A Phase 2, Double Blind, Randomized, Placebo-controlled Clinical Trial to Investigate the Safety and Effects of Oral Vitamin K2 Supplementation in COVID-19
Trial Snapshot
- Phase
- Not Applicable
- Status
- Completed
- Sponsor
- Enrollment
- 40
- Locations
- 2
- Primary Endpoint
- Plasma desmosine levels
Study Overview
Brief Summary
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.
Detailed Description
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).
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Prevention
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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
Outcomes
Primary Outcomes
Plasma desmosine levels
Time Frame: Day 1 until day 28 or until discharge if this is earlier.
Plasma desmosine levels before and during vitamin K supplementation in intervention versus control patients.
Plasma dp-ucMGP levels
Time Frame: Day 1 until day 28 or until discharge if this is earlier.
Plasma dp-uc MGP levels before and during vitamin K supplementation within the intervention group and in intervention versus control patients.
Secondary Outcomes
- Difference between the number of grade 3 and grade 4 adverse events(Day 1 until day 28)
- Serum PIVKA-II levels(Day 1 until day 28 or until discharge if this is earlier.)
Investigators
Ton Dofferhoff
Specialist in Internal Medicine and infectious diseases
Canisius-Wilhelmina Hospital