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Trial registered on ANZCTR


Registration number
ACTRN12613000702718
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
A comparative bioequivalence study of warfarin brands in cardiovascular patients
Scientific title
A randomized, open label, two-way, two-period, crossover study comparing therapeutic effect of two warfarin brands in clinically stable patients already receiving warfarin treatment
Secondary ID [1] 282723 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Atrial fibrillation 289444 0
Venous thrombosis 289445 0
Pulmonary embolism 289446 0
Recurrent emboli 289447 0
Prosthetic valve replacement 289448 0
Acute myocardial infarction (to prevent systemic embolism) 289449 0
Condition category
Condition code
Cardiovascular 289771 289771 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm: 1 The patients are randomly assigned with warfarin tablet brand A (reference) for 4 weeks then will be swapped over to warfarin tablet brand B (test) for next 4 weeks. The drug dose regimen are equal to the previous ones of the patients.
Arm 2: The patients are randomly assigned with warfarin tablet brand B (test) for 4 weeks then will be swapped over to warfarin tablet brand A (reference) for next 4 weeks. The drug dose regimen are equal to the previous ones of the patients.

The first week of the second warfarin brand treatment period is regarded as the washout period and time to get the second drug brand steady-state. Regarding that warfarin half-life is approximately 20-24 hours, one week period is considered sufficient as the washout period of the first brand and the steady-state for the second brand.

The adherence is evaluated by tablet count on each visit, along with a medication and food diary given to the patients to record for their drug administration. Also warfarin concentration (total and free concentration) in plasma, and warfarin metabolites (4'-, 6-, 7-, 8-, and 10-hydroxywarfarin) concentration in urine will be analyzed by LC-MS/MS.
Intervention code [1] 287387 0
Treatment: Drugs
Comparator / control treatment
Coumadin tablet is used as a reference drug brand and Marevan tablet is the test brand.
Control group
Active

Outcomes
Primary outcome [1] 289856 0
Percentage of the patients whose International Normalized Ratio fall within and outside target ranges.
Timepoint [1] 289856 0
At baseline, week 1, 2, 3, and 4 after each drug brand administration.
Secondary outcome [1] 303396 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] 303396 0
At baseline, week 1, 2, 3, and 4 after each drug brand administration

Eligibility
Key inclusion criteria
1. Age greater than or equal to 18 years
2. Receiving warfarin treatment
3. Clinically stable with the same dose of warfarin yielding a stable (less than 0.5 unit change over the lead-in period) of INR value that falls within the target therapeutic range (2.0 -3.0 or 2.5-3.5) for at least 6 weeks
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Age less than 18 years
2. Allergy to any ingredients in warfarin product
3. Pregnancy or breast feeding
4. Non-adherence tendency
5. Psychiatric disorder or dementia
6. Significant renal dysfunction (adjusted creatinine clearance calculated by Cockcroft-Gault equation < 60 mL/min)
7. Significant liver dysfunction (AST, ALT > 3 times of upper limits)
8. Excessive alcohol consumption
9. Taking any medications, food or dietary supplement that significantly interact with warfarin
10. Limited English communication proficiency

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)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 4
Type of endpoint/s
Bio-equivalence
Statistical methods / analysis
The sample size is determined by a power analysis program (G*Power 3.1.3) for a statistical test of difference between two dependence means (matched pairs). Base on the assuming effect size of 0.5, alpha=0.05, beta=0.1, a total of 44 participants is needed. So the sample size of 50 participants is included to assure a sufficient power of the study. This sample size is consistent with the previous studies with the similar design that approximately 30-40 subjects were needed (Handler et al. 1998; Neutel & Smith 1998; Namazi et al. 2004).

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 treatment periods.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/07/2013
Actual
Date of last participant enrolment
Anticipated
31/07/2014
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
50
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 1154 0
The Queen Elizabeth Hospital - Woodville
Recruitment postcode(s) [1] 7004 0
5011 - Woodville South

Funding & Sponsors
Funding source category [1] 287498 0
University
Name [1] 287498 0
Therapeutcs Research Centre
university of South Australia
Country [1] 287498 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] 286259 0
None
Name [1] 286259 0
Address [1] 286259 0
Country [1] 286259 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289473 0
Human Research Ethics Committee (TQEH/LMH/MH)
Ethics committee address [1] 289473 0
Basil Hetzel Institute DX465101
The Queen Elizabeth Hospital
28 Woodville Road
Woodville South SA 5011
Ethics committee country [1] 289473 0
Australia
Date submitted for ethics approval [1] 289473 0
Approval date [1] 289473 0
29/04/2013
Ethics approval number [1] 289473 0
HREC/12/TQEHLMH/194
Ethics committee name [2] 289474 0
UniSA's Human Research Ethics Committee
Ethics committee address [2] 289474 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] 289474 0
Australia
Date submitted for ethics approval [2] 289474 0
Approval date [2] 289474 0
21/06/2013
Ethics approval number [2] 289474 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
or Marevan. The study design is a randomized, open-label, two-way, two-period, crossover study. A total of 50
patients who are prescribed with either brand of warfarin and clinically stable will be recruited in accordance with the
inclusion and exclusion criteria. The patients will be allocated as the assigned randomized treatment sequence into 2 groups. For the first 4 weeks, Group I will start with Coumadin and Group II will start with Marevan. Then the
participants will be crossed over to the other brand for another 4 weeks. Participant blood samples will be collected
at baseline and weekly until the end of the study. 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,
warfarin dose variation, mean warfarin dose to achieve target INR, area under the plasma concentrationtime
curve, and warfarin metabolites to drug ratio. The safety profile evaluation will be achieved by recording any adverse drug.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 40990 0
Ms Rachada To-a-nan
Address 40990 0
Therapeutics Research Centre
Basil Hetzel Institute for Translational Research
37a Woodville Road, Woodville
SA 5011
Country 40990 0
Australia
Phone 40990 0
+61 8 8222 7719
Fax 40990 0
Email 40990 0
[email protected]
Contact person for public queries
Name 40991 0
Tom Robertson
Address 40991 0
Therapeutics Research Centre
Basil Hetzel Institute for Translational Research
37a Woodville Road, Woodville
SA 5011
Country 40991 0
Australia
Phone 40991 0
+61 8 8222 6521
Fax 40991 0
Email 40991 0
[email protected]
Contact person for scientific queries
Name 40992 0
Michael Roberts
Address 40992 0
Sansom Institute, University of South Australia
G.P.O. Box 2471, Adelaide, SA 5001
Country 40992 0
Australia
Phone 40992 0
+61 8 8302 2816
Fax 40992 0
Email 40992 0
[email protected], [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

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