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Trial registered on ANZCTR


Registration number
ACTRN12613000862741
Ethics application status
Approved
Date submitted
19/07/2013
Date registered
5/08/2013
Date last updated
6/08/2013
Type of registration
Prospectively registered

Titles & IDs
Public title
Efficacy and safety of a colistin loading dose, population pharmacokinetic-pharmacodynamic profiles and bacterial clearance rate in critically ill patients with extensively drug-resistant Acinetobacter baumanii (XDRAb) infections
Scientific title
In critically ill patients infected with extensively drug resistant Acinetobacter baumanii (XDRAb), does the use of colistin loading dose compared to the normal maintenance of colistin has better 30 day mortality outcome?
Secondary ID [1] 282870 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Infections with extensively drug resistant Acinetobacter baumanii 289688 0
Condition category
Condition code
Infection 290005 290005 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Colistin in this study will be given intravenously to all the patients.

The loading dose of colistin will be used in selected patient who will be randomised using a computer generated block. Colistin is a parenteral drug in the form of prodrug called colistimethate sodium (CMS). The generic drug is named colomycin.

We will use the Garonzik et. al. calculation method that was published in 2011, a study on colistin population PKPD. The maintenance will also be calculated using the formula from the paper that is dependent on the creatinine clearance.

We will provide the physicians and the investigators with the study protocol to ensure that there will be a systemic and
planned review of each participants.

The loading dose is calculated based on weight in which the formula used will be, 2 x 2 x ideal body weight.
The dose will be in colistin based activity (CBA) in which the loading dose is given irrespective of the creatinine clearance

This loading dose will be given only once pre maintenance amongst subjects randomized into the the loading dose arm

The maintenance as per the formula will be calculated based on creatinine clearance. We will use the online CKD EPI calculator for the calculation of creatinine clearance. The formula will be, 2 (1.5 x creatinine clearance + 30). The sum will be expressed in CBA too.

The subjects will be maintained on the maintenance dose for at 10 to 14 days depending on the clinical response and the type of infections.

The subjects will be followed up till 30 days post commencement of antibiotic or till he/she is discharged (whichever comes first)
Intervention code [1] 287570 0
Treatment: Drugs
Comparator / control treatment
The control group will be given maintenance of colistin without the loading dose using the same formula used to calculate the maintenance dose of loading arm.

We will provide the physicians and the investigators with the study protocol to ensure that there will be a systemic and planned review of each participants.

The maintenance dose calculated per day can be given in bd or tds dose depending on the physician jurisdiction.
All the calculated dose will be given intravenously to the subjects
Control group
Dose comparison

Outcomes
Primary outcome [1] 290055 0
30-day mortality rate. We will use crude mortality data rather than infection specific mortality data for the 30 day mortality
Timepoint [1] 290055 0
Assessed at the 30th day after treatment commencement
Secondary outcome [1] 303843 0
ICU length of stay

Timepoint [1] 303843 0
We will review the patient medical record to ascertain the length of stay post colistin commencement
Secondary outcome [2] 303929 0
Hospital length of stay
Timepoint [2] 303929 0
We will review the patient medical record to ascertain the length of stay post colistin commencement
Secondary outcome [3] 303930 0
PKPD parameters attainment
Timepoint [3] 303930 0
For PKPD parameters: the blood will be collected on day 1 and day 3, and the modelling of colistin will be done to ascertain the serum levels of colistin in both the study arms. Liquid chromatography mass spectrometry machine will be used for this
Secondary outcome [4] 303931 0
bacterial clearance (using PCR technique)
Timepoint [4] 303931 0
For RT PCR bacterial clearance: Day 0,1,2,3 and the final day of the treatment. An RT PCR machine will be used for this

Eligibility
Key inclusion criteria
1) Age 18 and above

2) Patients with a first episode of culture proven XDRAb from blood, CSF, sputum and tracheal aspirate samples.

3) Receive colistin treatment for more than 72 hours

4) Fulfill diagnostic criteria for ventilator-related pneumonia, hospital-acquired pneumonia, bacteremia (catheter- and non catheter-related), and meningitis or CSF infections, as defined in accordance with IDSA guidelines
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) Pregnant
2) Breastfeeding
3) ALT/AST more than 8 times upper limit of normal
5) Allergy to colistin or its prodrug

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)
The patients who fulfilled the criteria and are admitted into ICU or neuro ICU will be invited to participate in the study. The treatment allocation in term of loading dose will be decided using a randomised block.

However both the patients and the physicians will not be blinded of the treatment arms. Thus we will not be providing the concealment for both the arms post randomisation
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
R program is used to generate a block of random numbers for the treatment allocation
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
We will use SPSS version 21 to assess the outcome between the 2 groups. Fisher exact test and X2 test will be used for categorical data, t test for parametric and Mann Whitney U test for non parametric continuous variables will be used.

Multivariable regression will be used to adjust for confounding factors and effect modification. Variables with a P value of less than 0.1 on bivariable analyses will be fitted into a multivariable logistic regression model in a forward stepwise selection manner and the adjusted odd ratios of 95% confidence intervals and P values will be determined

The study is designed to identify an absolute mortality reduction of 30%. For sample size calculation, assuming raw 30-day mortality rate of 60% in the conventional (control group) arm, a 2-tailed significant level of 0.05, a power of 0.80, an allocation ratio of 1:1, and a drop out rate of 10%, 97 patients have to be enrolled.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
15/08/2013
Actual
Date of last participant enrolment
Anticipated
30/06/2014
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
100
Accrual to date
Final
Recruitment outside Australia
Country [1] 5234 0
Malaysia
State/province [1] 5234 0

Funding & Sponsors
Funding source category [1] 287650 0
University
Name [1] 287650 0
University Malaya
Country [1] 287650 0
Malaysia
Primary sponsor type
Individual
Name
Helmi B Sulaiman
Address
Department of Medicine
Faculty of Medicine
University Malaya
50603
Kuala Lumpur
Malaysia
Country
Malaysia
Secondary sponsor category [1] 286393 0
None
Name [1] 286393 0
Address [1] 286393 0
Country [1] 286393 0
Other collaborator category [1] 277530 0
Individual
Name [1] 277530 0
Dr Lo Yoke Lin
Address [1] 277530 0
University Malaya
Department of Pharmacy
Faculty of Medicine
50603
Kuala Lumpur
Malaysia
Country [1] 277530 0
Malaysia
Other collaborator category [2] 277531 0
Individual
Name [2] 277531 0
Dr Nadia Atiya
Address [2] 277531 0
University Malaya
Department of Microbiology
Faculty of Medicine
University of Malaya
50603
Kuala Lumpur
Malaysia
Country [2] 277531 0
Malaysia
Other collaborator category [3] 277547 0
Individual
Name [3] 277547 0
Dr. Wong Kang Kwong
Address [3] 277547 0
University Malaya
Department of Anaesthesiology
Faculty of Medicine
University of Malaya
50603
Kuala Lumpur
Country [3] 277547 0
Malaysia
Other collaborator category [4] 277548 0
Individual
Name [4] 277548 0
Dr. Vineya Rai A/L Hakumat Rai
Address [4] 277548 0
University Malaya
Department of Anaesthesiology
Faculty of Medicine
University of Malaya
50603
Kuala Lumpur
Country [4] 277548 0
Malaysia
Other collaborator category [5] 277549 0
Individual
Name [5] 277549 0
Dr. Mohd Shahnaz Bin Hasan
Address [5] 277549 0
University Malaya
Department of Anaesthesiology
Faculty of Medicine
University of Malaya
50603
Kuala Lumpur
Country [5] 277549 0
Malaysia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289619 0
University Malaya Medical Centre Medical Ethics Committee
Ethics committee address [1] 289619 0
Lembah Pantai,
59100
Kuala Lumpur Malaysia
Ethics committee country [1] 289619 0
Malaysia
Date submitted for ethics approval [1] 289619 0
11/09/2012
Approval date [1] 289619 0
07/11/2012
Ethics approval number [1] 289619 0
955.6

Summary
Brief summary
We aim to evaluate prospectively the efficacy and safety of a colistin loading dose, to determine the population pharmacokinetic/pharmacodynamic (PK/PD) profiles and the effect of initial rate of bacterial clearance on in-hospital in patients with infections of the lungs, blood, or CSF, caused by extensively drug-resistant Acinetobacter baumanii (XDRAb).


Objectives
The objectives of this study include:

1. To determine, the effect of a loading dose and initial rate of bacterial clearance on 30-day mortality in patients with XDRAb infections
2. To assess the changes in renal function of patients receiving a loading dose of collision
3. To estimate the pharmacokinetic parameters (such as clearance and volume of distribution) and pharmacodynamic parameters (such as ratios of Cmax/MIC, AUC/MIC or T greater than MIC) of colistin in patients with XDRAb infections in critically ill patients.
4. To evaluate whether the initial rate of bacterial clearance can be used to predict mortality.


Hypotheses to be investigated

1) A colistin loading dose is no superior to no loading in 30-day mortality in critically ill patients having infections caused by XDRAb.
2) A colistin loading dose is not associated with an increased risk of nephrotoxicity
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 41590 0
Dr Helmi B Sulaiman
Address 41590 0
Infectious disease unit,
Department of Medicine
Faculty of Medicine
University of Malaya
50603
Kuala Lumpur
Country 41590 0
Malaysia
Phone 41590 0
+60122327940
Fax 41590 0
Email 41590 0
[email protected]
Contact person for public queries
Name 41591 0
Helmi B Sulaiman
Address 41591 0
Infectious disease unit,
Department of Medicine
Faculty of Medicine
University of Malaya
50603
Kuala Lumpur
Country 41591 0
Malaysia
Phone 41591 0
+60122327940
Fax 41591 0
Email 41591 0
[email protected]
Contact person for scientific queries
Name 41592 0
Helmi B Sulaiman
Address 41592 0
Infectious disease unit,
Department of Medicine
Faculty of Medicine
University of Malaya
50603
Kuala Lumpur
Country 41592 0
Malaysia
Phone 41592 0
+60122327940
Fax 41592 0
Email 41592 0
[email protected]

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