The InterVitaminK Trial - Effects of Vitamin K Supplementation on Cardiovascular, Metabolic, and Bone Health

Arterial Stiffness Clinical Trial

— InterVitaminK  

Official title:

Novel Health Effects of Vitamin K: a Placebo-controlled Randomized Trial in the General Population (InterVitaminK)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05259046
• Other study ID #: InterVitaminK
• Status: Recruiting
• Phase: N/A
• Start date: June 21, 2022
• Est. completion date: December 1, 2026

Study information

• Verified date: April 2023
• Source: Bispebjerg Hospital
• Contact: Allan Linneberg, MD
• Phone: +45 38163118
• Email: allan.linneberg[@]regionh.dk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to examine the effect of menaquinone-7 (MK-7) supplementation on cardiovascular, metabolic, and bone health.

Description:

Background: Research suggest that vitamin K may have protective effects against non-communicable and age-related diseases as diverse as cardiovascular disease (CVD), osteoporosis, and type 2 diabetes (T2D). However, there is a need for larger studies investigating the potential health effects of vitamin K in the general population.

Objective: The objective of the InterVitaminK trial is to investigate the effects of vitamin K (menaquinone-7, MK-7) supplementation on cardiovascular, metabolic, and bone health.

Hypothesis: The primary hypothesis is that vitamin K supplementation will reduce the progression of coronary artery calcification (CAC) with 15% compared with placebo.

Methods: The InterVitaminK trial is a double-blinded, placebo-controlled, randomized intervention trial. The trial will be conducted in Denmark at the Center for Clinical Research and Prevention and the CT scans will be performed at Rigshospitalet, Denmark. Participants from the Inter99 cohort with detectable CAC (Agatson score >=10) are eligible for the trial. Participants will be randomized 1:1 to receive one daily tablet with MK-7 or placebo for a period of 3 years. Randomization is done in blocks of 6 using computer generated random numbers. Participants are invited for a health examination at baseline and after 1, 2, and 3 years intervention. CT scans are performed at baseline and at 3-year follow-up.

Outcomes: The primary study outcome is progression of CAC from baseline to 3-year follow-up, assessed by Cardiac CT scans. Secondary outcomes are bone mineral density, pulmonary function, and biomarkers of insulin resistance.

Power: Power calculation and sample size considerations are based on the primary endpoint (three-year progression in CAC). A total of 450 participants will be enrolled in the trial. Based on a previous vitamin K trial and data from the Danish cohort study DANCAVAS, it is assumed that the geometric mean three-year progression in CAC in the control group participants is 3.0 with an SD of 1.3. The hypothesis is that vitamin K supplementation can reduce the three-year progression in CAC by 15%. With an estimated dropout-rate of 25% during the study period, a total of 450 participants (225 participants in each group) enrolled at baseline, will provide 89% power to demonstrate an effect of at least 15% (alpha 0.05).

Statistical analyses: The effect of vitamin K supplementation on the primary outcome (CAC) will be analyzed using mixed effects linear regression. The mixed effects linear regression will include a fixed effect for group allocation (intervention/control), a fixed effect for time point (baseline and 3-year follow-up), fixed effect for baseline CAC score and an interaction between group allocation and time point. As baseline measurements are conducted prior to enrolment, treatment at baseline will be modelled as a common treatment category, constraining baseline measurements to no systematic treatment effect between the two arms. The mixed effects model will include a random intercept for each enrolled participant and a first order autoregressive correlation structure allowing correction of measurement for the same participant with higher correlation for measurements closer in time.

Likewise, secondary outcomes and supportive outcomes will be analyzed using mixed effects linear regression. Analysis and presentation of data will be in accordance with the CONSORT guidelines. For details, see the statistical analysis plan uploaded at clinicaltrials.gov (NCT05259046).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 450
• Est. completion date: December 1, 2026
• Est. primary completion date: October 1, 2026
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 50 Years to 85 Years

Eligibility

Inclusion Criteria:

• Detectable CAC (Agatson score >=10) assessed by Cardiac Computed Tomography (CT) scan in the Inter99 20-year follow-up study

Exclusion Criteria:

• Manifest CVD (prior cerebral infarct, prior myocardial infarct, prior percutaneous coronary intervention or prior coronary artery bypass surgery)

• Noise on the CT scan, which complicates an accurate assessment of CAC and interpretation of the CT scan. An example is a pacemaker

• Current treatment with Vitamin K antagonist (VKA).

• History of coagulation disorders (hemophilia, von Willebrand disease, sickle cell anemia)

• Active malignant disease (ongoing treatment)

• Previous surgical removal of the thyroid gland, or one or more of the parathyroid glands

• Regular use of vitamin K supplements other than trial tablets

• Pregnancy or breastfeeding

Related Conditions & MeSH terms

• Arterial Stiffness
• Calcinosis
• Coronary Artery Calcification

Intervention

Dietary Supplement:
• Menaquinone-7 (MK-7) tablet (333 µg)
One MK-7 tablet containing 333 µg MK-7 per day
• Placebo tablet
One placebo tablet per day

Locations

Country	Name	City	State
Denmark	Center for Clinical Research and Prevention	Copenhagen	Glostrup

Sponsors (1)

Lead Sponsor	Collaborator
Bispebjerg Hospital

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Biomarkers of bone resorption	Bone metabolism reflected by biomarkers of bone resorption including C-terminal telopeptide of type I collagen (CTX) (unit: picograms/milliliter)	Baseline to three years of follow-up
Other	Biomarkers of bone formation	Bone metabolism reflected by biomarkers of bone formation including osteocalcin (with different phosphorylation and carboxylation forms) (unit: nanograms/milliliter), Fibroblast growth factor 23 (FGF23) (unit: nanograms/milliliter), osteoprotegerin (unit: Picomoles/liter), and Procollagen 1 Intact N-Terminal Propeptide (P1NP) (unit: milligram/liter)	Baseline to three years of follow-up
Other	Lung function	Lung function reflected by expiratory forced vital capacity (FVC) and FEV1/FVC-ratio	Baseline to three years of follow-up
Other	Lung tissue density	Lung tissue density as a measure of lung fibrosis assessed by CT scan	Baseline to three years of follow-up
Other	Respiratory infections	Annual number of respiratory infectious disease episodes, both upper and lower respiratory infections including COVID-19 (registered through telephone interviews)	Baseline to three years of follow-up
Other	Glucose control	Glucose metabolism reflected by Glycated hemoglobin A1c (HbA1c) (unit: millimole/mol)	Baseline to three years of follow-up
Other	Lipid metabolism	Lipid metabolism biomarkers (including total cholesterol, triglycerides, low-density lipoprotein, high-density lipoprotein) (unit: milligrams/deciliter)	Baseline to three years of follow-up
Other	Inflammation	Inflammatory biomarkers including interleukin-6 (IL-6) (unit: picograms/milliliter) and Tumor necrosis factor a (TNF-a) (unit: picograms/milliliter).	Baseline to three years of follow-up
Other	Body composition	Anthropometry reflected by body fat percentage (%) assessed by bioimpedance (unit is estimated per cent fat mass).	Baseline to three years of follow-up
Primary	Total coronary artery calcification	Total coronary artery calcification score (unit: Agatston score) in the coronary arteries, assessed by non-contrast Cardiac CT scans. A high score reflects higher degree of calcification in the coronary arteries and increased risk of coronary artery disease. The outcome will be evaluated by randomization group (active versus placebo).	Baseline to three years of follow-up
Secondary	Coronary plaque composition	Total coronary plaque composition (calcified, non-calcified subcomponents) assessed by contrast Cardiac CT scans (unit: cubic millimeters)	Baseline to three years of follow-up
Secondary	Arterial stiffness	Arterial stiffness assessed by carotid-femoral pulse wave velocity examination (unit: meters/second)	Baseline to three years of follow-up
Secondary	Blood pressure	Blood pressure (unit: millimeter of mercury) assessed by a digital blood pressure device. Both systolic and diastolic blood pressure will be evaluated.	Baseline to three years of follow-up
Secondary	Aortic valve calcifications	Aortic valve calcifications assessed by non-contrast Cardiac CT scans (unit: Agatston score). A high score reflects higher degree of calcification	Baseline to three years of follow-up
Secondary	Bone mineral density	Bone mineral density assessed by quantitative CT scan of the columna thoracalis (unit: milligrams/cubic centimeter)	Baseline to three years of follow-up
Secondary	Pulmonary function	Pulmonary function reflected by forced expiratory volume in one second (FEV1) (unit: Volume in Liter)	Baseline to three years of follow-up
Secondary	Insulin resistance	Insulin resistance assessed by Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) (unit: millimoles/liter * picomoles/liter)	Baseline to three years of follow-up