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出境医 / 临床实验 / Effects of VitamIN K2 and D3 supplementaTion on PET/MRI in Carotid Artery Disease (INTRICATE)

Effects of VitamIN K2 and D3 supplementaTion on PET/MRI in Carotid Artery Disease (INTRICATE)

Study Description
Brief Summary:

Atherosclerosis is a disease of the arteries and is the result of various factors such as high blood cholesterol or diabetes, which lead to accumulations of fats, cells, and calcium deposits (i.e. plaques). It has been shown that people with a rapid increase in the amount of calcium deposits have a higher risk for stroke and heart attack than people with a decreased amount.

Previous scientific research has shown that a protein called Matrix Gla Protein plays an important role in the prevention of calcification. This protein works well only if there is enough Vitamin K in the blood vessels. In a large human studies, it has been shown that especially MK-7 (a form of Vitamin K2) is best absorbed by blood vessels. Moreover, studies suggest positive effects of vitamin D (especially D3) on vitamin K-dependent metabolism.

Over the last years, fluorine-18 sodium fluoride (18F-NaF) positron emission tomography (PET) emerged as a reliable clinical imaging tool able to detect micro-calcification in the blood vessels. Therefore, the present study will use 18F-NaF PET in combination with magnetic resonance imaging (MRI) to assess the influence of vitamin K and D supplementation in the development of arterial micro-calcification in the context of atherosclerosis.

The present study would like to confirm that MK-7 and vitamin D3 supplementation induces a significant reduction in the degree of micro-calcification from carotid artery disease patients, when comparing to a placebo, after 3 months.

This will be a prospective double blind randomised controlled feasibility study, in which one group will receive a MK-7 and vitamin D3 supplementation compared to a control group receiving a placebo.


Condition or disease Intervention/treatment Phase
Coronary Artery Disease Carotid Artery Disease Dietary Supplement: MK-7 and vitamin D3 Other: Placebo Not Applicable

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 52 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: One group will receive a MK-7 and vitamin D3 supplementation and the control group will receive a placebo.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Effects of Vitamin K2 and D3 Supplementation on 18F-NaF PET/MRI in Patients With Carotid and Coronary Artery Disease
Estimated Study Start Date : August 1, 2021
Estimated Primary Completion Date : January 1, 2023
Estimated Study Completion Date : April 1, 2023
Arms and Interventions
Arm Intervention/treatment
Experimental: MK-7 and vitamin D3 supplementation
Patients will receive a daily MK-7 and vitamin D3 supplementation for 3 months.
Dietary Supplement: MK-7 and vitamin D3
Patients will receive 400 micro-grams of Menaquinone-7 and 80 micro-grams of vitamin D3 per day.

Placebo Comparator: Placebo
Patients will receive a daily placebo for 3 months.
Other: Placebo
Patients will receive a placebo each day.

Outcome Measures
Primary Outcome Measures :
  1. The change in time of vascular micro-calcification via (18)F-NaF PET/MRI [ Time Frame: 3 months follow-up ]
    The primary outcome of this study is the mean rate of the change in time of vascular micro-calcification in the carotid arteries, measured as a difference between the intervention group and placebo group in (18)F-NaF uptake via hybrid PET/MRI after the 3 months of treatment.


Secondary Outcome Measures :
  1. The change in time of vascular calcification via coronary artery calcification score [ Time Frame: 3 months follow-up ]

    Investigating whether MK-7 and vitamin D3 supplementation can diminish, halt or even reverse the development of arterial micro-calcification in the coronary arteries, measured as a difference between the intervention group and placebo group in coronary artery calcification score after the 3 months.

    The Agatston coronary artery calcification score isis a semi-automated tool to calculate a score based on the extent of coronary artery calcification detected by an non-contrast low-dose CT scan. The score ranges from 0 arbitrary units to > 400. The higher the value of the score, the higher the degree of calcification is in the coronary arteries; hence, lower values usually represent a better outcome.


  2. The correlation between (18)F-NaF PET/MRI and coronary artery calcification score [ Time Frame: 3 months follow-up ]

    The correlation between the uptake of (18)F-NaF at 3 months and the coronary artery calcification score.

    The Agatston coronary artery calcification score isis a semi-automated tool to calculate a score based on the extent of coronary artery calcification detected by an non-contrast low-dose CT scan. The score ranges from 0 arbitrary units to > 400. The higher the value of the score, the higher the degree of calcification is in the coronary arteries; hence, lower values usually represent a better outcome.


  3. The influence of MK-7 and vitamin D3 supplementation on MRI parameters [ Time Frame: baseline vs 3 months follow-up ]
    Investigating whether MK-7 and vitamin D3 supplementation can influence the fibrous cap status on the MRI.


Other Outcome Measures:
  1. The influence of MK-7 and vitamin D3 supplementation on carotid intima-media thickness [ Time Frame: baseline vs 3 months follow-up ]
    Investigating whether MK-7 and vitamin D3 supplementation can influence the carotid intima-media thickness


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

Inclusion Criteria:

  • Asymptomatic carotid artery disease on at least one side with a degree of stenosis > 25% (according to on the ECST criteria). If the patient has a symptomatic carotid artery disease on the contra-lateral side, he/she will still be included in the study, if intensified medical treatment for this symptomatic stenosis (e.g. statins, antiplatelet medication) was started ≥ 6 month before inclusion of the patient. This protocol was chosen in order to widely assure a stable situation on the plaque(s), which avoids an overspill from this medication on the assumed effects of the MK-7 and vitamin D3 supplementation.
  • Age older than 18 years
  • Signed informed consent provided

Exclusion Criteria:

  • Antiplatelet or cholesterol lowering medication started within the past 6 months
  • Chronic or paroxysmal atrial fibrillation
  • Presence or scheduled coronary or carotid revascularisation procedure (e.g. stent implantation, coronary artery bypass graft, balloon-dilatation, endarterectomy, angioplasty)
  • History of myocardial infarction or stroke
  • Malignant disease (except for treated basal-cell or squamous cell carcinoma)
  • Use of vitamin K antagonists or any other anticoagulation treatment
  • A life-expectancy < 1 year
  • Claustrophobia
  • Presence of a pacemaker, intra-cardiac defibrillator, or metallic implant (e.g. vascular clip, neuro-stimulator, cochlear implant)
  • Body weight > 130kg or body habitus that does not fit into the gantry
  • Pregnancy or wish to become pregnant in the near future
  • Breast feeding
  • (History of) metabolic or gastrointestinal disease
  • Use of vitamin K or D containing supplements or vitamin K-rich foods (i.e. soya)
  • Chronic inflammatory disease
  • Systemic treatment or topical treatment likely to interfere with evaluation of the study parameters
  • Corticoid treatment
  • Participation in a clinical study more recently than one month before the current study
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Felix M Mottaghy, MD, PhD +31 43 3874746 felix.mottaghy@mumc.nl
Contact: Alexandru Florea, MD +49 241 80 89584 aflorea@ukaachen.de

Sponsors and Collaborators
Academisch Ziekenhuis Maastricht
Horizon 2020 - European Commission
Investigators
Layout table for investigator information
Principal Investigator: Felix M Mottaghy, MD, PhD Maastricht University Medical Center
Tracking Information
First Submitted Date  ICMJE July 1, 2019
First Posted Date  ICMJE July 8, 2019
Last Update Posted Date February 15, 2021
Estimated Study Start Date  ICMJE August 1, 2021
Estimated Primary Completion Date January 1, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 5, 2019)
The change in time of vascular micro-calcification via (18)F-NaF PET/MRI [ Time Frame: 3 months follow-up ]
The primary outcome of this study is the mean rate of the change in time of vascular micro-calcification in the carotid arteries, measured as a difference between the intervention group and placebo group in (18)F-NaF uptake via hybrid PET/MRI after the 3 months of treatment.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 11, 2021)
  • The change in time of vascular calcification via coronary artery calcification score [ Time Frame: 3 months follow-up ]
    Investigating whether MK-7 and vitamin D3 supplementation can diminish, halt or even reverse the development of arterial micro-calcification in the coronary arteries, measured as a difference between the intervention group and placebo group in coronary artery calcification score after the 3 months. The Agatston coronary artery calcification score isis a semi-automated tool to calculate a score based on the extent of coronary artery calcification detected by an non-contrast low-dose CT scan. The score ranges from 0 arbitrary units to > 400. The higher the value of the score, the higher the degree of calcification is in the coronary arteries; hence, lower values usually represent a better outcome.
  • The correlation between (18)F-NaF PET/MRI and coronary artery calcification score [ Time Frame: 3 months follow-up ]
    The correlation between the uptake of (18)F-NaF at 3 months and the coronary artery calcification score. The Agatston coronary artery calcification score isis a semi-automated tool to calculate a score based on the extent of coronary artery calcification detected by an non-contrast low-dose CT scan. The score ranges from 0 arbitrary units to > 400. The higher the value of the score, the higher the degree of calcification is in the coronary arteries; hence, lower values usually represent a better outcome.
  • The influence of MK-7 and vitamin D3 supplementation on MRI parameters [ Time Frame: baseline vs 3 months follow-up ]
    Investigating whether MK-7 and vitamin D3 supplementation can influence the fibrous cap status on the MRI.
Original Secondary Outcome Measures  ICMJE
 (submitted: July 5, 2019)
  • The change in time of vascular calcification via coronary artery calcification score [ Time Frame: 3 months follow-up ]
    Investigating whether vitamin K2 supplementation can diminish, halt or even reverse the development of arterial micro-calcification in the coronary arteries, measured as a difference between the intervention group and placebo group in coronary artery calcification score after the 3 months. The Agatston coronary artery calcification score isis a semi-automated tool to calculate a score based on the extent of coronary artery calcification detected by an non-contrast low-dose CT scan. The score ranges from 0 arbitrary units to > 400. The higher the value of the score, the higher the degree of calcification is in the coronary arteries; hence, lower values usually represent a better outcome.
  • The correlation between (18)F-NaF PET/MRI and coronary artery calcification score [ Time Frame: 3 months follow-up ]
    The correlation between the uptake of (18)F-NaF at 3 months and the coronary artery calcification score. The Agatston coronary artery calcification score isis a semi-automated tool to calculate a score based on the extent of coronary artery calcification detected by an non-contrast low-dose CT scan. The score ranges from 0 arbitrary units to > 400. The higher the value of the score, the higher the degree of calcification is in the coronary arteries; hence, lower values usually represent a better outcome.
  • The influence of vitamin K2 supplementation on MRI parameters [ Time Frame: baseline vs 3 months follow-up ]
    Investigating whether vitamin K2 supplementation can influence the fibrous cap status on the MRI.
Current Other Pre-specified Outcome Measures
 (submitted: February 11, 2021)
The influence of MK-7 and vitamin D3 supplementation on carotid intima-media thickness [ Time Frame: baseline vs 3 months follow-up ]
Investigating whether MK-7 and vitamin D3 supplementation can influence the carotid intima-media thickness
Original Other Pre-specified Outcome Measures
 (submitted: July 5, 2019)
The influence of vitamin K2 supplementation on carotid intima-media thickness [ Time Frame: baseline vs 3 months follow-up ]
Investigating whether vitamin K2 supplementation can influence the carotid intima-media thickness
 
Descriptive Information
Brief Title  ICMJE Effects of VitamIN K2 and D3 supplementaTion on PET/MRI in Carotid Artery Disease
Official Title  ICMJE Effects of Vitamin K2 and D3 Supplementation on 18F-NaF PET/MRI in Patients With Carotid and Coronary Artery Disease
Brief Summary

Atherosclerosis is a disease of the arteries and is the result of various factors such as high blood cholesterol or diabetes, which lead to accumulations of fats, cells, and calcium deposits (i.e. plaques). It has been shown that people with a rapid increase in the amount of calcium deposits have a higher risk for stroke and heart attack than people with a decreased amount.

Previous scientific research has shown that a protein called Matrix Gla Protein plays an important role in the prevention of calcification. This protein works well only if there is enough Vitamin K in the blood vessels. In a large human studies, it has been shown that especially MK-7 (a form of Vitamin K2) is best absorbed by blood vessels. Moreover, studies suggest positive effects of vitamin D (especially D3) on vitamin K-dependent metabolism.

Over the last years, fluorine-18 sodium fluoride (18F-NaF) positron emission tomography (PET) emerged as a reliable clinical imaging tool able to detect micro-calcification in the blood vessels. Therefore, the present study will use 18F-NaF PET in combination with magnetic resonance imaging (MRI) to assess the influence of vitamin K and D supplementation in the development of arterial micro-calcification in the context of atherosclerosis.

The present study would like to confirm that MK-7 and vitamin D3 supplementation induces a significant reduction in the degree of micro-calcification from carotid artery disease patients, when comparing to a placebo, after 3 months.

This will be a prospective double blind randomised controlled feasibility study, in which one group will receive a MK-7 and vitamin D3 supplementation compared to a control group receiving a placebo.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
One group will receive a MK-7 and vitamin D3 supplementation and the control group will receive a placebo.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Coronary Artery Disease
  • Carotid Artery Disease
Intervention  ICMJE
  • Dietary Supplement: MK-7 and vitamin D3
    Patients will receive 400 micro-grams of Menaquinone-7 and 80 micro-grams of vitamin D3 per day.
  • Other: Placebo
    Patients will receive a placebo each day.
Study Arms  ICMJE
  • Experimental: MK-7 and vitamin D3 supplementation
    Patients will receive a daily MK-7 and vitamin D3 supplementation for 3 months.
    Intervention: Dietary Supplement: MK-7 and vitamin D3
  • Placebo Comparator: Placebo
    Patients will receive a daily placebo for 3 months.
    Intervention: Other: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: July 5, 2019)
52
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 1, 2023
Estimated Primary Completion Date January 1, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Asymptomatic carotid artery disease on at least one side with a degree of stenosis > 25% (according to on the ECST criteria). If the patient has a symptomatic carotid artery disease on the contra-lateral side, he/she will still be included in the study, if intensified medical treatment for this symptomatic stenosis (e.g. statins, antiplatelet medication) was started ≥ 6 month before inclusion of the patient. This protocol was chosen in order to widely assure a stable situation on the plaque(s), which avoids an overspill from this medication on the assumed effects of the MK-7 and vitamin D3 supplementation.
  • Age older than 18 years
  • Signed informed consent provided

Exclusion Criteria:

  • Antiplatelet or cholesterol lowering medication started within the past 6 months
  • Chronic or paroxysmal atrial fibrillation
  • Presence or scheduled coronary or carotid revascularisation procedure (e.g. stent implantation, coronary artery bypass graft, balloon-dilatation, endarterectomy, angioplasty)
  • History of myocardial infarction or stroke
  • Malignant disease (except for treated basal-cell or squamous cell carcinoma)
  • Use of vitamin K antagonists or any other anticoagulation treatment
  • A life-expectancy < 1 year
  • Claustrophobia
  • Presence of a pacemaker, intra-cardiac defibrillator, or metallic implant (e.g. vascular clip, neuro-stimulator, cochlear implant)
  • Body weight > 130kg or body habitus that does not fit into the gantry
  • Pregnancy or wish to become pregnant in the near future
  • Breast feeding
  • (History of) metabolic or gastrointestinal disease
  • Use of vitamin K or D containing supplements or vitamin K-rich foods (i.e. soya)
  • Chronic inflammatory disease
  • Systemic treatment or topical treatment likely to interfere with evaluation of the study parameters
  • Corticoid treatment
  • Participation in a clinical study more recently than one month before the current study
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Felix M Mottaghy, MD, PhD +31 43 3874746 felix.mottaghy@mumc.nl
Contact: Alexandru Florea, MD +49 241 80 89584 aflorea@ukaachen.de
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04010578
Other Study ID Numbers  ICMJE NL69450.068.19
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: All IPD that underlie results in a publication will be shared.
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Time Frame: IPD will be shared stating with 6 months after publication.
Access Criteria: Access criteria will be discussed with all the study members, then it will be published.
Responsible Party Felix Mottaghy, Academisch Ziekenhuis Maastricht
Study Sponsor  ICMJE Academisch Ziekenhuis Maastricht
Collaborators  ICMJE Horizon 2020 - European Commission
Investigators  ICMJE
Principal Investigator: Felix M Mottaghy, MD, PhD Maastricht University Medical Center
PRS Account Academisch Ziekenhuis Maastricht
Verification Date February 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP