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

NCT04770740 | Completed

• 1 other identifier: KOVIT
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

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.

Conditions

Covid19

Keywords

Vitamin K; Desmosine; Elastic fibers; Dp-ucMGP; PIVKA-II

Outcome Measures

Primary Outcomes (2)

• Plasma desmosine levels

  Plasma desmosine levels before and during vitamin K supplementation in intervention versus control patients.

  Day 1 until day 28 or until discharge if this is earlier.

• Plasma dp-ucMGP levels

  Plasma dp-uc MGP levels before and during vitamin K supplementation within the intervention group and in intervention versus control patients.

  Day 1 until day 28 or until discharge if this is earlier.

Secondary Outcomes (2)

• 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.

Study Arms (2)

Experimental: Vitamin K2

ACTIVE COMPARATOR

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)

Control: Placebo

PLACEBO COMPARATOR

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

Interventions

Vitamin K2 in the form of Menaquinone-7 (MK-7) DIETARY_SUPPLEMENT

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.

Experimental: Vitamin K2

Placebo DIETARY_SUPPLEMENT

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.

Control: Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• Known allergy to any of the components of the study medication or placebo
• Patients who are hemodialysis dependent at admission

Sponsors & Collaborators

• Canisius-Wilhelmina Hospital: lead
• Kappa Bioscience AS: collaborator

Study Sites (1)

Canisius Wilhelmina Hospital

Nijmegen, Gelderland, 6532SZ, Netherlands

Location

Related Publications (2)

• Janssen R, Visser MPJ, Dofferhoff ASM, Vermeer C, Janssens W, Walk J. Vitamin K metabolism as the potential missing link between lung damage and thromboembolism in Coronavirus disease 2019. Br J Nutr. 2021 Jul 28;126(2):191-198. doi: 10.1017/S0007114520003979. Epub 2020 Oct 7.

  PMID: 33023681 BACKGROUND

• Dofferhoff ASM, Piscaer I, Schurgers LJ, Visser MPJ, van den Ouweland JMW, de Jong PA, Gosens R, Hackeng TM, van Daal H, Lux P, Maassen C, Karssemeijer EGA, Vermeer C, Wouters EFM, Kistemaker LEM, Walk J, Janssen R. Reduced Vitamin K Status as a Potentially Modifiable Risk Factor of Severe Coronavirus Disease 2019. Clin Infect Dis. 2021 Dec 6;73(11):e4039-e4046. doi: 10.1093/cid/ciaa1258.

  PMID: 32852539 BACKGROUND

Related Links

• Kappa Bioscience

MeSH Terms

Conditions

COVID-19

Interventions

Vitamin K 2

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Vitamin K; Naphthoquinones; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Phytol; Diterpenes; Terpenes; Quinones; Polycyclic Compounds

Study Officials

• A. Dofferhoff, M.D. PhD

  Canisius-Wilhelmina Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Specialist in Internal Medicine and infectious diseases

Model Details: double blind, randomized, placebo-controlled (phase 2)

Study Record Dates

• First Submitted: February 24, 2021
• First Posted: February 25, 2021
• Study Start: February 22, 2021
• Primary Completion: March 1, 2022
• Study Completion: March 1, 2022
• Last Updated: June 13, 2022

Record last verified: 2022-06

Locations

NL (1)