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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]

None

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Atrial fibrillation

Venous thrombosis

Pulmonary embolism

Recurrent emboli

Prosthetic valve replacement

Acute myocardial infarction (to prevent systemic embolism)

Condition category

Condition code

Cardiovascular

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]

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]

Percentage of the patients whose International Normalized Ratio fall within and outside target ranges.

Timepoint [1]

At baseline, week 1, 2, 3, and 4 after each drug brand administration.

Secondary outcome [1]

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]

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?

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

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

Recruitment hospital [1]

The Queen Elizabeth Hospital - Woodville

Recruitment postcode(s) [1]

5011 - Woodville South

Funding & Sponsors

Funding source category [1]

University

Name [1]

Therapeutcs Research Centre
university of South Australia

Address [1]

37a Woodville Road
Woodville South
SA 5011

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Human Research Ethics Committee (TQEH/LMH/MH)

Ethics committee address [1]

Basil Hetzel Institute DX465101
The Queen Elizabeth Hospital
28 Woodville Road
Woodville South SA 5011

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

29/04/2013

Ethics approval number [1]

HREC/12/TQEHLMH/194

Ethics committee name [2]

UniSA's Human Research Ethics Committee

Ethics committee address [2]

Research and Innovation Services
Ethics and Integrity
Mawson Lakes Campus 
University of South Australia 
GPO Box 2471, Adelaide, SA, 5001

Ethics committee country [2]

Australia

Date submitted for ethics approval [2]

Approval date [2]

21/06/2013

Ethics approval number [2]

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

Ms Rachada To-a-nan

Address

Therapeutics Research Centre
Basil Hetzel Institute for Translational Research
37a Woodville Road, Woodville
SA 5011

Country

Australia

Phone

+61 8 8222 7719

Fax

[email protected]

Contact person for public queries

Name

Tom Robertson

Address

Therapeutics Research Centre
Basil Hetzel Institute for Translational Research
37a Woodville Road, Woodville
SA 5011

Country

Australia

Phone

+61 8 8222 6521

Fax

[email protected]

Contact person for scientific queries

Name

Michael Roberts

Address

Sansom Institute, University of South Australia
G.P.O. Box 2471, Adelaide, SA 5001

Country

Australia

Phone

+61 8 8302 2816

Fax

[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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