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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

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.


Condition or disease Intervention/treatment Phase
Covid19 Dietary Supplement: Vitamin K2 in the form of Menaquinone-7 (MK-7) Dietary Supplement: Placebo Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
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
Official Title: A Phase 2, Double Blind, Randomized, Placebo-controlled Clinical Trial to Investigate the Safety and Effects of Oral Vitamin K2 Supplementation in COVID-19
Actual Study Start Date : February 22, 2021
Estimated Primary Completion Date : June 1, 2021
Estimated Study Completion Date : October 1, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Vitamin K
Drug Information available for: Menadione

Arm Intervention/treatment
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.
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.

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.
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.




Primary Outcome Measures :
  1. 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.

  2. 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 Outcome Measures :
  1. 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.

  2. 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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04770740


Contacts
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Contact: Margot Visser, M.D. 0243657657 m.visser@cwz.nl
Contact: Jona Walk, M.D. PhD +3124368200 jona.walk@cwz.nl

Locations
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Netherlands
Canisius Wilhelmina Hospital Recruiting
Nijmegen, Gelderland, Netherlands, 6532SZ
Contact: Margot Visser, M.D.    +31-24 365 7657    m.visser@cwz.nl   
Contact: Jona Walk, PhD, M.D.    +31-24368200    jona.walk@cwz.nl   
Sponsors and Collaborators
Canisius-Wilhelmina Hospital
Kappa Bioscience
Investigators
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Principal Investigator: A. Dofferhoff, M.D. PhD Canisius-Wilhelmina Hospital
Additional Information:
Publications:
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Responsible Party: Ton Dofferhoff, Specialist in Internal Medicine and infectious diseases, Canisius-Wilhelmina Hospital
ClinicalTrials.gov Identifier: NCT04770740    
Other Study ID Numbers: KOVIT
First Posted: February 25, 2021    Key Record Dates
Last Update Posted: March 3, 2021
Last Verified: February 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: Not sure yet.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Ton Dofferhoff, Canisius-Wilhelmina Hospital:
Vitamin K
Desmosine
Elastic fibers
Dp-ucMGP
PIVKA-II
Additional relevant MeSH terms:
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Vitamin K
Vitamin K 2
Vitamin MK 7
Vitamins
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs
Antifibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Hemostatics
Coagulants