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Trial registered on ANZCTR

Registration number

ACTRN12612000665831

Ethics application status

Approved

Date submitted

4/06/2012

Date registered

21/06/2012

Date last updated

24/10/2012

Type of registration

Prospectively registered

Titles & IDs

Public title

Efficacy of Oral Vitamin K to reverse chronic Warfarin Anticoagulation at 24 hours: A Phase 2 pharmacological Modelling Study.

Scientific title

In a population of patients receiving chronic warfarin therapy, what is the dose of oral vitamin K required to reverse 95% of the population to an INR<1.5 at 24 hours after a single dose administration and cessation of warfarin?

Secondary ID [1]

Nil

Universal Trial Number (UTN)

U1111-1131-43

Trial acronym

VitKer24

Linked study record

Health condition

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

Anticoagulation

Condition category

Condition code

Blood

Clotting disorders

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Eligible consecutive patients, who will be completing a defined duration of warfarin anticoagulation (between 3 to 6 months) for venous thrombo-embolic disease, will receive a single dose of oral vitamin K in the morning of the day of warfarin cessation. We will enrol a total of 30 patients, i.e 6 patients in each of the 5 dose arms, according to a single dose ascending design. In particular, block of 3 patients will be enrolled consecutively in each of the 0mg, 1mg, 3mg, 5mg, and 7mg arms until six patients is enrolled in each arm.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

This is a phase 2 study with a total of 5 dose arms at the time of warfarin cessation, including the control group (0mg).

Control group

Dose comparison

Outcomes

Primary outcome [1]

The lowest effective dose of oral Vitamin K (Neokay) that is capable of at least 95% reversal of an INR to <1.5 at 24 hours following oral administation derived from a non linear, mixed effects population PK-PD pharmacological model.

Timepoint [1]

T=24 hours

Secondary outcome [1]

Generation of a pharmacological model of the dose and time dependent vitamin K induced reversal of warfarin. Pharmacokinetic (PK) data for warfarin and Vitamin K will be combined with pharmacodynamic (PD) endpoint data, and simultaneously analysed by nonlinear mixed-effects modelling (NONMEM version 7, Globomax, USA). Between-subject variability (BSV) will be calculated exponentially and assumed to follow a lognormal distribution. Residual unexplained variability will be modelled as additive and/or exponential random error. Initially, the PK of warfarin and Vitamin K will be analysed independently, prior to simultaneous PK and PD modelling. The latter will be adapted to a previously well established model that describes the delay between warfarin concentration and PD (INR and coagulation factors) response (*). Model selection will be based on the objective function value computed by NONMEM, visual inspection of diagnostic scatter plots and the biological plausibility of parameter estimates. For nested models, statistical comparison will be undertaken on the basis of a chi-squared test in which a decrease in the OBJ of 3.84 units (p < 0.05) is considered significant.

(*) Holford, N. H.G. Clinical Pharmacokinetics and Pharmacodynamics of Warfarin: Understanding the Dose-Effect Relationship. Clinical Pharmacokinetics. 11(6):483-504 (1986).

Timepoint [1]

T=24 hours

Eligibility

Key inclusion criteria

Patients aged 18 years and older, capable of giving informed consent, who are receiving warfarin for the treatment of VTE and who are about to end anticoagulation or temporarily cease anticoagulation as they are deemed to be at low risk of thrombo-embolic recurrence.

Minimum age

18 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

Any indications for the need for ongoing anticoagulation or high thromboembolic risk patients (e.g: AF, antiphospholipid syndrome, recurrent idiopathic VTE , Stroke or TIA).
Fat malabsorption syndromes, biliary atresia, pancreatic insufficiency.
Allergic reaction to Vitamin K and coconut oil.
Unstable INR, or recent INR<2, or INR>4
Pregnant women.

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)

Consecutive eligible patients will be enrolled in the study according to a standard single ascending dose design in the five arms of the study (0mg, 1mg, 3mg, 5mg,7mg)

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Standard Single Ascending Dose Design (SAD)

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Other

Other design features

This is a standard Phase 2 study design using sequential standard single ascending dose design (SAD).

Phase

Phase 2

Type of endpoint/s

Pharmacokinetics / pharmacodynamics

Statistical methods / analysis

Recruitment

Recruitment status

Recruiting

Date of first participant enrolment

Anticipated

2/07/2012

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)

Funding & Sponsors

Funding source category [1]

Hospital

Name [1]

Department of Clinical Haematology

Address [1]

Monash Medical Centre,
246 Clayton Rd
Clayton, Vic 3168

Country [1]

Australia

Primary sponsor type

Individual

Name

Dr Noel Chan

Address

Department of Clinical Haematology
Monash Medical Centre
246 Clayton Rd
Clayton, Vic 3168

Country

Australia

Secondary sponsor category [1]

Individual

Name [1]

Dr Sanjeev Chunilal

Address [1]

Department of Clinical Haematolgy
Monash Medical Centre
246 Clayton Rd
Clayton, Vic 3168

Country [1]

Australia

Secondary sponsor category [2]

Individual

Name [2]

Dr Huyen Tran

Address [2]

Thrombosis and Haemostasis Unit
Department of Haematology
The Alfred Hospital
Commercial Road
Prahran
Vic 3181

Country [2]

Australia

Other collaborator category [1]

Individual

Name [1]

Professor Carl Kirkpatrick

Address [1]

Faculty of Pharmacy and Pharmaceutical Sciences
Monash University
381 Royal Parade
Parkville, VIC 3052

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Southern Health Human Research Ethics Commitee A

Ethics committee address [1]

Research Directorate 
Southern Health
Monash Medical Centre
246 Clayton Rd
Clayton
Vic 3168

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

18/04/2012

Approval date [1]

09/05/2012

Ethics approval number [1]

12118A

Summary

Brief summary

The peri-operative management of patients on long-term warfarin therapy is a common clinical problem which poses particular problems and uncertainties given the absence of clinical trials. Approximately 400,000 patients are assessed annually in North America for temporary interruption of warfarin therapy for elective surgical or invasive procedures. In Australia, this amounts to approximately 23,000 patients per year, and it is estimated that 700 such patients undergo surgical intervention annually at Southern Health. It is also likely that warfarin will remain the predominant form of anticoagulation for a long time despite the arrival of the novel anticoagulants.

For many procedures, patients need to stop their warfarin to avoid bleeding at surgery and resume this postoperatively to prevent thrombosis. The literature does not define a standard of care so that there is considerable variability in how this is achieved with strategies ranging from cessation of warfarin 5 days prior, to “bridging” with heparin therapy when the INR falls below 2. The former approach is simpler but can expose high-risk patients to a significant risk of thrombosis whereas the latter requires timely coordination, and is resource intensive as well as costly. On the other hand, if warfarin is inadequately reversed many elective procedures might be cancelled at short notice inconveniencing patients and wasting valuable surgical operating times. 

Therefore, there is a need to identify a safe, simple, effective and readily available strategy to reverse warfarin across a broad spectrum of perioperative scenarios.  Recently, Burbury et al (BJH 2011) demonstrated that 3 mg of intravenous (IV) Vitamin K (VK1) administered on the eve of surgery is effective and safe at reversing the anticoagulant effect warfarin in most patients. Furthermore, neither warfarin “resistance” nor thrombo-embolism was observed when warfarin was resumed postoperatively (0%, 95%CI: 0% to 2.6%). However, this approach requires the inconvenience of attending an outpatient clinic for insertion of an intravenous cannula for IV VK1 administration.  Moreover, there is a small risk (3 in 10, 000) of allergic/anaphylactic reaction with the IV route. 

Although slower in its onset of action, a few studies have shown that given sufficient time, oral VK1 is as effective and safe in reversing warfarin as IV VK1.  The oral dose represents a convenient and cheaper way of administration with minimal adverse reaction when compared to the IV formulation.  Moreover, oral VK1 is a convenient way of administration with minimal adverse reaction compared to the IV route. This oral approach, if proven, would simplify pre-operative management of warfarin therapy, and has the potential to improve the care of thousands of patients in the perioperative setting. 

However, the optimal dose of VK1 that is required to reverse the INR of the majority (95%) of patients without causing warfarin resistance is uncertain. Firstly, we propose a prospective phase 2 dose finding study using pharmacological modeling and simulation to predict the effective dose for oral VK1 capable of reversing warfarin induced anticoagulation in a group of patients who are going to complete a defined period of anticoagulation therapy and therefore at minimal risk. Once an effective oral VK1 dose is identified, we plan to validate this dose in a prospective phase 3 clinical trial involving elective surgical patients.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Address

Country

Phone

Fax

Contact person for public queries

Name

Dr Noel Chan

Address

Department of Clinical Haematology
Monash Medical Centre
246 Clayton Rd
Clayton
Vic 3168

Country

Australia

Phone

+61 3 9594 4044

Fax

+61 3 9594 6240

noel.chan@southernhealth.org.au

Contact person for scientific queries

Name

Dr Noel Chan

Address

Department of Clinical Haematology
Monash Medical Centre
246 Clayton Rd
Clayton
Vic 3168

Country

Australia

Phone

+61 3 9594 4044

Fax

+61 3 9594 6240

noel.chan@southernhealth.org.au

No information has been provided regarding IPD availability

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No Supporting Document Provided

Results publications and other study-related documents

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