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Trial registered on ANZCTR


Trial ID
ACTRN12613000703707
Ethics application status
Approved
Date submitted
24/06/2013
Date registered
27/06/2013
Date last updated
27/06/2013
Type of registration
Prospectively registered

Titles & IDs
Public title
An observational study comparing efficacy and safety of warfarin brands in cardiovascular patients
Scientific title
An open-label, prospective, observational study comparing efficacy and safety of two warfarin brands in adult patients already receiving warfarin treatment
Secondary ID [1] 282724 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Atrial fibrillation 289450 0
Venous thrombosis 289451 0
Pulmonary embolism 289452 0
Recurrent emboli 289453 0
Prosthetic valve replacement 289454 0
Acute myocardial infarction (to prevent systemic embolism) 289455 0
Condition category
Condition code
Cardiovascular 289772 289772 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
The participants will be opportunistically followed up for the clinical outcome of warfarin for 6 months. The participants will continue with their usual treatment with the same brand of warfarin for the whole study period. Warfarin dosage adjustment is determined by physicians as necessary at any time during the study period in accordance with the standard treatment guidelines.
Intervention code [1] 287388 0
Not applicable
Comparator / control treatment
This study is designed as an open label, prospective, observational study. Three hundred patients currently receiving warfarin (any brand) treatment will be recruited and allocated into 2 groups. Group I is the patients receiving the brand Coumadin (n=150) and Group II is the patients receiving the brand Marevan (n=150). The participants will be followed opportunistically as their usual anticoagulant visits. The duration of study is approximately 1 year (from 1 July 2013– 31 July 2014).
Control group
Active

Outcomes
Primary outcome [1] 289857 0
Percentage of the patients whose International Normalized Ratio fall within and outside target ranges
Timepoint [1] 289857 0
For 6 months after enrolment
Secondary outcome [1] 303397 0
Safety profile (adverse drug events). The significant adverse events of warfarin are bleeding at any tissues.
The adverse events will be evaluated by a questionnaire given to the patients on each visit about "head to toe" disorders that they experience during each brand treatment period.

Also the investigator will interview the patients and evaluate the adverse events to double check with the answers in the questionnaire.

The data from the questionnaire and interview will be compared with warfarin concentrations and INR values to confirm the drug-induced adverse events possibility.
Timepoint [1] 303397 0
For 6 months after enrolment

Eligibility
Key inclusion criteria
1. Age greater than or equal to 18 years
2. Receiving warfarin treatment
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Age less than 18 years
2. Pregnancy or breast feeding
3. Non-adherence tendency
4. Psychiatric disorder or dementia
5. Taking any medications, food or dietary supplement that significantly interact with warfarin
6. Limited English communication proficiency

Study design
Purpose
Duration
Selection
Timing
Statistical methods / analysis
Statistical Package for Social Sciences (SPSS version 15.0) will be used for data analysis. Student’s paired t-test will be used for comparison of continuous variables, including mean warfarin dose requirement, warfarin concentrations in plasma and percentage of adverse events. Two-way ANOVA will be used to detect the differences of ratios of means INR and warfarin concentration between the groups. A Chi-square test will be used for the analysis and comparison of the proportions of participants with INR “within target range” and “outside target range” between the two brands. Time-in-therapeutic-range (TTR) of these two groups will also be compared by using a Student’s t-test for independent samples.

Recruitment
Recruitment status
Not yet recruiting
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] 1155 0
The Queen Elizabeth Hospital - Woodville
Recruitment postcode(s) [1] 7003 0
5011 - Woodville South

Funding & Sponsors
Funding source category [1] 287499 0
University
Name [1] 287499 0
Therapeutcs Research Centre
University of South Australia
Address [1] 287499 0
37a Woodville Road
Woodville South
SA 5011
Country [1] 287499 0
Australia
Primary sponsor type
University
Name
Therapeutcs Research Centre, University of South Australia
Address
37a Woodville Road
Woodville South
SA 5011
Country
Australia
Secondary sponsor category [1] 286260 0
None
Name [1] 286260 0
Address [1] 286260 0
Country [1] 286260 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289475 0
Human Research Ethics Committee (TQEH/LMH/MH)
Ethics committee address [1] 289475 0
Basil Hetzel Institute DX465101
The Queen Elizabeth Hospital
28 Woodville Road
Woodville South SA 5011
Ethics committee country [1] 289475 0
Australia
Date submitted for ethics approval [1] 289475 0
Approval date [1] 289475 0
10/05/2013
Ethics approval number [1] 289475 0
HREC/13/TQEHLMH/45
Ethics committee name [2] 289476 0
UniSA's Human Research Ethics Committee
Ethics committee address [2] 289476 0
Research and Innovation Services
Ethics and Integrity
Mawson Lakes Campus
University of South Australia
GPO Box 2471, Adelaide, SA, 5001
Ethics committee country [2] 289476 0
Australia
Date submitted for ethics approval [2] 289476 0
Approval date [2] 289476 0
21/06/2013
Ethics approval number [2] 289476 0

Summary
Brief summary
Substitution of an innovator to a generic drug product has been continuously rising. In the US, approximately $8 billion to $10 billion is the average cost saving per year of brand substitution and the generic drug prescription has increased from 19% in 1984 to 60-70% in 2009. The increase in drug brand substitution is a call for scientific
attention of the appropriateness of available bioequivalence (BE) study guidelines at present. If two products are said to be bioequivalent it means that they would be expected to be, for all intents and purposes, the same. The conclusion of BE studies is based on the assumption that if the test and reference drug products exhibit similar in vitro (i.e. acceptable drug content, similar dissolution/release profile) and in vivo performance (i.e. acceptable bioavailability), these drug products should possess therapeutic equivalence which includes efficacy and safety. However, because bioequivalence studies are conducted in healthy volunteers, these studies may or may not provide definitive evidence to guarantee the therapeutic equivalence in patients.
This study aims to compare efficacy and safety of two warfarin products marketed in Australia, namely Coumadin registered trademark or Marevan registered trademark. The study is designed as an openlabel,
prospective, observational trial. A total of 300 patients who
are prescribed with either brand of warfarin will be recruited in accordance with the inclusion and exclusion criteria.
The patients will be followed up opportunistically as their medical appointments for anticoagulant evaluation. The
additional 5 mL of the participant blood samples and about 25 mL of urine samples will be collected at each visit.
Total and free racemic, R- and S-warfarin enantiomer concentration in plasma, as well as 4',6,7,8, and 10hydroxywarfarin metabolites in urine will be quantified by LC MS/MS. The efficacy of the two warfarin brands will be
compared by evaluating International Normalized Ratio (INR) values. The safety profile evaluation will be achieved by recording any adverse drug reactions or adverse events in a questionnaire. The frequency of adverse events
reported from two groups of patients will be analyzed and compared.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 40998 0
Ms Rachada To-a-nan
Address 40998 0
Therapeutics Research Centre
Basil Hetzel Institute for Translational Research
37a Woodville Road, Woodville South
SA 5011
Country 40998 0
Australia
Phone 40998 0
+61 8 8222 7719
Fax 40998 0
Email 40998 0
toyry002@mymail.unisa.edu.au
Contact person for public queries
Name 40999 0
Dr Tom Robertson
Address 40999 0
Therapeutics Research Centre
Basil Hetzel Institute for Translational Research
37a Woodville Road, Woodville South
SA 5011
Country 40999 0
Australia
Phone 40999 0
+61 8 8222 6521
Fax 40999 0
Email 40999 0
Tom.Robertson@unisa.edu.au
Contact person for scientific queries
Name 41000 0
Prof Michael Roberts
Address 41000 0
Sansom Institute, University of South Australia
G.P.O. Box 2471, Adelaide
SA 5001
Country 41000 0
Australia
Phone 41000 0
+61 8 8302 2816
Fax 41000 0
Email 41000 0
m.roberts@uq.edu.au, Michael.Roberts@unisa.edu.au