E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients will be recruited who are receiving long term warfarin therapy for the treatment or prevention of venous or arterial thrombosis or embolism |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10043566 |
E.1.2 | Term | Thromboembolism |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Vitamin K is necessary for the activation of clotting proteins normally needed to stop us from bleeding. Warfarin causes anticoagulation (blood−thinning) by inhibiting the vitamin K epoxide reductase (VKOR) enzyme responsible for the recycling of vitamin K in the liver. VKOR enzyme production is controlled by the vitamin K epoxide reductase gene (termed VKORC1). Some individuals can have mutations of the VKORC1 gene. These individuals produce VKOR enzyme with reduced activity. Vitamin K in the diet works in a directly opposite way to warfarin, counteracting the anticoagulation(blood thinning) response to warfarin. There are theoretical reasons, and a small amount of evidence to support that the antagonistic effect of dietary vitamin K might not be the same between patients with different genotypes. Our principal research objective is to assess this by exploring the inter−relationships between stability of anticoagulation control, dietary vitamin K intake and VKORC1 genotype. |
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E.2.2 | Secondary objectives of the trial |
Warfarin is metabolised, in part, by an enzyme called cytochrome P4502C9. There are 3 types of this enzyme, one with highest activity, one with medium activity, and one with low activity. By measuring the gene which controls this enzyme we will be able to look at the prevalence of CYP2C9 and VKORC1 polymorphisms in this large population. This will allow us to assess the contribution of both genes together, particularly having two genes giving enzymes of low activity, to how sensitive people are to warfarin and how stable their control of anticoagulation is. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patient being on warfarin for 9 months or more (so that percentage time in target range over the previous 6 months is not affected by the induction period of therapy where the correct maintenance dose is being established), and a target INR of 2.5.
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E.4 | Principal exclusion criteria |
Starting or stopping medication during the 6 months prior to study entry that might have interfered with warfarin, or having an illness during this time which might have affected warfarin dose, or having issues known to result in compliance with warfarin therapy being unreliable. |
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E.5 End points |
E.5.1 | Primary end point(s) |
. Weekly dietary intake of vitamin K will be assessed by asking a set of questions about their diet . Each participant will give a single blood sample (20 ml venous) for later VKORC1 and CYP2C9 genotyping. The former will be carried out using an established in-house PCR assay (Hatch et al. 2006), the latter by a published method (Kamali et al 2004). The percentage time each patient has spent in his/her target range in the previous 6 months will be calculated by the interpolation method (Azar et al. 1994) using a computer programme.
General linear Modelling will be used to assess the difference in mean distribution of percentage time in range for a six month period between GG and GA+AA groups, between high, medium and low vitamin K intake groups, and any interaction between genotype and vitamin K intake. Allowance will be made for covariates of age and gender and CYP2C9 genotype. The association between CYP2C9 and VKORC1 polymorphisms in combination and warfarin dose requirement will be assessed using appropriate tests. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | No |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Information not present in EudraCT |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the study will be the last assessment of the last patient. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |