Clinical trial NCT01742273: Vitamin K1 to Slow Progression of Vascular Calcification in HD Patients
Official title: Vitamin K1 to Slow Progression of Vascular Calcification in Hemodialysis Patients
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Cardiovascular Diseases
Lead sponsor: RWTH Aachen University
Sponsor class: OTHER
First posted: 2012-12-05
Enrollment: 63
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Patients on hemodialysis (HD) exhibit an immensely increased cardiovascular mortality associated with extensive vascular calcification (VC). In the past years the development of VC was discovered to be actively regulated and as being influenced by inhibitors of calcification (e.g. matrix-Gla-protein, fetuin-A). MGP is produced by vascular smooth muscle cells and needs post-translational modification by vitamin K dependent gamma-carboxylation to be fully active. Based on the demonstration of increased PIVKA-II levels, about 97% of all HD patients exhibit insufficient carboxylation activity. We therefore aim in this randomized, controlled study to retard the progress of coronary and aortal calcification as assessed by thoracic multislice-CT by the thrice weekly administration of 5 mg vitamin K1 (phylloquinone) to about 100 HD patients over a period of 18 months.

Detailed description: Patients on hemodialysis (HD) exhibit an immensely increased cardiovascular mortality associated with extensive vascular calcification (VC). This forms - at least partially - the reason for the excessively increased cardiovascular mortality in this population.

In the past years the development of VC was discovered to be actively regulated and as being influenced by inhibitors of calcification (e.g. matrix-Gla-protein, fetuin-A). Matrix Gla protein (MGP) is a powerful vascular wall-based inhibitor of VC. MGP is produced by vascular smooth muscle cells and needs post-translational modification by vitamin K dependent gamma-carboxylation to be fully active. The role of MGP was discovered in knock-out mice, which died from rupture of a massively calcified aorta. Functional vitamin K deficiency induced by administration of warfarin leads to the development of VC, which in turn can be inhibited by subsequent administration of vitamin K1. Warfarin inhibits the vitamin K mediated gamma-carboxylation, which leads to the production of noncarboxylated and inactive MGP (ucMGP).

Warfarin is widely used due to its inhibitory capacity on the activation of coagulation factors. Now it has been discovered that the use of vitamin K inhibitors influences vascular health: long-term use of warfarin is associated with an increased prevalence and extent of VC in the normal population and HD patients. Warfarin is also a crucial risk factor for the development of calciphylaxis, a life-threatening complication in HD patients characterised by calcified cutaneous vessels. In turn, administration of vitamin K1 was accompanied by reduced intima-media-thickness (IMT) and increased elasticity of vessels in postmenopausal women.

Based on the demonstration of increased PIVKA-II levels, about 97% of all HD patients exhibit insufficient carboxylation activity. Together with the increased VC they represent an ideal population for interventional trials in the vitamin K system. Recently we were able to demonstrate that supplementation of vitamin K1 in such patients is well tolerated, shows only very few side effects and induces a dose dependent decrease of the inactive form Dephosphorylated noncarboxylated matrix Gla protein (dpucMGP) in serum over a six weeks period. In this trial we also observed that all dialysis patients included had insufficient vitamin K serum levels, indicating no substantial influence of food intake on vitamin K deficiency. In addition, this demonstrates that all patients have insufficient vitamin K levels to facilitate adequate MGP carboxylation.

Eligibility criteria: Inclusion Criteria:

* Male or Female minimum 18 years of age
* Not less than 6 months on hemodialysis
* Cardiovascular calcification percent (coronary artery volume score \> 100)
* Written consent to take part in the study
* Life expectancy not less than 18 months

Exclusion Criteria:

* Known hypersensitivity against Vitamin K1
* History of thrombosis
* intake of Vitamin K
* tumor disease
* pulse \>100/min (resting heart rate)
* Intake of vitamin K antagonists (e.g. Marcumar) at baseline or in the 3 months prior to baseline
* Inflammatory bowel disease
* Short-bowel syndrome
* Significant liver dysfunction
* more than one stent in one coronary artery plus one or more stents in an additional artery
* Hemoglobin \< 70 g/L
* Women who are pregnant or breastfeeding
* Women without sufficient contraception
* Alcohol or drug abuse
* Mental condition rendering the subject unable to understand the nature, scope and possible consequences of the study
* Subject unlikely to comply with protocol, e.g. uncooperative attitude, inability to return for follow-up-visits and unlikelihood of completing the study
* Participation in a parallel clinical trial or participation in another clinical trial within the previous 3 months
* Subjects who are in any state of dependency to the sponsor or the investigators
* Employees of the sponsor or the investigators
* Subjects who have been committed to an institution by legal or regulatory order

Primary outcomes:
measure: Progression of coronary artery calcification and thoracic aortic calcification
timeFrame: 18 months
Secondary outcomes:
measure: Progression of aortic valve calcification
timeFrame: 18 months
measure: Progression of mitral valve calcification
timeFrame: 18 months
measure: Mortality from any cause within 18 months after the treatment
timeFrame: 6 years
measure: Major adverse cardiovascular events: myocardial infarction, stroke, acute coronary syndrome,embolism, symptom-driven revascularization, death from cardiovascular cause within 18 months after start of treatment
timeFrame: 6 years
Other outcomes:
Locations:
city: Brussels
country: Belgium
facility: Université catholique de Louvain - Department of Nephrology
city: Leuven
country: Belgium
facility: UZ Leuven, Dept. of Nephrology
city: Aachen
country: Germany
facility: KfH Curatorship for Dialysis and Renal transplantation e.V.
city: Aachen
country: Germany
facility: University Hospital of RWTH Aachen, Department of Medicine II
city: Coburg
country: Germany
facility: Clinical Center of Coburg - Department of Medical Clinic III, Nephrology
city: Düsseldorf
country: Germany
facility: MVZ DaVita Düsseldorf
city: Düsseldorf
country: Germany
facility: KfH Curatorchip for Dialysis and Renal Transplantation e.V.
city: Düsseldorf
country: Germany
facility: University Hospital Düsseldorf - Department of Nephrology
city: Erkelenz
country: Germany
facility: MVZ Diaverum Erkelenz/ Heinsberg
city: Erlangen
country: Germany
facility: University hospital of Erlangen - Department of Medicine 4, Nephrology and Hypertension
city: Geilenkirchen
country: Germany
facility: Internistische Facharztpraxis, Abteilung Kardiologie - Nephrologie, Dialyse Geilenkirchen
city: Stolberg
country: Germany
facility: KfH Curatorchip for Dialysis and Renal Transplantation e.V.
city: Stockholm
country: Sweden
facility: University Hospital at Huddings, Karolinska Institute Stockholm - Department of Renal Medicine K56
Study officials:
affiliation: University Hospital of RWTH Aachen -Department of Medicine II, Nephrology and Clinical Immunology
name: Jürgen Floege, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References: