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 calcificationProgression 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
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