Vitamin K1 to Slow Progression of Vascular Calcification in HD Patients (VitaVasK)

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2012 by RWTH Aachen University
Sponsor:
Information provided by (Responsible Party):
RWTH Aachen University
ClinicalTrials.gov Identifier:
NCT01742273
First received: December 3, 2012
Last updated: January 3, 2014
Last verified: July 2012
  Purpose

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.


Condition Intervention Phase
Vitamin K1 to Slow the Progression of Thoracic Aortic and Coronary Artery Calcification
Drug: Vitamin K1
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Vitamin K1 to Slow Progression of Vascular Calcification in Hemodialysis Patients

Resource links provided by NLM:


Further study details as provided by RWTH Aachen University:

Primary Outcome Measures:
  • Progression of coronary artery calcification and thoracic aortic calcification [ Time Frame: 18 months ] [ Designated as safety issue: No ]
    Progression of coronary artery calcification and thoracic aortic calcification(absolute change of the volume score at the 18-month MSCT versus the baseline MSCT)


Secondary Outcome Measures:
  • Progression of aortic valve calcification [ Time Frame: 18 months ] [ Designated as safety issue: No ]
    Progression of aortic valve calcification (absolute change of the Agatston-Score and volume score at the 18-month MSCT versus the baseline MSCT)

  • Progression of mitral valve calcification [ Time Frame: 18 months ] [ Designated as safety issue: No ]
    Progression of mitral valve calcification (absolute change of the Agatston-Score and volume score at the 18-month MSCT versus the baseline MSCT)

  • Mortality from any cause within 18 months after the treatment [ Time Frame: 6 years ] [ Designated as safety issue: No ]
    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 [ Time Frame: 6 years ] [ Designated as safety issue: No ]
    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


Estimated Enrollment: 348
Study Start Date: October 2013
Estimated Primary Completion Date: September 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
No Intervention: standard treatment (usual care)
standard treatment (usual care)
Experimental: Vitamin K1
Vitamin K1 (phylloquinone), thrice weekly p.o. (5mg)
Drug: Vitamin K1
Vitamin K1 to slow vascular calcification

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01742273

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

Locations
Belgium
Université catholique de Louvain - Department of Nephrology Not yet recruiting
Brussels, Belgium
Contact: Michel Jadoul, Prof. Dr.         
Principal Investigator: Michel Jadoul, Prof. Dr.         
Germany
University Hospital of RWTH Aachen, Department of Medicine II Recruiting
Aachen, Germany
Contact: Prof. Dr. Floege         
Principal Investigator: Jürgen Floege, Prof. Dr.         
Clinical Center of Coburg - Department of Medical Clinic III, Nephrology Not yet recruiting
Coburg, Germany
Contact: Markus Ketteler, Prof. Dr.         
Principal Investigator: Markus Ketteler, Prof. Dr.         
University Hospital Düsseldorf - Department of Nephrology Not yet recruiting
Düsseldorf, Germany
Contact: Ralf Westenfeld, PD Dr.         
Principal Investigator: Ralf Westenfeld, PD Dr.         
University hospital of Erlangen - Department of Medicine 4, Nephrology and Hypertension Not yet recruiting
Erlangen, Germany
Contact: Johannes Jacobi, PD Dr.         
Principal Investigator: Johannes Jacobi, PD Dr.         
Italy
University of Milan - Renal Division Not yet recruiting
Milano, Italy
Contact: Mario Cozzolino, Prof. Dr.         
Principal Investigator: Mario Cozzolino, Prof. Dr.         
Netherlands
University Hospital Maastricht- Department of Internal Medicine & Nephrology Not yet recruiting
Maastricht, Netherlands
Contact: Karel Leunissen, Prof. Dr.         
Principal Investigator: Karel Leunissen, Prof. Dr.         
Poland
University Hospital Katowice - Department of Nephrology Not yet recruiting
Katowice, Poland
Contact: Andzej Wiecek, Prof. Dr.         
Principal Investigator: Andzej Wiecek, Prof. Dr.         
Sweden
University Hospital at Huddings, Karolinska Institute Stockholm - Department of Renal Medicine K56 Not yet recruiting
Stockholm, Sweden
Contact: Peter Stenvinkel, Prof. Dr.         
Principal Investigator: Peter Stenvinkel, Prof. Dr.         
Sponsors and Collaborators
RWTH Aachen University
Investigators
Principal Investigator: Jürgen Floege, Prof. Dr. University Hospital of RWTH Aachen -Department of Medicine II, Nephrology and Clinical Immunology
  More Information

No publications provided

Responsible Party: RWTH Aachen University
ClinicalTrials.gov Identifier: NCT01742273     History of Changes
Other Study ID Numbers: VitaVasK, 2010-021264-14
Study First Received: December 3, 2012
Last Updated: January 3, 2014
Health Authority: Germany: Federal Institute for Drugs and Medical Devices

Additional relevant MeSH terms:
Calcinosis
Coronary Artery Disease
Arteriosclerosis
Calcium Metabolism Disorders
Metabolic Diseases
Coronary Disease
Myocardial Ischemia
Heart Diseases
Cardiovascular Diseases
Arterial Occlusive Diseases
Vascular Diseases
Vitamin K 1
Vitamin K
Vitamins
Micronutrients
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions
Antifibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Hemostatics
Coagulants
Hematologic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on July 26, 2014