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

Effects of Vitamin K2 and D3 Supplementation on 18F-NaF PET/MRI in Patients With Carotid and Coronary Artery Disease

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Coronary Artery Disease; Carotid Artery Disease
• Intervention / Treatment: Dietary supplement: MK-7 and vitamin D3; Other: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 52
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Felix M Mottaghy, MD, PhD; Phone Number: +31 43 3874746; Email: felix.mottaghy@mumc.nl
• Study Contact Backup: Name: Alexandru Florea, MD; Phone Number: +49 241 80 89584; Email: aflorea@ukaachen.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The change in time of vascular micro-calcification via (18)F-NaF PET/MRI	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.	3 months follow-up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The change in time of vascular calcification via coronary artery calcification score	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.	3 months follow-up
The correlation between (18)F-NaF PET/MRI and coronary artery calcification score	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 months follow-up
The influence of MK-7 and vitamin D3 supplementation on MRI parameters	Investigating whether MK-7 and vitamin D3 supplementation can influence the fibrous cap status on the MRI.	baseline vs 3 months follow-up

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
The influence of MK-7 and vitamin D3 supplementation on carotid intima-media thickness	Investigating whether MK-7 and vitamin D3 supplementation can influence the carotid intima-media thickness	baseline vs 3 months follow-up

Collaborators and Investigators

• Sponsor: Academisch Ziekenhuis Maastricht
• Collaborators: Horizon 2020 - European Commission
• Investigators: Principal Investigator: Felix M Mottaghy, MD, PhD, Maastricht University Medical Center

Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2024
• Primary Completion (Estimated): January 1, 2025
• Study Completion (Estimated): April 1, 2025

Study Registration Dates

• First Submitted: July 1, 2019
• First Submitted That Met QC Criteria: July 5, 2019
• First Posted (Actual): July 8, 2019

Study Record Updates

• Last Update Posted (Actual): September 21, 2023
• Last Update Submitted That Met QC Criteria: September 20, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Coronary Artery Disease; 18F-NaF; Vitamin D3; Carotid Artery Disease; Vitamin K2; hybrid PET/MRI; Coronary artery calcification score; Menaquinone-7
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Carotid Artery Diseases; Physiological Effects of Drugs; Micronutrients; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Vitamin D; Cholecalciferol
• Other Study ID Numbers: NL69450.068.19

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All IPD that underlie results in a publication will be shared.
• IPD Sharing Time Frame: IPD will be shared stating with 6 months after publication.
• IPD Sharing Access Criteria: Access criteria will be discussed with all the study members, then it will be published.
• IPD Sharing Supporting Information Type: SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No