Trial Review

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12617000637347
Ethics application status
Approved
Date submitted
2/03/2017
Date registered
2/05/2017
Date last updated
2/05/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Optimised drug therapy during extracorporeal circulation
Scientific title
Changes in the pharmacokinetics of drugs administered to patients during extracorporeal circulation: a pilot study
Secondary ID [1] 291176 0
Nil
Universal Trial Number (UTN)
U1111-1193-2526
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Unpredicted response to critical drugs during heart surgery with cardiopulmonary bypass (CPB) and Extracorporeal Membrane Oxygenation (ECMO) 302141 0
Condition category
Condition code
Cardiovascular 301686 301686 0 0
Other cardiovascular diseases
Surgery 301687 301687 0 0
Other surgery

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
5 substrates of liver enzymes in a low and single doses will be administered orally to participants before and a day after heart surgery with CPB (Cardiopulmonary bypass) or at the beginning, during and a day after termination of treatment with ECMO (Extracorporeal membrane oxygenation) to estimate the impact of treatment on the activities of liver enzymes.
The substrates are caffeine 100 mg, losartan 5 mg, omeprazole 20 mg, dextromethorphan 30 mg, and midazolam 1 mg. Then, 5 blood samples (one teaspoon) will be collected from participants at time 0, 1, 2 and 4 hours after taking the substrates. The blood samples will then be analysed to measure the amount of each substrate and its product after being broken down with the liver enzymes. Using well-establish metrics, the activity of each 5 liver enzyme will be estimated.
*Each participant receives all five substrates pre and post CPB; during and after ECMO.
The drugs are administered at a single time point.
Intervention code [1] 297223 0
Treatment: Drugs
Comparator / control treatment
Patients undergoing a different surgery not involving extracorporeal circuits ( laparoscopic cholecystectomy) will be used as control group.. The control group will receive the same liver enzymes substrates and blood sampling schedule as the study groups; 1-2 days before and 1-2 days after the surgery.
Control group
Active

Outcomes
Primary outcome [1] 301153 0
The activities of liver enzymes before and after treatment with short-term (CPB) and at the beginning, during and after termination of long-term (ECMO) extracorporeal circuits will be evaluated.
CYP1A2: Ratio of paraxanthine to caffeine plasma concentrations (micro mol/L) at 4 hours post-dose.
CYP3A4: Ratio of 1´-hydroxymidazolam AUC0-6h to midazolam AUC0-6h in Plasma.
Timepoint [1] 301153 0
CYP1A2: 0, 1, 2, 4, 6 h
CYP3A4: 0, 1, 2, 4, 6 h
Primary outcome [2] 301353 0
CYP2C19: Ratio of 5-hydroxyomeprazole to omeprazole plasma concentrations (micro mol/L) at 4 or 6 hours post-dose (at 4 hours if detectable otherwise at 6 hours).
CYP2C9: Ratio of EXP-3174 Losartan carboxylic acid Area Under the plasma concentration Vs Time Curve (AUC)0-6h to losartan AUC0-6h.
Timepoint [2] 301353 0
CYP2C19: 0, 1, 2, 4, & 6 h
CYP2C9: 0, 1, 2, 4, & 6 h
Primary outcome [3] 301927 0
CYP2D6: Ratio of dextrorphan AUC0-6h to dextromethorphan AUC0-6h in plasma
Timepoint [3] 301927 0
0, 1, 2, 4, 6 h
Secondary outcome [1] 334288 0
None
Timepoint [1] 334288 0
None

Eligibility
Key inclusion criteria
For study group:
Age > 18 years and < 90 years.
Eligible for mitral valve and aortic root surgeries involving CPB or
Eligible for ECMO support

For control Group:
Age >18 years & <90 Years
Written informed consent by patient or legally authorized person
Patients undergoing Laparoscopic cholecystectomy
Minimum age
18 Years
Maximum age
90 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
No consent
Pregnancy
Serum bilirubin > 150 micro mol/L
Ongoing massive blood transfusion requirement (> 50% blood volume transfused in the previous 8 hours)
Therapeutic plasma exchange in the preceding 24 hours
Adverse reaction to any elements of the cocktail mixture
People with cognitive impairment or mental illness
Patients with significant coronary artery disease and /or aortic stenosis

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Phase
Not Applicable
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis
The activity of major liver enzymes before/ at the beginning, and after CPB/ECMO/Laparoscopic cholecystectomy, and also among study and control groups will be statistically analysed using non-parametric Mann-Whitney test.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
22/05/2017
Actual
Date of last participant enrolment
Anticipated
22/05/2018
Actual
Date of last data collection
Anticipated
22/06/2018
Actual
Sample size
Target
80
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 7515 0
The Prince Charles Hospital - Chermside
Recruitment postcode(s) [1] 15340 0
4032 - Chermside

Funding & Sponsors
Funding source category [1] 295618 0
Charities/Societies/Foundations
Name [1] 295618 0
The Prince Charles Hospital Foundation
Country [1] 295618 0
Australia
Primary sponsor type
University
Name
The University of Queensland
Address
The University of Queensland, St. Lucia, Brisbane, Queensland, Australia. 4072
Country
Australia
Secondary sponsor category [1] 294521 0
None
Name [1] 294521 0
Address [1] 294521 0
Country [1] 294521 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296937 0
The Prince Charles Hospital Human Research Ethics Committee
Ethics committee address [1] 296937 0
The Prince Charles Hospital
Building 14
Rode Road, Chermside QLD 4032
Ethics committee country [1] 296937 0
Australia
Date submitted for ethics approval [1] 296937 0
Approval date [1] 296937 0
12/09/2016
Ethics approval number [1] 296937 0
HREC/16/QPCH/39
Ethics committee name [2] 296988 0
The University of Queensland Human Research Ethics Committee
Ethics committee address [2] 296988 0
Cumbrae-Stewart Building #72
The University of Queensland
St Lucia, QLD 4072
Ethics committee country [2] 296988 0
Australia
Date submitted for ethics approval [2] 296988 0
Approval date [2] 296988 0
10/01/2017
Ethics approval number [2] 296988 0
2016001643

Summary
Brief summary
Heart surgery using extracorporeal circulation alters how drugs stay and move within the body, which can lead to sub optimal therapy and adverse effects in patients. Although multiple factors potentially contributing to these changes have been identified, there has been minimal research on the impact of extracorporeal circulation on the function of liver enzymes that have a major role in clearing medications from the body. Extracorporeal circulation is associated with an intense inflammatory response which may alter the extent to which liver enzymes breakdown essential drugs leading to sub optimal dosing and adverse effects. Changes in liver enzyme activities may be associated with unpredictable responses seen in patients during and after treatment with extracorporeal circulation, e.g. increased ventilation times or memory impairment.

This pilot study aims to identify factors contributing to the altered breakdown of critical medications and estimate the extent to which changes in the activity of liver enzymes in patients undergoing treatment with short-term (surgeries requiring CPB) or long-term (treatment with ECMO) extracorporeal cuircuits , compared with a control group undergoing a different surgery without extracorporeal circulation (laparoscopic cholecystectomy).

Hypothesis
Extracorporeal circulation, triggers an inflammatory response in patients altering the capability of liver enzymes to breakdown critical drugs.

Outcomes and benefits of the completed pilot study include:
1. Understanding the inflammatory response triggered by extracorporeal circulation and how this affects the ability of liver enzymes to breakdown essential medications.
2 .Utilising new approaches to measure the activities of major enzymes in the clinical setting.
3. Informing the design of a future larger clinical study.
4. Developing guidelines to assist clinicians in delivering optimised drug therapy and personalised health care.
5. Minimising adverse effects associated with altered breakdown of medications in patients thereby reducing length of stay in the ICU and costs associated with complications caused by sub optimal drug therapy.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 72490 0
Dr Sussan Ghassabian
Address 72490 0
Room 717A, Level 7, Block 6, Herston Campus, University of Queensland, Brisbane, QLD.4029
Country 72490 0
Australia
Phone 72490 0
+61733465194
Fax 72490 0
Email 72490 0
[email protected]
Contact person for public queries
Name 72491 0
Mr Santosh Kumar Sreevatsav Adiraju
Address 72491 0
Room 717B, Level 7, Block 6, Herston Campus, University of Queensland, Brisbane, QLD,4029.
Country 72491 0
Australia
Phone 72491 0
+61452347421
Fax 72491 0
+61733655444
Email 72491 0
[email protected]
Contact person for scientific queries
Name 72492 0
Dr Sussan Ghassabian
Address 72492 0
Room 717A, Level 7, Block 6, Herston Campus, University of Queensland, Brisbane, QLD. 4029
Country 72492 0
Australia
Phone 72492 0
+61733465194
Fax 72492 0
Email 72492 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.