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

• ClinicalTrials.gov Identifier: NCT04010578
• Recruitment Status: Not yet recruiting
• First Posted: July 8, 2019
• Last Update Posted: February 15, 2021
• Sponsor: Academisch Ziekenhuis Maastricht
• Collaborator: Horizon 2020 - European Commission
• Information provided by (Responsible Party): Felix Mottaghy, Academisch Ziekenhuis Maastricht

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

• 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

• 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

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

• Principal Investigator: Felix M Mottaghy, MD, PhD; Maastricht University Medical Center

More Information

• Responsible Party: Felix Mottaghy, Univ.-Prof. Dr. med., Academisch Ziekenhuis Maastricht
• ClinicalTrials.gov Identifier: NCT04010578
• Other Study ID Numbers: NL69450.068.19
• First Posted: July 8, 2019
• Last Update Posted: February 15, 2021
• Last Verified: February 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: All IPD that underlie results in a publication will be shared.
• Supporting Materials: Statistical Analysis Plan (SAP); 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.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Felix Mottaghy, Academisch Ziekenhuis Maastricht:

Vitamin K2; 18F-NaF; hybrid PET/MRI; Coronary artery calcification score; Menaquinone-7; Carotid Artery Disease; Coronary Artery Disease; Vitamin D3

Additional relevant MeSH terms:

Carotid Artery Diseases; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Heart Diseases; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vitamin D; Cholecalciferol; Vitamins; Micronutrients; Physiological Effects of Drugs; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents