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Vitamin K1 to Slow Progression of Vascular Calcification in HD Patients

Information source: RWTH Aachen University
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Cardiovascular Diseases

Intervention: Vitamin K1 (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: RWTH Aachen University

Official(s) and/or principal investigator(s):
Jürgen Floege, Prof. Dr., Principal Investigator, Affiliation: University Hospital of RWTH Aachen -Department of Medicine II, Nephrology and Clinical Immunology

Overall contact:
Jürgen Floege, Prof. Dr., Phone: 0049 241 80-89530, Email: juergen.floege@rwth.aachen.de

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 a total of 348 HD patients over a period of 18 months.

Clinical Details

Official title: Vitamin K1 to Slow Progression of Vascular Calcification in Hemodialysis Patients

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Progression of coronary artery calcification and thoracic aortic calcification

Secondary outcome:

Progression of aortic valve calcification

Progression of mitral valve calcification

Mortality from any cause within 18 months after the treatment

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

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

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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

- Coronary stent

- Hemoglobin < 70 g/L

- Women who are pregnant or breastfeeding

- 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

Locations and Contacts

Jürgen Floege, Prof. Dr., Phone: 0049 241 80-89530, Email: juergen.floege@rwth.aachen.de

Université catholique de Louvain - Department of Nephrology, Brussels, Belgium; Not yet recruiting
Michel Jadoul, Prof. Dr.
Michel Jadoul, Prof. Dr., Principal Investigator

KfH curatorship of dialysis and Renal transplantation e.V., Aachen 52074, Germany; Recruiting
Robert Böhm, MD, Phone: 0049 241 98900 0, Email: robert.boehm@kfh-dialyse.de
Robert Böhm, MD, Principal Investigator

University Hospital of RWTH Aachen, Department of Medicine II, Aachen, Germany; Recruiting
Prof. Dr. Floege
Jürgen Floege, Prof. Dr., Principal Investigator

Clinical Center of Coburg - Department of Medical Clinic III, Nephrology, Coburg, Germany; Not yet recruiting
Markus Ketteler, Prof. Dr.
Markus Ketteler, Prof. Dr., Principal Investigator

KfH curatorchip of dialysis and Renal transplantation e.V., Düsseldorf, Germany; Not yet recruiting
Stegbauer Johannes, MD, Email: johannes.stegbauer@med.uni-duesseldorf.de
Stegbauer Johannes, MD, Principal Investigator

University Hospital Düsseldorf - Department of Nephrology, Düsseldorf, Germany; Not yet recruiting
Ralf Westenfeld, PD Dr.
Ralf Westenfeld, PD Dr., Principal Investigator

MVZ Diaverum Erkelenz/ Heinsberg, Erkelenz, Germany; Recruiting
Thilo Krüger, MD, Phone: 0049 241 80 35425, Email: tkrueger@ukaachen.de
Thilo Krüger, MD, Principal Investigator

University hospital of Erlangen - Department of Medicine 4, Nephrology and Hypertension, Erlangen, Germany; Recruiting
Johannes Jacobi, PD Dr.
Johannes Jacobi, PD Dr., Principal Investigator

KfH curatorchip of dialysis and Renal transplantation e.V., Nürnberg, Germany; Recruiting
Michael Leidig, MD, Phone: 0049 911 9809 140, Email: michael.leidig@klinikum-nuernberg.de
Michael Leidig, MD, Principal Investigator

University of Milan - Renal Division, Milano, Italy; Not yet recruiting
Mario Cozzolino, Prof. Dr.
Mario Cozzolino, Prof. Dr., Principal Investigator

University Hospital Maastricht- Department of Internal Medicine & Nephrology, Maastricht, Netherlands; Not yet recruiting
Karel Leunissen, Prof. Dr.
Karel Leunissen, Prof. Dr., Principal Investigator

University Hospital Katowice - Department of Nephrology, Katowice, Poland; Not yet recruiting
Andzej Wiecek, Prof. Dr.
Andzej Wiecek, Prof. Dr., Principal Investigator

University Hospital at Huddings, Karolinska Institute Stockholm - Department of Renal Medicine K56, Stockholm, Sweden; Not yet recruiting
Peter Stenvinkel, Prof. Dr.
Peter Stenvinkel, Prof. Dr., Principal Investigator

Additional Information

Starting date: October 2013
Last updated: November 4, 2014

Page last updated: August 23, 2015

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