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Effect of Vitamin K2 (MK7) on Cardiovascular and Bone Disease in Dialysis Patients (RenaKvit)

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ClinicalTrials.gov Identifier: NCT02976246
Recruitment Status : Recruiting
First Posted : November 29, 2016
Last Update Posted : November 29, 2016
Sponsor:
Information provided by (Responsible Party):
Zealand University Hospital

Brief Summary:

Cardiovascular disease (CVD) is the most frequent cause of death in patients (ptt.) with chronic kidney disease (CKD). Compared to the general population death due to CVD is 10-20 times higher in CKD ptt. being treated with hemodialysis. Vascular calcification and hence arterial stiffness is of great importance for the high incidence of CVD.

CKD ptt. in dialysis treatment also have a 3 times higher risk of bone fractures. Both vertebral and other fractures of low energy are associated with a high mortality.

Matrix Gla Protein (MGP) is an important inhibitor of vascular calcification and Osteocalcin (OC) is an important regulator of bone metabolism. The function of both MGP and OC depend on vitamin K.

Vitamin K is supplied with food. The content is low in food recommended to CKD ptt. which is reflected in very low concentrations of vitamin K in their blood samples. A correlation between vitamin K level, incidence of vascular calcification and bone density has been proven; yet there are no trials elucidating the clinical effect of vitamin K on vascular calcification or bone strength.

The investigators will conduct a randomized placebo controlled trial examining the clinical effects of vitamin K2 on vascular calcification and bone mineralization in order to prevent and treat CVD and bone disease in CKD ptt.

Primary study endpoints:

  1. Changes in arterial stiffness assessed by pulse wave examination
  2. Changes in bone mineral density (BMD) in distal radius assessed by DXA-scans.

Secondary study endpoints:

Changes in coronary artery and valvular calcification assessed by heart-CT-scans, blood pressure, body composition, total and regional BMD, lateral column/aortic calcification score as well as a panel of correlating blood tests.


Condition or disease Intervention/treatment Phase
Vitamin K Supplementation Endstage Renal Disease Cardiovascular Disease Bone Disease Dietary Supplement: Vitamin K2 (MK7) Other: Placebo Phase 2 Phase 3

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Detailed Description:

BACKGROUND

Vascular calcification is a significant problem among patients (ptt.) with chronic kidney disease (CKD) and the prevalence of aortic calcification is twice as high as the general population e.g. Cardiovascular disease (CVD) is the most frequent cause of death in ptt. with CKD. Death due to CVD is 10-20 times higher in CKD ptt. being treated with hemodialysis compared to the background population. Whereas atherosclerosis is a dominating cause of CVD in the general population CKD ptt. tend to develop medial calcification and hence arterial stiffness which is thought to be of great importance in the high incidence of CVD.

CKD ptt. in dialysis treatment also have a 3 times higher risk of bone fractures compared to the general population. Both vertebral and other fractures of low energy are associated with a high mortality in CKD ptt.

The genesis of the arteriosclerosis is still unresolved but seems to be multifactorial. The impaired kidney function itself and the treatment so far both seem to be of importance. The vitamin K-dependent Gla proteins; Matrix Gla Protein (MGP) and Osteocalcin (OC) are described as the most potent inhibitors of vascular calcification and osteoporosis. Until recently CKD ptt. have been treated with vitamin K antagonists which just adds to the focus on vitamin K in this progressive, vascular calcification- and bone demineralization process.

Vitamin K is supplied with food. It consists of several subtypes, e.g. vitamin K1 which is transformed into K2 during digestion. The recommended diet for CKD ptt. is low on vitamin K which is reflected in very low concentrations of vitamin K in blood samples from CKD ptt. in hemodialysis. A supplement of vitamin K1 or K2 will make activation possible for MGP and OC by increasing the concentration of vitamin K2.

A correlation between vitamin K level and incidence of vascular calcification in dialysis ptt. has been proven; yet there are no trials elucidating the clinical effect of vitamin K on vascular calcification in CKD ptt. There are not any trials elucidating the effect of vitamin K on bone strength or number of fractures in dialysis ptt, although a relation between vitamin K and bone mineral density in dialysis ptt. has been shown and a significant increase in age related bone strength was found in a study by introducing a daily supplement of vitamin K.

OBJECTIVE AND HYPOYHESIS

To examine the clinical effect of vitamin K2(MK7) on arterial stiffness assessed by pulse wave examination and bone mineral density assessed by DXA-scans in a group of dialysis ptt. in order to be able to prevent and treat cardiovascular and bone disease in CKD ptt. in the future.

The hypothesis is that a daily supplement of vitamin K2 (MK7) will reduce the calcification process in larger arteries, coronary arteries and -valves and hence reduce the risk of CVD as well as increase the bone mineral density and hence the frequency of bone fractures.

DESIGN

RenaKvit is an investigator initiated, prospective, randomized, double-blinded, placebo controlled intervention trial performed as a nationally, multicenter trial that will run for 2 years. Data will be compiled after 1 and 2 years.

The trial is divided into two sub-studies; RenaKvit-kar (vessel) and RenaKvit-knogle (bone), in which the effect of vitamin K2(MK7) on larger arteries, coronary arteries- and valves and the effect on bone with regards to bone mineral density and frequency of fractures are respectively examined.

PATIENTS AND RECRUITMENT

Ptt. will be equally divided by randomization and hence daily be given a tablet of either vitamin K2(MK7) or placebo. According to the criteria of inclusion ptt. will either join the RenaKvit-vessel or the bone group. If criteria are fulfilled ptt. are to join both vessel and bone groups.

Determined by calculation of statistical power, incl. a level of significance of 5%, a standard deviation of 0,95 and strength of 80%, a minimum of 40 + 140 ptt. will be included, thus taking potentially drop-outs in account. Both ptt. in hemo- and peritoneal dialysis treatment will be included.

Ptt. will be recruited by the dialysis departments at Roskilde, Nykoebing falster, Holbaek and Slagelse Hospitals.

There will be no fee for participating ptt.

MEDICINE

Patients are given either vitamin K 360 micrograms or placebo once daily during a period of 2 x 12 months. Both types of tablets will be of similar look and content, besides vitamin K2.

METHODS

  • Pulse Wave examination: Includes both pulse wave analysis and pulse wave velocity measurements. Done by using SphygmoCor©-pulse wave apparatus. Pulse wave examination is used as a measure of the arterial stiffness and is performed after standardized method.
  • 24-hour blood pressure and blood pressure measurements: Done by current Danish guidelines (17).
  • Coronary artery and -valve calcification: Assessed by CT-scans of the heart using the Agatston Score.
  • Bone Mineral Density: Assessed by DEXA-scans.
  • Lateral lumbal x- ray and aortic calcification score: A semi-quantitative scoring system used to describe the plaques on the front and the back of the aorta level with each level of the lumbar vertebrae. The method has been found to be predictive of vascular morbidity and mortality.
  • Measuring predictors/establishing a biobank: Partly as "routine tests" during dialysis and partly as special kits developed at Vejle Hospital.

STATISTICS

Both groups will have descriptive statistics performed for as well as the presentation of the total population, stratified for gender, age and weight.

Normal-distributed data will be expressed as mean value +/- standard deviation (SD), while other distributed data also will be expressed as median values (interquartile range; interquartile range, IQR). Categorical values will be expressed in numbers and percentages.

Normal-distributed variables will be compared with Student's t-test. Where found appropriate, logarithmic transformation shall be performed. Non-normally distributed variables will be compared with the Mann Whitney U test. Categorical values are to be compared with the Chi Square test.

Changes in the two groups over time will be analyzed by paired analysis, and the two groups compared with the non-paired analysis. Forward stepwise multivariate logistic regression analysis is carried out to correct significant confounders of the primary and secondary endpoints.

Analysis of Cox proportional hazards will be performed from time to first clinical event.

P≤0.05 will be considered statistically significant. All results - negative and positive - are expected to be published in peer-review magazines.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 140 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Effect of Vitamin K2 (MK7) on Cardiovascular and Bone Disease in Dialysis Patients: A Prospective, Randomized Placebo-controlled Double Blind Trial
Study Start Date : November 2016
Estimated Primary Completion Date : June 2019
Estimated Study Completion Date : August 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Menadione

Arm Intervention/treatment
Active Comparator: RenaKvit-vessel Active
One tablet of 360 micrograms vitamin K2 given once daily to examine the effect on vascular calcification
Dietary Supplement: Vitamin K2 (MK7)
One tablet of vitamin K2 (MK7) 360 micrograms given once daily.
Other Names:
  • menaquinon 7
  • MK7

Placebo Comparator: RenaKvit-vessel Control
One tablet of non-active drug given once daily
Other: Placebo
One tablet of placebo given once daily.

Active Comparator: RenaKvit-bone Active
One tablet of 360 micrograms vitamin K2 given once daily to examine the effect on bone metabolism
Dietary Supplement: Vitamin K2 (MK7)
One tablet of vitamin K2 (MK7) 360 micrograms given once daily.
Other Names:
  • menaquinon 7
  • MK7

Placebo Comparator: RenaKvit-bone control
One tablet of non-active drug given once daily
Other: Placebo
One tablet of placebo given once daily.




Primary Outcome Measures :
  1. For RenaKvit-vessel: Changes in arterial stiffness assessed by pulse wave examination reflecting vascular calcification (unit: m/s). [ Time Frame: 2 years ]
  2. For RenaKvit-bone: Changes in bone mineral density (BMD) in the distal radial bone (unit T-score). [ Time Frame: 2 years ]

Secondary Outcome Measures :
  1. For RenaKvit-vessel: Changes in coronary vascular and -valve calcification assessed by CT-scans of the heart (unit: Agatston-Score). [ Time Frame: 2 years ]
  2. For RenaKvit-vessel: Changes in vascular calcification measured by changes in blood pressure measurements (unit: mmHg). [ Time Frame: 2 years ]
  3. For RenaKvit-bone: Changes in body composition, BMD in the lumbar column, hip and whole body (unit: T-score). [ Time Frame: 2 years ]
  4. For RenaKvit-bone: Changes in abdominal aortic calcification measured by lateral X-ray of lumbar column (unit: abdominal aortic calcification score). [ Time Frame: 2 years ]

Other Outcome Measures:
  1. For both RenaKvit-vessel and bone: Changes in specific biochemical markers in blood related to increase in vitamin K-treatment (unit mol/L) [ Time Frame: 2 years ]
    Measuring levels of vitamin K1, vitamin K2, de-/phosphorylated stages of MGP and OC, PIVKA-II, FGF-23, bone specific alkaline phosphatase, CTx-1, P1NP.

  2. For both RenaKvit-vessel and bone: Changes in non-specific biochemical markers in blood related to increase in vitamin K-treatment (unit/L) [ Time Frame: 2 years ]
    Measuring levels of creatinine, urea, ionic calcium, phosphate, 25-OH vitamin D, 1,25-OH2-vitamin D, PTH, sodium, potassium, total CO2, magnesium, HGB, white cells, platelets, ferritin, iron, transferrin, HS CRP, cholesterol, ALT, LDH, alkaline phosphatase, bilirubin, albumin, APTT, haptoglobin, trombingeneration (CAT), F1 + F2.

  3. For both RenaKvit-vessel and bone: Changes in urine production [ Time Frame: 2 years ]
    Monitoring volume, creatinine, urea, protein, albumin.

  4. For both RenaKvit-vessel and bone: Changes in medication [ Time Frame: 2 years ]
    Monitoring phosphate binders, vitamin D analogues, calcimimetics, antihypertensives, cholesterol-lowering drugs.

  5. For both RenaKvit-vessel and bone: monitoring clinical events expected to have relation to trial outcomes. [ Time Frame: 2 years ]

    Monitoring thromboembolic events, bone fractures, parathyroidectomy, death A selection of clinical events will be monitored (occurrence of bone fractures, thromboembolic events, parathyroidectomy as well as changes in medicine consumption during the trial calculated in DDD) and clinical consultations will be held.

    In order to register a potential change during treatment with vitamin K all of the above mentioned are to be performed regularly.




Information from the National Library of Medicine

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, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age ≥ 18 years old
  • Life expectancy > 2 years
  • Written consent following oral information
  • Permanent treatment with dialysis ≥ 3 months with either peritoneal or hemodialysis

Exclusion Criteria:

  • Treatment with vitamin K or vitamin K-antagonist by the beginning of the trial or 1 months within.
  • Chronic GI-malabsorption leading to a slower bowel transit (e.g. Celiac disease, Short bowel syndrome).
  • Ongoing malignancy (ongoing treatment/clinical controlled visits or diagnosed less than 5 years ago), excl. Non-Melanoma-Skin-Cancer (NMSC).
  • Abuse of alcohol or other euphoric drug.
  • Women who are pregnant or breast-feeding and women who are in the childbearing age without contraception.
  • Total/subtotal parathyroidectomy
  • Treatment with recombined PTH.
  • Treatment with bisphosphonates or other anti-osteoporotic drugs (Selective Estrogen Reuptake Modulators (SERM), strontium, renalat, denosumab).

Only RenaKvit-kar (vessel):

  • Atrial fibrillation/other arrhythmia of significance
  • Aortic stenosis of significance
  • Agatston score < 100 by heart-CT-scan
  • Bilateral upper arm fistula
  • Amputation above metatarsal level

Criteria of withdrawal:

  • Kidney transplantation
  • Starting treatment with vitamin K-antagonists
  • Wish to with draw from the participant
  • Unacceptable side effect to ingestion of vitamin K or placebo
  • Reasonable suspicion of lacking compliance regarding medication

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02976246


Contacts
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Contact: Karin Levy-Schousboe, phd student +45 2335 1803 kshb@regionsjaelland.dk
Contact: Peter Marckmann, MDS +45 2335 1228 pmar@regionsjaelland.dk

Locations
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Denmark
Holbaek Hospital Not yet recruiting
Holbaek, Denmark, 4300
Contact: Marianne Berthelsen, MDS       mbte@regionsjaelland.dk   
Zealand University Hospital Recruiting
Roskilde, Denmark, 4000
Contact: Karin Levy-Schousboe, phd student    +45 23351803    kshb@regionsjaelland.dk   
Contact: Peter Marckmann, MDS    +45 23351228    pmar@regionsjaelland.dk   
Sponsors and Collaborators
Zealand University Hospital
Investigators
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Study Director: Peter Marckmann, MDS Zealand University Hospital
Study Director: Ditte Hansen, MDS Herlev Hospital
Study Director: Marie Frimodt-Moeller, MDS Steno Diabetes Center Copenhagen

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Responsible Party: Zealand University Hospital
ClinicalTrials.gov Identifier: NCT02976246     History of Changes
Other Study ID Numbers: RenaKvit
First Posted: November 29, 2016    Key Record Dates
Last Update Posted: November 29, 2016
Last Verified: November 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Additional relevant MeSH terms:
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Cardiovascular Diseases
Bone Diseases
Kidney Failure, Chronic
Musculoskeletal Diseases
Renal Insufficiency, Chronic
Renal Insufficiency
Kidney Diseases
Urologic Diseases
Vitamins
Vitamin K
Vitamin K 2
Vitamin MK 7
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs
Antifibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Hemostatics
Coagulants