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Trial registered on ANZCTR


Registration number
ACTRN12615000086561
Ethics application status
Approved
Date submitted
13/01/2015
Date registered
3/02/2015
Date last updated
9/06/2015
Type of registration
Retrospectively registered

Titles & IDs
Public title
Therapeutic drug monitoring guided dose optimization of beta-lactam antibiotics in haematology/oncology patients with febrile neutropenia
Scientific title
A randomised controlled study of the role of therapeutic drug monitoring guided dose optimisation in improving exposure of beta-lactam antibiotics in patients with febrile neutropenia and haematological malignancies.
Secondary ID [1] 285960 0
Nil
Universal Trial Number (UTN)
U1111-1166-0231
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Febrile neutropenia 293893 0
haematological malignancies 293998 0
Condition category
Condition code
Infection 294196 294196 0 0
Other infectious diseases
Cancer 294292 294292 0 0
Leukaemia - Acute leukaemia
Blood 294293 294293 0 0
Haematological diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Initially all patients will receive standard starting doses of beta-lactam antibiotics (e.g 4.5g piperacillin-tazobactam every 8-hourly, 2g cefepime every 8-hourly, 1g meropenem every 8 hourly) via intermittent intravenous infusion. For the intervention group, the unbound (free) concentrations of beta-lactam antibiotics will be calculated from the total concentration assay of blood samples taken at the mid of dosing interval and 15 minutes before the next dose as a trough. Based on the free antibiotic concentration at the specified blood sampling times, whether pharmacokinetic/pharmacodynamic (PK/PD) target is achieved or not will be determined. The PK/PD target is achievement of 100%fT>MIC (the free antibiotic concentration remains above the MIC for the entire duration of the dosing interval). This will be determined by using local institutional antibiograms at the study hospital or European Committee on Antimicrobial Susceptibility Testing (EUCAST) (http://www.eucast.org/clinical breakpoints) recommendations will be used as reference bacterial susceptibility breakpoints. The proposed sampling time allows determination of PK/PD target without calculating the exact time above MIC. Results of the free antibiotic blood concentration and target attainment will be communicated to clinicians treating the patient. Based on the results, investigators of the study will then identify the need for dose adjustment in conjunction with the clinicians. When deemed necessary, dose adjustment will be performed. Doses will be adjusted as necessary either by increasing the frequency by 25 to 50% or changing the mode of administration into extended infusion or both. If trough concentrations are greater than ten times the MIC, dose reduction will be performed by reducing the frequency by 25 to 50 % or decreasing the dose by 50%. The overall duration of treatment will be at clinician discretion. Adherence to the interventional dosing changes was monitored using the drug administration charts which describe the details of drug administration which are signed by and confirmed by nursing staff.
Intervention code [1] 290935 0
Treatment: Drugs
Comparator / control treatment
In the control group, all patients will receive standard doses of beta-lactam antibiotics ((e.g 4.5g piperacillin-tazobactam every 8-hourly, 2g cefepime every 8-hourly, 1g meropenem every 8 hourly) via intermittent intravenous infusion. Therapeutic drug monitoring will be performed similar to the intervention group; however no dose adjustment is made based on the determined concentrations and if any will be at the discretion of the clinician and not based on the therapeutic concentrations monitoring. The duration of treatment will be at the discretion of the clinicians.
Control group
Dose comparison

Outcomes
Primary outcome [1] 293985 0
Attainment of pharmacokinetic/pharmacodynamic target (100%fT>MIC). This will be determined by using the trough concentration measured from venous blood samples in reference to MIC breakpoints. Local institutional antibiograms at the study hospital or European Committee on Antimicrobial Susceptibility Testing (EUCAST) (http://www.eucast.org/clinical breakpoints) recommendations will be used as reference bacterial susceptibility breakpoints. Note that the trough concentration monitoring allows determination of this outcome measure with out determining the actual time the free drug concentration remains above MIC.
Timepoint [1] 293985 0
Baseline and the following two consecutive days
Secondary outcome [1] 312286 0
Duration of fever defined as as the time between commencement of antibiotic treatment immediately after diagnosis of febrile neutropenia and the first day of at least 2 consecutive days that temperature will be less than 38 degree celsius. This will be assessed by recording daily core body temperature from patients medical chart measured using clinical thermometers.
Timepoint [1] 312286 0
during antibiotic treatment

Eligibility
Key inclusion criteria
diagnosis of febrile neutropenia, diagnosis of cancer or hematological malignancy, prescribed to receive a beta-lactam antibiotics, ability to get prior informed consent
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
know or suspected allergy to the study antibiotics, pregnancy, inability to get informed consent

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)
Patients are randomly assigned into control and intervention groups using computer generated randomization list put in sequentially numbered opaque envelopes.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
computer generated randomization list
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Pharmacokinetics / pharmacodynamics
Statistical methods / analysis
Where appropriate, descriptive statistics, the Mann–Whitney U test, chi-square test or Fisher’s exact test and student’s t-test will be used. p value less than 0.05 will be considered as the level of statistical significance.

Sample size calculation was performed using G*Power program version 3.1.3. Power and the degree of type I error were set at 80% and 5% respectively. The effect size was set at 0.4 (moderate effect size) and to detect differences in the proportions of the primary measure of outcome between the two groups (Df=1) by chi-square test, a total sample size of 50 patients was determined. As a contingency to account for the likelihood of dropout, a total samples size of 60 patients was considered.

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)
SA
Recruitment hospital [1] 3322 0
The Queen Elizabeth Hospital - Woodville
Recruitment postcode(s) [1] 9103 0
5011 - Woodville

Funding & Sponsors
Funding source category [1] 290542 0
Self funded/Unfunded
Name [1] 290542 0
Address [1] 290542 0
Country [1] 290542 0
Primary sponsor type
University
Name
Therapeutics Research Centre, University of South Australia
Address
Therapeutics Research Centre, University of South Australia
Lever 2, Basil Hetzel Institute for Translational Health Research The Queen Elizabeth Hospital
28 Woodville Road, Woodville SA 5011
Country
Australia
Secondary sponsor category [1] 289234 0
None
Name [1] 289234 0
Address [1] 289234 0
Country [1] 289234 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292190 0
Human Research Ethics Committee (TQEH/LMH/MH)
Ethics committee address [1] 292190 0
Basil Hetzel Institute DX465101
The Queen Elizabeth Hospital
28 Woodville Road
Woodville South SA 5011
Ethics committee country [1] 292190 0
Australia
Date submitted for ethics approval [1] 292190 0
Approval date [1] 292190 0
24/01/2014
Ethics approval number [1] 292190 0
HREC/13/TQEHLMH/301
Ethics committee name [2] 292191 0
Human Research Ethics Committee of University of South Australia
Ethics committee address [2] 292191 0
Research and Innovation Services
Mawson Lakes Campus
University of South Australia
GPO Box 2471, Adelaide, SA, 5001
Ethics committee country [2] 292191 0
Australia
Date submitted for ethics approval [2] 292191 0
Approval date [2] 292191 0
28/01/2014
Ethics approval number [2] 292191 0
Application ID: 0000032581

Summary
Brief summary
The aim of this study is to evaluate a dose optimisation strategy to improve exposure of beta-lactam antibiotics in haematology/oncology patients with febrile neutropenia.

Who is it for?

You may be eligible to join this study if you are aged 18 years or above and have a diagnosis of febrile neutropenia and cancer/haematological malignancy, for which you have been prescribed to receive beta-lactam antibiotics.

Study details

Participants in this study will be randomly (by chance) allocated to one of two groups. Participants in one group will continue to receive standard dosing of beta-lactam antibiotics at the discretion of their treating clinician. Participants in the other group will have their beta-lactam antibiotics dosed according to a new dose optimisation strategy guided by measurements of antibiotic concentration in the blood.

All participants will be regularly monitored to determine how well the antibiotic dosing target is met and how long it takes for their fever to subside. It is hoped that the new dose optimisation strategy will help avoid the likelihood of inadequate antibiotic exposure, thereby improving treatment of infections and reducing antibiotic resistance.
Trial website
Trial related presentations / publications
ime FB, Roberts MS, Tiong IS, Gardner JH, Lehman S, Peake SL, Hahn U, Warner MS, Roberts JA: Can therapeutic drug monitoring optimize exposure to piperacillin in febrile neutropenic patients with haematological malignancies? A randomized controlled trial. J Antimicrob Chemother 2015. [Epub ahead of print], DOI: 10.1093/jac/dkv123.
Public notes

Contacts
Principal investigator
Name 53994 0
Mr Fekade Bruck Sime
Address 53994 0
Therapeutics Research Centre
Basil Hetzel Institute for Translational Health Research
The Queen Elizabeth Hospital
28 Woodville Road
Woodville South SA 5011
Country 53994 0
Australia
Phone 53994 0
+61412181027
Fax 53994 0
Email 53994 0
fekade.sime@mymail.unisa.edu.au
Contact person for public queries
Name 53995 0
Mr Fekade Bruck Sime
Address 53995 0
Therapeutics Research Centre
Basil Hetzel Institute for Translational Health Research
The Queen Elizabeth Hospital
28 Woodville Road
Woodville South SA 5011
Country 53995 0
Australia
Phone 53995 0
+61412181027
Fax 53995 0
Email 53995 0
fekade.sime@mymail.unisa.edu.au
Contact person for scientific queries
Name 53996 0
Mr Fekade Bruck Sime
Address 53996 0
Therapeutics Research Centre
Basil Hetzel Institute for Translational Health Research
The Queen Elizabeth Hospital
28 Woodville Road
Woodville South SA 5011
Country 53996 0
Australia
Phone 53996 0
+61412181027
Fax 53996 0
Email 53996 0
fekade.sime@mymail.unisa.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