To test our hypothesis that vitamin K2 supplementation will induce a clinically relevant reduction in the degree of micro-calcification from carotid artery disease patients, when comparing to a placebo, after 3 months.
ID
Source
Brief title
Condition
- Arteriosclerosis, stenosis, vascular insufficiency and necrosis
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
We hypothesize that intervention with vitamin K2 will lead to a regression or
at least to non-progression of micro-calcifications compared to treatment with
a placebo. Therefore, the main parameter/end point of this study is The main
parameter/end point of this study is the mean rate of progression of vascular
micro-calcifications in the carotid arteries, measured as a difference between
the intervention group and placebo group in 18F-NaF uptake via hybrid PET/MRI
at baseline and after the 3 months follow-up.
Secondary outcome
1. 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 CAC score at baseline and after the 3 months follow-up.
2. The mean rate of progression of vascular calcification, measured as a
difference in CAC score at baseline and after a follow-up of 3 months.
3. The mean rate of progression of vascular calcification, measured as a
difference in carotid 18F-NaF uptake at baseline and after a follow-up of 3
months.
4. The correlation between the uptake of 18F-NaF at 3 months and the CAC score.
5. Investigating whether vitamin K2 supplementation can influence MRI
parameters such as normalized wall index (i.e. measurement of plaque burden),
intra-plaque haemorrhage volume, lipid-rich necrotic core volume, and fibrous
cap status.
6. The correlation between 18F-NaF uptake and cIMT.
7. The correlation between vitamin K2 supplementation and cIMT.
8. The correlation between vitamin K2 supplementation and the plasma levels of
MGP
9. The correlation between acute events (i.e. myocardial infarction and stroke)
and the plasma levels of MGP
10. The correlation between serum vitamin K2 concentrations and PIVKA-II plasma
level, PT, and the INR value.
Background summary
Coronary and carotid arteries are the first two causes of cardiovascular (CV)
mortality in Global Burden of Disease 2013 Study, leading to more than
10.000.000 deaths worldwide in 2013. Atherosclerosis is the underlying
pathophysiological process of almost 90% of all CV diseases. The high-risk
features of any atherosclerotic plaque include micro-calcifications within the
arterial wall, which has been proven to act as an independent CV risk factor.
Arterial calcification is an active process and results from imbalance between
calcification promoting and inhibiting factors. In the last two decades, a
series of proteins that are able to bind calcium ions and to inhibit
calcification have been discovered, including matrix Gla protein (MGP). These
circulating proteins share a common feature, the *-carboxyglutamic acid (Gla)
rich domain, which requires vitamin K to become biologically active. Vitamin K
supplementation is associated with several positive outcomes. All together,
these studies support the idea that vitamin K protects against calcification.
After an extensive literature research, the fluorine-18 sodium fluoride
positron emission tomography/magnetic resonance imaging (18F-NaF PET/MRI)
emerged as the safest and most reliable clinical imaging platform that can
noninvasively detect micro-calcifications in the arterial wall. Therefore, we
will use 18F-NaF PET/MRI to assess the influence of vitamin K supplementation
in the development of arterial micro-calcification in the context of
atherosclerosis.
Study objective
To test our hypothesis that vitamin K2 supplementation will induce a clinically
relevant reduction in the degree of micro-calcification from carotid artery
disease patients, when comparing to a placebo, after 3 months.
Study design
This will be a prospective double blind randomized controlled feasibility
study, in which one group will receive a vitamin K2 supplementation compared to
a control group receiving a placebo.
Intervention
Subjects will be randomised into an intervention group (i.e.receive two daily
capsules each containing 200*g of Menaquinone-7 and 40*g of vitamin D3) or into
the control group (i.e. will receive a placebo capsule that will identical to
the intervention capsule, but without Menaquinone-7). Both subjects and
researchers will be blinded to the treatment allocation of subjects.
Study burden and risks
The duration of the trial is 3 months. After being randomised into one of the
two arms of the study (i.e. treatment or placebo), the patients will have to
visit the hospital after 3 months. During these visits, drug-compliance will be
monitored, carotid intima-media thickness (cIMT) will be measured and blood
samples will be obtained via standard venous puncture. At baseline and after 3
months, an 18F-NaF PET/MRI will be performed in order to assess changes in
calcium metabolism of carotid arteries. Moreover, the CAC score will be
determined by a non-contrast enhanced CT scan of the heart at baseline and at 3
months, in order to assess changes in the degree of calcification.
There have been no side effects reported in subjects using a daily 360µg
supplementation of vitamin K2 (i.e. MK-7). Vitamin K2 supplementation does not
induce or increase a state of hypercoagulability. The proposed measurement of
carotid intima-media thickness will add no burden to the patients. The average
effective radiation exposures associated with the proposed two PET/MRI and two
CAC scans are 3,15mSv/scan and 0,74mSv/scan, respectively. Each 18F-NaF PET/MRI
scan will take about 1 hour, while each CAC scan will take about 2-3 minutes.
Another burden of this study will be the venipunctures of 25mL each taken at
baseline and at 3 months follow-up. The side effects of MRI contrast agent
(i.e. Gadobutrol) are rare, amongst others nausea (0,25%), vomiting (0,05%),
urticaria (0,04%), feeling of warmth, wheals (i.e. localized itchy oedema) (for
each 0,03%), dizziness (0,02%), cough, dyspnoea (for each 0,01%), severe
anaphylactic reaction (2 out of 14299 patients). The MRI contrast agent will be
injected only in patients without any known allergy to gadolinium and with a
GFR * 45mL/min/1,73m2 or * 60mL/min/1,73m2 in patients with diabetes mellitus.
Menaquinone-7 supplementation may halt or even diminish the development of
arterial calcification your plaques, but this is not certain.
P. Debyelaan 25
Maastricht 6229 HX
NL
P. Debyelaan 25
Maastricht 6229 HX
NL
Listed location countries
Age
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., iIf intensified medical treatment for this
symptomatic stenosis (e.g. statins, antiplatelet medication) was started * 6
month before inclusion of the patient, he/she will still be included in the
study. 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 vitamin K supplementation.
* Age older than 18 years
* Signed informed consent provided
Exclusion criteria
* Antiplatelet or cholesterol lowering medication started in 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-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
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| ClinicalTrials.gov | NCT04010578 |
| CCMO | NL69450.068.19 |