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Randomized Controlled Clinical Trial to Investigate Effects of Vitamin K2 in COVID-19 (KOVIT)

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ClinicalTrials.gov Identifier: NCT04770740
Recruitment Status : Recruiting
First Posted : February 25, 2021
Last Update Posted : March 3, 2021
Sponsor:
Collaborator:
Kappa Bioscience
Information provided by (Responsible Party):
Ton Dofferhoff, Canisius-Wilhelmina Hospital

Tracking Information
First Submitted Date  ICMJE February 24, 2021
First Posted Date  ICMJE February 25, 2021
Last Update Posted Date March 3, 2021
Actual Study Start Date  ICMJE February 22, 2021
Estimated Primary Completion Date June 1, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 24, 2021)
  • 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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 24, 2021)
  • Safety [ Time Frame: Day 1 until day 28 ]
    Difference between the number of grade 3 and grade 4 adverse events between the intervention and control group during treatment, with special attention for: progression of respiratory insufficiency, thrombotic events, pulmonary embolism or deep venous thrombosis, bleeding, renal insufficiency, cardiac decompensation, liver enzyme abdnormalities and/or liver failure.
  • Serum PIVKA-II levels [ Time Frame: Day 1 until day 28 or until discharge if this is earlier. ]
    Serum PIVKA-II levels before and during vitamin K supplementation in intervention versus control patients.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Randomized Controlled Clinical Trial to Investigate Effects of Vitamin K2 in COVID-19
Official Title  ICMJE A Phase 2, Double Blind, Randomized, Placebo-controlled Clinical Trial to Investigate the Safety and Effects of Oral Vitamin K2 Supplementation in COVID-19
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).

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
double blind, randomized, placebo-controlled
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Other
Condition  ICMJE Covid19
Intervention  ICMJE
  • Dietary Supplement: Vitamin K2 in the form of Menaquinone-7 (MK-7)
    Patients will take three tablets of vitamin K2 menaquinone-7 (333mcg) per day. Patients taking vitamin K2 MK-7 will receive the total of 999mcg per day from day 1 until day 14 or discharge, whichever occurs earlier. All subjects can be treated with prophylactic or therapeutic heparin-based (heparin or any low-molecular weight heparin) anticoagulants, according to local hospital protocols. Provided by Kappa Bioscience.
  • Dietary Supplement: Placebo
    Patients will take three tablets of placebo containing only inactive ingredients per day, from day 1 until day 14 or until discharge, whichever occurs first. The placebo is provided by Kappa Bioscience.
Study Arms  ICMJE
  • Active Comparator: Experimental: Vitamin K2
    Patients with COVID-19 who get our dietary supplement vitamin K2, three tablets of 333mcg a day, for 14 days or until discharge, whichever occurs earlier.
    Intervention: Dietary Supplement: Vitamin K2 in the form of Menaquinone-7 (MK-7)
  • Placebo Comparator: Control: Placebo
    Patients with COVID-19 who get placebo as control, three tablets a day, for 14 days or until discharge, whichever occurs earlier.
    Intervention: Dietary Supplement: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 24, 2021)
40
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE October 1, 2021
Estimated Primary Completion Date June 1, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Margot Visser, M.D. 0243657657 m.visser@cwz.nl
Contact: Jona Walk, M.D. PhD +3124368200 jona.walk@cwz.nl
Listed Location Countries  ICMJE Netherlands
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04770740
Other Study ID Numbers  ICMJE KOVIT
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Plan Description: Not sure yet.
Responsible Party Ton Dofferhoff, Canisius-Wilhelmina Hospital
Study Sponsor  ICMJE Canisius-Wilhelmina Hospital
Collaborators  ICMJE Kappa Bioscience
Investigators  ICMJE
Principal Investigator: A. Dofferhoff, M.D. PhD Canisius-Wilhelmina Hospital
PRS Account Canisius-Wilhelmina Hospital
Verification Date February 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP