Study protocol of the InterVitaminK trial: a Danish population-based randomised double-blinded placebo-controlled trial of the effects of vitamin K (menaquinone-7) supplementation on cardiovascular, metabolic and bone health

Abstract

Introduction: Vitamin K has been suggested to have protective effects against progression of vascular calcification and development of cardiovascular disease (CVD). However, few well-powered randomised controlled trials have examined whether vitamin K prevents progression of vascular calcification in individuals from the general population. The aim of the InterVitaminK trial is to investigate the effects of vitamin K supplementation (menaquinone-7, MK-7) on cardiovascular, metabolic, respiratory and bone health in a general ageing population with detectable vascular calcification.

Methods and analysis: The InterVitaminK trial is a randomised, double-blinded, placebo-controlled, trial. A total of 450 men and women aged 52-82 years with detectable coronary artery calcification (CAC), but without manifest CVD, will be randomised (1:1) to receive daily MK-7 (333 µg/day) or placebo tablets for 3 years. Health examinations are scheduled at baseline, and after 1, 2 and 3 years of intervention. Health examinations include cardiac CT scans, measurements of arterial stiffness, blood pressure, lung function, physical function, muscle strength, anthropometric measures, questionnaires on general health and dietary intake, and blood and urine sampling. The primary outcome is progression of CAC from baseline to 3-year follow-up. The trial has 89% power to detect a between-group difference of at least 15%. Secondary outcomes are bone mineral density, pulmonary function and biomarkers of insulin resistance.

Ethics and dissemination: Oral MK-7 supplementation is considered safe and has not been found to cause severe adverse events. The Ethical Committee of the Capital Region (H-21033114) approved the protocol. Written informed consent is obtained from all participants and the trial is conducted in accordance with the Declaration of Helsinki II. Both negative and positive findings will be reported.

Trial registration number: NCT05259046.

Keywords: CARDIOLOGY; Calcium & bone; General endocrinology; NUTRITION & DIETETICS.

Figure 1

Trial design and time schedule: Baseline health examinations are conducted at three visits (V0-A, V0-B and V0-C). V0-A: Baseline examination (conducted as part of the Inter99 20-year follow-up study), V0-B: Baseline examination (Cardiac CT scan and screening prior to invitation), V0-C: Enrolment visit and randomisation, V1: 1-year follow-up visit, V2: 2 years follow-up visit, V3: 3 years follow-up visit. Examinations marked with (x) will be applied as baseline measurements for the InterVitaminK trial. Red circles illustrate phone calls to register treatment compliance. FFQ, food frequency questionnaire.

Figure 2

Timeline of the project. The Gantt chart illustrates the timeline of the entire InterVitaminK trial. Baseline health examinations for the trial are performed as part of the Inter99 20-year follow-up study. Enrolment in the InterVitaminK trial was initiated in June 2022 and is expected to run for 18 months. We expect to complete follow-up of the last participant in December 2026.