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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] 280611 0
Nil
Universal Trial Number (UTN)
U1111-1131-43
Trial acronym
VitKer24
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Anticoagulation 286623 0
Condition category
Condition code
Blood 286900 286900 0 0
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] 285006 0
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] 287252 0
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] 287252 0
T=24 hours
Secondary outcome [1] 297756 0
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] 297756 0
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?
No
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
30
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)

Funding & Sponsors
Funding source category [1] 285371 0
Hospital
Name [1] 285371 0
Department of Clinical Haematology
Country [1] 285371 0
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] 284225 0
Individual
Name [1] 284225 0
Dr Sanjeev Chunilal
Address [1] 284225 0
Department of Clinical Haematolgy
Monash Medical Centre
246 Clayton Rd
Clayton, Vic 3168
Country [1] 284225 0
Australia
Secondary sponsor category [2] 284226 0
Individual
Name [2] 284226 0
Dr Huyen Tran
Address [2] 284226 0
Thrombosis and Haemostasis Unit
Department of Haematology
The Alfred Hospital
Commercial Road
Prahran
Vic 3181
Country [2] 284226 0
Australia
Other collaborator category [1] 276840 0
Individual
Name [1] 276840 0
Professor Carl Kirkpatrick
Address [1] 276840 0
Faculty of Pharmacy and Pharmaceutical Sciences
Monash University
381 Royal Parade
Parkville, VIC 3052
Country [1] 276840 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 287386 0
Southern Health Human Research Ethics Commitee A
Ethics committee address [1] 287386 0
Research Directorate
Southern Health
Monash Medical Centre
246 Clayton Rd
Clayton
Vic 3168
Ethics committee country [1] 287386 0
Australia
Date submitted for ethics approval [1] 287386 0
18/04/2012
Approval date [1] 287386 0
09/05/2012
Ethics approval number [1] 287386 0
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 34260 0
Address 34260 0
Country 34260 0
Phone 34260 0
Fax 34260 0
Email 34260 0
Contact person for public queries
Name 17507 0
Dr Noel Chan
Address 17507 0
Department of Clinical Haematology
Monash Medical Centre
246 Clayton Rd
Clayton
Vic 3168
Country 17507 0
Australia
Phone 17507 0
+61 3 9594 4044
Fax 17507 0
+61 3 9594 6240
Email 17507 0
[email protected]
Contact person for scientific queries
Name 8435 0
Dr Noel Chan
Address 8435 0
Department of Clinical Haematology
Monash Medical Centre
246 Clayton Rd
Clayton
Vic 3168
Country 8435 0
Australia
Phone 8435 0
+61 3 9594 4044
Fax 8435 0
+61 3 9594 6240
Email 8435 0
[email protected]

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