<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02976246</url>
  </required_header>
  <id_info>
    <org_study_id>RenaKvit</org_study_id>
    <nct_id>NCT02976246</nct_id>
  </id_info>
  <brief_title>Effect of Vitamin K2 (MK7) on Cardiovascular and Bone Disease in Dialysis Patients</brief_title>
  <acronym>RenaKvit</acronym>
  <official_title>Effect of Vitamin K2 (MK7) on Cardiovascular and Bone Disease in Dialysis Patients: A Prospective, Randomized Placebo-controlled Double Blind Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Zealand University Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Zealand University Hospital</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Cardiovascular disease (CVD) is the most frequent cause of death in patients (ptt.) with&#xD;
      chronic kidney disease (CKD). Compared to the general population death due to CVD is 10-20&#xD;
      times higher in CKD ptt. being treated with hemodialysis. Vascular calcification and hence&#xD;
      arterial stiffness is of great importance for the high incidence of CVD.&#xD;
&#xD;
      CKD ptt. in dialysis treatment also have a 3 times higher risk of bone fractures. Both&#xD;
      vertebral and other fractures of low energy are associated with a high mortality.&#xD;
&#xD;
      Matrix Gla Protein (MGP) is an important inhibitor of vascular calcification and Osteocalcin&#xD;
      (OC) is an important regulator of bone metabolism. The function of both MGP and OC depend on&#xD;
      vitamin K.&#xD;
&#xD;
      Vitamin K is supplied with food. The content is low in food recommended to CKD ptt. which is&#xD;
      reflected in very low concentrations of vitamin K in their blood samples. A correlation&#xD;
      between vitamin K level, incidence of vascular calcification and bone density has been&#xD;
      proven; yet there are no trials elucidating the clinical effect of vitamin K on vascular&#xD;
      calcification or bone strength.&#xD;
&#xD;
      The investigators will conduct a randomized placebo controlled trial examining the clinical&#xD;
      effects of vitamin K2 on vascular calcification and bone mineralization in order to prevent&#xD;
      and treat CVD and bone disease in CKD ptt.&#xD;
&#xD;
      Primary study endpoints:&#xD;
&#xD;
        1. Changes in arterial stiffness assessed by pulse wave examination&#xD;
&#xD;
        2. Changes in bone mineral density (BMD) in distal radius assessed by DXA-scans.&#xD;
&#xD;
      Secondary study endpoints:&#xD;
&#xD;
      Changes in coronary artery and valvular calcification assessed by heart-CT-scans, blood&#xD;
      pressure, body composition, total and regional BMD, lateral column/aortic calcification score&#xD;
      as well as a panel of correlating blood tests.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      BACKGROUND&#xD;
&#xD;
      Vascular calcification is a significant problem among patients (ptt.) with chronic kidney&#xD;
      disease (CKD) and the prevalence of aortic calcification is twice as high as the general&#xD;
      population e.g. Cardiovascular disease (CVD) is the most frequent cause of death in ptt. with&#xD;
      CKD. Death due to CVD is 10-20 times higher in CKD ptt. being treated with hemodialysis&#xD;
      compared to the background population. Whereas atherosclerosis is a dominating cause of CVD&#xD;
      in the general population CKD ptt. tend to develop medial calcification and hence arterial&#xD;
      stiffness which is thought to be of great importance in the high incidence of CVD.&#xD;
&#xD;
      CKD ptt. in dialysis treatment also have a 3 times higher risk of bone fractures compared to&#xD;
      the general population. Both vertebral and other fractures of low energy are associated with&#xD;
      a high mortality in CKD ptt.&#xD;
&#xD;
      The genesis of the arteriosclerosis is still unresolved but seems to be multifactorial. The&#xD;
      impaired kidney function itself and the treatment so far both seem to be of importance. The&#xD;
      vitamin K-dependent Gla proteins; Matrix Gla Protein (MGP) and Osteocalcin (OC) are described&#xD;
      as the most potent inhibitors of vascular calcification and osteoporosis. Until recently CKD&#xD;
      ptt. have been treated with vitamin K antagonists which just adds to the focus on vitamin K&#xD;
      in this progressive, vascular calcification- and bone demineralization process.&#xD;
&#xD;
      Vitamin K is supplied with food. It consists of several subtypes, e.g. vitamin K1 which is&#xD;
      transformed into K2 during digestion. The recommended diet for CKD ptt. is low on vitamin K&#xD;
      which is reflected in very low concentrations of vitamin K in blood samples from CKD ptt. in&#xD;
      hemodialysis. A supplement of vitamin K1 or K2 will make activation possible for MGP and OC&#xD;
      by increasing the concentration of vitamin K2.&#xD;
&#xD;
      A correlation between vitamin K level and incidence of vascular calcification in dialysis&#xD;
      ptt. has been proven; yet there are no trials elucidating the clinical effect of vitamin K on&#xD;
      vascular calcification in CKD ptt. There are not any trials elucidating the effect of vitamin&#xD;
      K on bone strength or number of fractures in dialysis ptt, although a relation between&#xD;
      vitamin K and bone mineral density in dialysis ptt. has been shown and a significant increase&#xD;
      in age related bone strength was found in a study by introducing a daily supplement of&#xD;
      vitamin K.&#xD;
&#xD;
      OBJECTIVE AND HYPOYHESIS&#xD;
&#xD;
      To examine the clinical effect of vitamin K2(MK7) on arterial stiffness assessed by pulse&#xD;
      wave examination and bone mineral density assessed by DXA-scans in a group of dialysis ptt.&#xD;
      in order to be able to prevent and treat cardiovascular and bone disease in CKD ptt. in the&#xD;
      future.&#xD;
&#xD;
      The hypothesis is that a daily supplement of vitamin K2 (MK7) will reduce the calcification&#xD;
      process in larger arteries, coronary arteries and -valves and hence reduce the risk of CVD as&#xD;
      well as increase the bone mineral density and hence the frequency of bone fractures.&#xD;
&#xD;
      DESIGN&#xD;
&#xD;
      RenaKvit is an investigator initiated, prospective, randomized, double-blinded, placebo&#xD;
      controlled intervention trial performed as a nationally, multicenter trial that will run for&#xD;
      2 years. Data will be compiled after 1 and 2 years.&#xD;
&#xD;
      The trial is divided into two sub-studies; RenaKvit-kar (vessel) (n= 48) and RenaKvit-knogle&#xD;
      (bone) (n=123), in which the effect of vitamin K2(MK7) on larger arteries, coronary arteries-&#xD;
      and valves and the effect on bone with regards to bone mineral density and frequency of&#xD;
      fractures are respectively examined.&#xD;
&#xD;
      PATIENTS AND RECRUITMENT&#xD;
&#xD;
      Ptt. will be equally divided by randomization and hence daily be given a tablet of either&#xD;
      vitamin K2(MK7) or placebo. According to the criteria of inclusion ptt. will either join the&#xD;
      RenaKvit-vessel or the bone group. If criteria are fulfilled ptt. are to join both vessel and&#xD;
      bone groups.&#xD;
&#xD;
      Determined by calculation of statistical power, incl. a level of significance of 5%, a&#xD;
      standard deviation of 0,95 and strength of 80%, a minimum of 40 ptt (RenaKvit-vessel) and 140&#xD;
      ptt. (RenaKvit-bone) will be included, thus taking potentially drop-outs in account. Both&#xD;
      ptt. in hemo- and peritoneal dialysis treatment will be included.&#xD;
&#xD;
      Ptt. will be recruited by the dialysis departments at Zealand University Hospital Roskilde,&#xD;
      Holbaek Hospitals, Aarhus University Hospital and Aalborg University Hospital.&#xD;
&#xD;
      There will be no fee for participating ptt.&#xD;
&#xD;
      MEDICINE&#xD;
&#xD;
      Patients are given a daily tablet of either vitamin K 360 micrograms or placebo during a&#xD;
      period of 2 x 12 months. Both types of tablets will be of similar look and content, besides&#xD;
      vitamin K2.&#xD;
&#xD;
      METHODS&#xD;
&#xD;
        -  Pulse Wave examination: Includes both pulse wave analysis and pulse wave velocity&#xD;
           measurements. Done by using SphygmoCor©-pulse wave apparatus. Pulse wave examination is&#xD;
           used as a measure of the arterial stiffness and is performed after standardized method.&#xD;
&#xD;
        -  24-hour blood pressure and blood pressure measurements: Done by current Danish&#xD;
           guidelines (17).&#xD;
&#xD;
        -  Coronary artery and -valve calcification: Assessed by CT-scans of the heart using the&#xD;
           Agatston Score.&#xD;
&#xD;
        -  Bone Mineral Density: Assessed by DEXA-scans.&#xD;
&#xD;
        -  Lateral lumbal x- ray and aortic calcification score: A semi-quantitative scoring system&#xD;
           used to describe the plaques on the front and the back of the aorta level with each&#xD;
           level of the lumbar vertebrae. The method has been found to be predictive of vascular&#xD;
           morbidity and mortality.&#xD;
&#xD;
        -  Measuring predictors/establishing a biobank: Partly as &quot;routine tests&quot; during dialysis&#xD;
           and partly as special kits developed at Vejle Hospital.&#xD;
&#xD;
      STATISTICS&#xD;
&#xD;
      Both groups will have descriptive statistics performed for as well as the presentation of the&#xD;
      total population, stratified for gender, age and weight.&#xD;
&#xD;
      Normal-distributed data will be expressed as mean value +/- standard deviation (SD), while&#xD;
      other distributed data also will be expressed as median values (interquartile range;&#xD;
      interquartile range, IQR). Categorical values will be expressed in numbers and percentages.&#xD;
&#xD;
      Normal-distributed variables will be compared with Student's t-test. Where found appropriate,&#xD;
      logarithmic transformation shall be performed. Non-normally distributed variables will be&#xD;
      compared with the Mann Whitney U test. Categorical values are to be compared with the Chi&#xD;
      Square test.&#xD;
&#xD;
      Changes within the treatment groups over time will be analyzed by paired analysis, and&#xD;
      between the treatment groups compared with the non-paired analysis. Forward stepwise&#xD;
      multivariate logistic regression analysis is carried out to correct significant confounders&#xD;
      of the primary and secondary endpoints.&#xD;
&#xD;
      Analysis of Cox proportional hazards will be performed from time to first clinical event.&#xD;
&#xD;
      P≤0.05 will be considered statistically significant. All results - negative and positive -&#xD;
      are expected to be published in peer-review magazines.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 2016</start_date>
  <primary_completion_date type="Actual">June 26, 2020</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>For RenaKvit-vessel: Changes in arterial stiffness assessed by pulse wave examination reflecting vascular calcification (unit: m/s).</measure>
    <time_frame>2 years</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>For RenaKvit-bone: Changes in bone mineral density (BMD) in the distal radial bone (unit T-score).</measure>
    <time_frame>2 years</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>For RenaKvit-vessel: Changes in coronary vascular and -valve calcification assessed by CT-scans of the heart (unit: Agatston-Score).</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>For RenaKvit-vessel: Changes in vascular calcification measured by changes in blood pressure measurements (unit: mmHg).</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>For RenaKvit-bone: Changes in body composition, BMD in the lumbar column, hip and whole body (unit: T-score).</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>For RenaKvit-bone: Changes in abdominal aortic calcification measured by lateral X-ray of lumbar column (unit: abdominal aortic calcification score).</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <other_outcome>
    <measure>For both RenaKvit-vessel and bone: Changes in specific biochemical markers in blood related to increase in vitamin K-treatment (unit mol/L)</measure>
    <time_frame>2 years</time_frame>
    <description>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.</description>
  </other_outcome>
  <other_outcome>
    <measure>For both RenaKvit-vessel and bone: Changes in non-specific biochemical markers in blood related to increase in vitamin K-treatment (unit/L)</measure>
    <time_frame>2 years</time_frame>
    <description>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.</description>
  </other_outcome>
  <other_outcome>
    <measure>For both RenaKvit-vessel and bone: Changes in urine production</measure>
    <time_frame>2 years</time_frame>
    <description>Monitoring volume, creatinine, urea, protein, albumin.</description>
  </other_outcome>
  <other_outcome>
    <measure>For both RenaKvit-vessel and bone: Changes in medication</measure>
    <time_frame>2 years</time_frame>
    <description>Monitoring phosphate binders, vitamin D analogues, calcimimetics, antihypertensives, cholesterol-lowering drugs.</description>
  </other_outcome>
  <other_outcome>
    <measure>For both RenaKvit-vessel and bone: monitoring clinical events expected to have relation to trial outcomes.</measure>
    <time_frame>2 years</time_frame>
    <description>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.&#xD;
In order to register a potential change during treatment with vitamin K all of the above mentioned are to be performed regularly.</description>
  </other_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">123</enrollment>
  <condition>Vitamin K Supplementation</condition>
  <condition>Endstage Renal Disease</condition>
  <condition>Cardiovascular Disease</condition>
  <condition>Bone Disease</condition>
  <arm_group>
    <arm_group_label>RenaKvit-vessel Active</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>One tablet of 360 micrograms vitamin K2 given once daily to examine the effect on vascular calcification</description>
  </arm_group>
  <arm_group>
    <arm_group_label>RenaKvit-vessel Control</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>One tablet of non-active drug given once daily</description>
  </arm_group>
  <arm_group>
    <arm_group_label>RenaKvit-bone Active</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>One tablet of 360 micrograms vitamin K2 given once daily to examine the effect on bone metabolism</description>
  </arm_group>
  <arm_group>
    <arm_group_label>RenaKvit-bone control</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>One tablet of non-active drug given once daily</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Vitamin K2 (MK7)</intervention_name>
    <description>One tablet of vitamin K2 (MK7) 360 micrograms given once daily.</description>
    <arm_group_label>RenaKvit-bone Active</arm_group_label>
    <arm_group_label>RenaKvit-vessel Active</arm_group_label>
    <other_name>menaquinon 7</other_name>
    <other_name>MK7</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>One tablet of placebo given once daily.</description>
    <arm_group_label>RenaKvit-bone control</arm_group_label>
    <arm_group_label>RenaKvit-vessel Control</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age ≥ 18 years old&#xD;
&#xD;
          -  Life expectancy &gt; 2 years&#xD;
&#xD;
          -  Written consent following oral information&#xD;
&#xD;
          -  Permanent treatment with dialysis ≥ 3 months with either peritoneal or hemodialysis&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Treatment with vitamin K or vitamin K-antagonist by the beginning of the trial or 1&#xD;
             months within.&#xD;
&#xD;
          -  Chronic GI-malabsorption leading to a slower bowel transit (e.g. Celiac disease, Short&#xD;
             bowel syndrome).&#xD;
&#xD;
          -  Ongoing malignancy (ongoing treatment/clinical controlled visits or diagnosed less&#xD;
             than 5 years ago), excl. Non-Melanoma-Skin-Cancer (NMSC).&#xD;
&#xD;
          -  Abuse of alcohol or other euphoric drug.&#xD;
&#xD;
          -  Women who are pregnant or breast-feeding and women who are in the childbearing age&#xD;
             without contraception.&#xD;
&#xD;
          -  Total/subtotal parathyroidectomy&#xD;
&#xD;
          -  Treatment with recombined PTH.&#xD;
&#xD;
          -  Treatment with bisphosphonates or other anti-osteoporotic drugs (Selective Estrogen&#xD;
             Reuptake Modulators (SERM), strontium, renalat, denosumab).&#xD;
&#xD;
        Only RenaKvit-kar (vessel):&#xD;
&#xD;
          -  Atrial fibrillation/other arrhythmia of significance&#xD;
&#xD;
          -  Aortic stenosis of significance&#xD;
&#xD;
          -  Agatston score &lt; 100 by heart-CT-scan&#xD;
&#xD;
          -  Bilateral upper arm fistula&#xD;
&#xD;
          -  Amputation above metatarsal level&#xD;
&#xD;
        Criteria of withdrawal:&#xD;
&#xD;
          -  Kidney transplantation&#xD;
&#xD;
          -  Starting treatment with vitamin K-antagonists&#xD;
&#xD;
          -  Wish to with draw from the participant&#xD;
&#xD;
          -  Unacceptable side effect to ingestion of vitamin K or placebo&#xD;
&#xD;
          -  Reasonable suspicion of lacking compliance regarding medication&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Peter Marckmann, MDS</last_name>
    <role>Study Director</role>
    <affiliation>Zealand University Hospital</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Ditte Hansen, MDS</last_name>
    <role>Study Director</role>
    <affiliation>Herlev Hospital</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Marie Frimodt-Moeller, MDS</last_name>
    <role>Study Director</role>
    <affiliation>Steno Diabetes Center Copenhagen</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Zealand University Hospital</name>
      <address>
        <city>Roskilde</city>
        <zip>4000</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Denmark</country>
  </location_countries>
  <verification_date>June 2020</verification_date>
  <study_first_submitted>November 3, 2016</study_first_submitted>
  <study_first_submitted_qc>November 28, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 29, 2016</study_first_posted>
  <last_update_submitted>June 29, 2020</last_update_submitted>
  <last_update_submitted_qc>June 29, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">July 1, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Bone Diseases</mesh_term>
    <mesh_term>Kidney Failure, Chronic</mesh_term>
    <mesh_term>Cardiovascular Diseases</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vitamin K</mesh_term>
    <mesh_term>Vitamin K 2</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02976246
org study id: RenaKvit
nct id: NCT02976246
lead sponsor: 
has dmc: No
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.
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) (n= 48) and RenaKvit-knogle
      (bone) (n=123), 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 ptt (RenaKvit-vessel) and 140
      ptt. (RenaKvit-bone) 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 Zealand University Hospital Roskilde,
      Holbaek Hospitals, Aarhus University Hospital and Aalborg University Hospital.

      There will be no fee for participating ptt.

      MEDICINE

      Patients are given a daily tablet of either vitamin K 360 micrograms or placebo 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 within the treatment groups over time will be analyzed by paired analysis, and
      between the treatment 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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: For RenaKvit-vessel: Changes in arterial stiffness assessed by pulse wave examination reflecting vascular calcification (unit: m/s).
time frame: 2 years
measure: For RenaKvit-bone: Changes in bone mineral density (BMD) in the distal radial bone (unit T-score).
time frame: 2 years
measure: For RenaKvit-vessel: Changes in coronary vascular and -valve calcification assessed by CT-scans of the heart (unit: Agatston-Score).
time frame: 2 years
measure: For RenaKvit-vessel: Changes in vascular calcification measured by changes in blood pressure measurements (unit: mmHg).
time frame: 2 years
measure: For RenaKvit-bone: Changes in body composition, BMD in the lumbar column, hip and whole body (unit: T-score).
time frame: 2 years
measure: 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
measure: 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
description: 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.
measure: 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
description: 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.
measure: For both RenaKvit-vessel and bone: Changes in urine production
time frame: 2 years
description: Monitoring volume, creatinine, urea, protein, albumin.
measure: For both RenaKvit-vessel and bone: Changes in medication
time frame: 2 years
description: Monitoring phosphate binders, vitamin D analogues, calcimimetics, antihypertensives, cholesterol-lowering drugs.
measure: For both RenaKvit-vessel and bone: monitoring clinical events expected to have relation to trial outcomes.
time frame: 2 years
description: 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.
arm group label: RenaKvit-vessel Active
arm group type: Active Comparator
description: One tablet of 360 micrograms vitamin K2 given once daily to examine the effect on vascular calcification
arm group label: RenaKvit-vessel Control
arm group type: Placebo Comparator
description: One tablet of non-active drug given once daily
arm group label: RenaKvit-bone Active
arm group type: Active Comparator
description: One tablet of 360 micrograms vitamin K2 given once daily to examine the effect on bone metabolism
arm group label: RenaKvit-bone control
arm group type: Placebo Comparator
description: One tablet of non-active drug given once daily
intervention type: Dietary Supplement
intervention name: Vitamin K2 (MK7)
description: One tablet of vitamin K2 (MK7) 360 micrograms given once daily.
arm group label: RenaKvit-bone Active
arm group label: RenaKvit-vessel Active
other name: menaquinon 7
other name: MK7
intervention type: Other
intervention name: Placebo
description: One tablet of placebo given once daily.
arm group label: RenaKvit-bone control
arm group label: RenaKvit-vessel Control
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Peter Marckmann, MDS
role: Study Director
affiliation: Zealand University Hospital
last name: Ditte Hansen, MDS
role: Study Director
affiliation: Herlev Hospital
last name: Marie Frimodt-Moeller, MDS
role: Study Director
affiliation: Steno Diabetes Center Copenhagen
facility: 
country: Denmark
responsible party type: Sponsor
mesh term: Bone Diseases
mesh term: Kidney Failure, Chronic
mesh term: Cardiovascular Diseases
mesh term: Vitamin K
mesh term: Vitamin K 2
sharing ipd: Undecided