia
Secondary sponsor category [1] 257665 0
University
Name [1] 257665 0
The University of Queensland
Address [1] 257665 0
Burns Trauma and Critical Care Research Centre
School of Medicine
The University of Queensland
Level 7, Block 6
Royal Brisbane and Women's Hospital
Butterfield St
Herston QLD 4029
Country [1] 257665 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 260499 0
Royal Brisbane and Women's Hospital Human Research Ethics Committee
Ethics committee address [1] 260499 0
Level 7 Block 7
Royal Brisbane and Women?s Hospital
Butterfield Street
HERSTON 4029
Ethics committee country [1] 260499 0
Australia
Date submitted for ethics approval [1] 260499 0
08/10/2010
Approval date [1] 260499 0
05/01/2011
Ethics approval number [1] 260499 0
HREC/10/QRBW/395

Summary
Brief summary
Presently, there is no information to guide clinicians on how to dose a new antibiotic, doripenem, in critically ill patients receiving a form of dialysis called continuous venovenous haemodiafiltration.

The aim of this study is to describe the how concentrations of Doripenem (a carbapenem antibiotic) in critically ill patients are affected by Continuous Venovenous Haemodiafiltration (CVVHDF). We will then analyse the changing concentrations and use this information to provide strong evidence on what dose of doripenem to use in these patients.

We hypothesise that a dose of 500mg every eight hours by intravenous infusion will provide therapeutic doripenem concentrations.

Our process will be to enroll 12 patients who clinically need both doripenem and CVVHDF. We will collect various blood samples and analyse the changing concentrations with computer software to enable description of what doses future patients will need.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 32236 0
Prof Jeffrey Lipman
Address 32236 0
Level 3, Ned Hanlon Building, Royal Brisbane and Women's Hospital, Butterfield St, Herston, QLD, 4029
Country 32236 0
Australia
Phone 32236 0
+617 3646 1852
Fax 32236 0
Email 32236 0
j.lipman@uq.edu.au
Contact person for public queries
Name 15483 0
Dr Jason Roberts
Address 15483 0
Department of Intensive Care Medicine
Level 3 Ned Hanlon Building
Royal Brisbane and Women's Hospital
Butterfield St
Herston QLD 4029
Country 15483 0
Australia
Phone 15483 0
+61736368111
Fax 15483 0
Email 15483 0
j.roberts2@uq.edu.au
Contact person for scientific queries
Name 6411 0
Dr Jason Roberts
Address 6411 0
Department of Intensive Care Medicine
Level 3 Ned Hanlon Building
Royal Brisbane and Women's Hospital
Butterfield St
Herston QLD 4029
Country 6411 0
Australia
Phone 6411 0
+61736368111
Fax 6411 0
Email 6411 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