Clinical trial NCT05259046: The InterVitaminK Trial - Effects of Vitamin K Supplementation on Cardiovascular, Metabolic, and Bone Health
Official title: Novel Health Effects of Vitamin K: a Placebo-controlled Randomized Trial in the General Population (InterVitaminK)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Coronary Artery Calcification
Arterial Stiffness
Lead sponsor: Bispebjerg Hospital
Sponsor class: OTHER
First posted: 2022-02-28
Enrollment: 450
Sex: ALL
Minimum age (years): 50
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Participants will be randomized in a double-blinded manner 1:1 to MK-7 tablets or placebo tablets. Randomisation is conducted in blocks of 6 using computer generated random numbers. A total of 450 participants will be enrolled (225 in each group).
Primary purpose: PREVENTION

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

Detailed 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).

Eligibility criteria: 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

Primary outcomes:
measure: Total coronary artery calcification
timeFrame: Baseline to three years of follow-up
Secondary outcomes:
measure: Coronary plaque composition
timeFrame: Baseline to three years of follow-up
measure: Arterial stiffness
timeFrame: Baseline to three years of follow-up
measure: Blood pressure
timeFrame: Baseline to three years of follow-up
measure: Aortic valve calcifications
timeFrame: Baseline to three years of follow-up
measure: Bone mineral density
timeFrame: Baseline to three years of follow-up
measure: Pulmonary function
timeFrame: Baseline to three years of follow-up
measure: Insulin resistance
timeFrame: Baseline to three years of follow-up
Other outcomes:
measure: Biomarkers of bone resorption
timeFrame: Baseline to three years of follow-up
measure: Biomarkers of bone formation
timeFrame: Baseline to three years of follow-up
measure: Lung function
timeFrame: Baseline to three years of follow-up
measure: Lung tissue density
timeFrame: Baseline to three years of follow-up
measure: Respiratory infections
timeFrame: Baseline to three years of follow-up
measure: Glucose control
timeFrame: Baseline to three years of follow-up
measure: Lipid metabolism
timeFrame: Baseline to three years of follow-up
measure: Inflammation
timeFrame: Baseline to three years of follow-up
measure: Body composition
timeFrame: Baseline to three years of follow-up
Locations:
city: Copenhagen
country: Denmark
facility: Center for Clinical Research and Prevention
state: Glostrup
Study officials:
References: