Randomized Controlled Clinical Trial to Investigate Effects of Vitamin K2 in COVID-19
Randomized Controlled Clinical Trial to Investigate Effects of Vitamin K2 in COVID-19
Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome
 coronavirus-2 (SARS-CoV-2). While the majority of people recover after mild symptoms, a
 portion of COVID-19 patients develops respiratory failure. Coagulopathy and thromboembolism
 are prevalent in severe COVID-19, and these factors are associated with decreased survival.
 Coagulation is an intricate balance between clot promoting and dissolving processes in which
 vitamin K plays an essential role. Elastin is a major component of dynamic tissues such as
 lungs and arteries, and elastin calcification stimulates elastin degradation and vice versa.
 The vitamin K-dependent Matrix Gla Protein (MGP) protects elastin from both calcification and
 degradation.

 Although technically feasible, direct quantification of blood vitamin K levels is not an
 appropriate method to assess overall vitamin K status due to differences in bioavailability
 and half-life time between the two naturally occurring vitamin K forms (vitamin K1 and K2).
 Measuring inactive levels of vitamin K-dependent proteins in the circulation is the method
 recommended by most experts, as it represents the systemic availability of both vitamin K1
 and K2. Dp-uc (dephospho uncarboxylated, i.e. inactive) MGP and proteins induced by vitamin K
 absence (PIVKA-II) both inversely correlate with vitamin K status and can be used as
 surrogate markers of total vitamin K status.

 Recently, we found a severely reduced vitamin K status (as quantified by dp-ucMGP) in
 COVID-19 patients compared to controls. In COVID-19 patients, low vitamin K status was also
 associated with poor outcome (defined as the need for invasive ventilation or death),
 accelerated elastin degradation (quantified by plasma (iso)desmosine (DES) a byproduct of
 elastin degradation). Based on these finding and previous studies, we hypothesize that
 improving vitamin K-status by vitamin K supplementation could have favorable effects on
 pulmonary damage and coagulopathy in COVID-19.
The outbreak of coronavirus 2019 disease (COVID-19) has a major impact on health care
 worldwide. This infectious disease is caused by the severe acute respiratory syndrome
 coronavirus (SARS-CoV-2). The majority of individuals who contract COVID-19 have mild
 symptoms, but a significant part develops respiratory failure due to severe pneumonia and/or
 acute respiratory distress syndrome (ARDS). The virus may also have extra pulmonary
 manifestations, including coagulopathy and venous thromboembolism, associated with decreased
 survival. The pathogenesis of this coagulopathy, and the links between pulmonary and
 thromboembolic manifestations of COVID-19 are incompletely understood. In KOVIT trial, the
 roll of vitamin K in the pathogenesis of these manifestations will be elucidated.

 Vitamin K in coagulation and elastic fiber metabolism

 Coagulation is an intricate balance between clot promoting and dissolving processes in which
 vitamin K plays an important role. Pro-coagulation factors II, VII, IX and X depend on
 vitamin K for carboxylation to fulfill their biological function. Besides this, vitamin K is
 also cofactor of anticoagulant protein C and protein S. A significant proportion of protein S
 is extrahepatically synthesized in endothelial cells, in contrast to the pro-coagulant
 factors and protein C. Protein S plays a local suppressive role against thrombosis.

 Matrix Gla protein (MGP) is also vitamin K-dependent but not involved in intravascular
 coagulation. MGP has been generally studied as an inhibitor of vascular mineralization, and
 its role in the pulmonary compartment seems to be comparable. Besides preventing soft tissue
 calcification, it also protects against elastic fiber degradation. Elastic fibers are
 fundamental matrix components in lungs and have high calcium affinity. Degradation and
 mineralization of elastic fibers are related processes. Desphospho-uncarboxylated MGP
 (dp-ucMGP) i.e. inactive MGP is a robust biomarker of extrahepatic vitamin K status since it
 is inversely associated with vitamin K.

 Insufficiency of vitamin K may develop within days of poor intake, particularly in
 pathological conditions of increased vitamin K utilization. During times of scarcity,
 micronutrients are reserved for use in processes that form the greatest threat to short-term
 survival. With regard to vitamin K insufficiency, it appears to be preferentially transported
 to the liver for the activation (via carboxylation) of procoagulant factors at the expense of
 extrahepatic vitamin K-dependent proteins such as MGP and protein S (figure 1).

 Assessment of vitamin K status

 In nature, vitamin K is found in food as vitamin K1 (phylloquinone) and vitamin K2
 (menaquinones). Measuring circulating levels of these two forms of vitamin K is technically
 feasible but the value of such measurements is limited. Quantification of vitamin K-dependent
 proteins that have not been carboxylated yet, is a valuable method reflecting the functional
 deficit of vitamin K1 and K2. Determination of dp-ucMGP levels as well as the ratio between
 uncarboxylated and carboxylated osteocalcin are validated assays of extrahepatic vitamin K
 status.

 Dp-ucMGP is a biomarker of extrahepatic vitamin K status. High dp-ucMGP reflects low vitamin
 K status and vice versa. Although increasing vitamin K consumption decreases the amount of
 dp-ucMGP. Circulating dp-ucMGP concentration can best be regarded as a reflection of the
 total extrahepatic vitamin K deficit, which refers to the amount of vitamin K that is needed
 to carboxylate all the uncarboxylated vitamin K-dependent proteins in the body. Hepatic
 vitamin K status is usually quantified by measuring levels of protein induced by vitamin K
 absence (PIVKA)-II (i.e. uncarboxylated prothrombin).

 Rationale for study treatment

 Recently, a reduced vitamin K status was found, as quantified by dp-ucMGP, in patients
 suffering from COVID-19 as compared to controls. In these patients, low vitamin K status was
 also associated with poor outcome (defined as the need for invasive ventilation or death) and
 accelerated elastic fiber degradation (quantified by plasma (iso)desmosine (DES) a byproduct
 of elastin degradation). In contrast, hepatic vitamin K status, measured by inactive factor
 II (also called protein-induced by vitamin K absence (PIVKA)-II) was unaffected in most
 patients (figure 2). Considering the preferential activation of hepatic over extrahepatic
 proteins.

 In COVID-19, inflammation causes pulmonary elastic fiber damage, which could also lead to an
 upregulation of MGP and a draining of extrahepatic vitamin K. The significant correlation
 between increased dp-ucMGP levels, and elastic fiber degeneration and poor prognosis supports
 the theory that vitamin K insufficiency contributes to pulmonary pathology.

 Hypothesis

 It is hypothesized that improving vitamin K-status by vitamin K supplementation could have
 favorable effects on both pulmonary damage and coagulation abnormalities in COVID-19
 patients.

 Objective

 The objective of the KOVIT trial is to evaluate the safety of oral vitamin K2 supplementation
 in patients suffering from COVID-19 requiring hospital admission.
Inclusion Criteria:

 -  COVID-19 patients who are admitted to the CWZ with COVID-19, with a laboratory
 confirmed SARS-CoV-2 infection within the previous 96 hours

 -  Respiratory failure requiring supplemental oxygen, defined as requiring supplemental
 oxygen to sustain an arterial PO2 ≥70mmHg (measured by arterial blood gas) or an
 oxygen saturation of ≥94% (measured using a pulse oximeter)

 -  At least 18 years old

 -  Able to safely swallow the study medication or possibility of safely administering
 this through a nasogastric tube

 -  Use of prophylactic heparin or LWMH according to hospital protocols, or use of
 therapeutic dosages if there is a medical indication for this

 -  Informed consent signed by patient

 Exclusion Criteria:

 -  Use of oral anticoagulation drugs; patients may be included when they have been
 switched to LMWH

 -  Patients on vitamin K antagonists with a supra-therapeutic anticoagulation at
 admission who require vitamin K supplementation to correct this, or were administered
 vitamin K for this reason within the preceding 5 days

 -  Patients already using vitamin K supplements at admission

 -  Participation in another intervention study

 -  Direct admission to an intensive care unit (ICU) for invasive ventilation at
 presentation

 -  Confirmed active pulmonary embolism or deep venous thrombosis prior to inclusion

 -  Known allergy to any of the components of the study medication or placebo

 -  Patients who are hemodialysis dependent at admission

 -  Pregnancy at the time of inclusion

 -  Diagnosed malignancy at the time of inclusion