Treatment to Reduce Vascular Calcification in Hemodialysis Patients Using Vitamin K (TReVasc-HDK)

Treatment to Reduce Vascular Calcification in Hemodialysis Patients Using Vitamin K (Trevasc-HDK): A Study Protocol for a Randomized Controlled Trial

The proposed study will seek to evaluate the prevalence and the progression of vascular calcification in a cohort of maintenance hemodialysis patients in Asian population. It will also evaluate the efficacy of vitamin K 2 supplementation in reducing the progression of vascular calcification in this group of patients.

This will be a single-center randomized, prospective and open-label interventional clinical trial of end stage renal failure patients on hemodialysis.Primary outcome will be absolute difference in coronary artery calcium (CAC) score at 18-month between control and intervention arms. Secondary outcomes will be to compare absolute difference in aortic valve calcification, percentage of patients with regression of coronary artery calcification of at least 10%, absolute difference in aortic and systemic arterial stiffness, mortality from any cause and major adverse cardiovascular events (MACE) over the same period.

Study Overview

• Status: Completed
• Conditions: Vascular Calcification; Complication of Hemodialysis; Deficiency of Vitamin K2; Systemic and Arterial Stiffness
• Intervention / Treatment: Drug: menaquinone-7

• Study Type: Interventional
• Enrollment (Actual): 178
• Phase: Phase 2

Contacts and Locations

Study Locations

• Singapore
  • Singapore, Singapore
    • National University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age ≥ 45 years and less than 80 years
2. At least 12 months on Hemodialysis
3. Coronary artery calcium score of ≥ 30 in the baseline Multislice Computed Tomography
4. Able to give informed consent
5. Life expectancy of at least18 months

Exclusion Criteria:

1. History of thrombosis in the last 6 months except vascular access thrombosis
2. Need for vitamin K antagonists therapy at baseline or in the 3 months prior to baseline
3. Presence of significant gut disease (inflammatory bowel disease, short-bowel syndrome)
4. Liver dysfunction
5. Alcohol or drug abuse
6. Presence of coronary stent or have undergone coronary artery bypass grafting
7. Women who are pregnant or breast feeding,
8. Those who are fearful of confined space and cannot lie still for Multislice Computed Tomography
9. Lack of safe contraceptive measures.
10. Those who had parathyroid surgery done.
11. Those with parathyroid hormone (PTH) > 150 pmol/l
12. Patient taking multivitamins containing vitamin K
13. Patient allergic to soy based products

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Vitamin K2; Vitamin K comes in various isoforms and we have elected to use the K2 isoform - menaquinone-7. We have chosen a dose of 360mcg 3x/week as previous studies using menaquinone-7 demonstrated an increasing dose efficacy relationship up to this strength. Vitamin K2 is manufactured by Nattopharma	Drug: menaquinone-7; Oral supplement given post dialysis 3x/week
No Intervention: Standard Therapy; Subjects randomised to standard therapy will continue to receive dialysis and chronic kidney disease-metabolic bone disease (CKD-MBD) management in accordance to current best practise guidelines

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute difference in coronary artery calcium score at 18-month between control and intervention arms	Comparison made using the t-test following log transformation. Adjustment for baseline CAC scores made via the analysis of covariance.	18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute difference in AVC score at 18-months	Comparison made using the t-test following log transformation. Adjustment for baseline AVC scores made via the analysis of covariance.	18 months
Percentage of patients with regression of CAC of ≥ 10% over 18-month		18 months
Absolute difference in cfPWV and AI at 18-months		18 months
Mortality from any cause within the study period		18 months
MACE defined as non-fatal myocardial infarction, heart failure, acute coronary syndrome, need for coronary revascularization, non-fatal stroke, significant peripheral vascular disease		18 months
Difference in plasma levels of dp-ucMGP at 18 months		18 months
Vascular access events, including clotting requiring insertion of a new dialysis catheter, declotting or exchange of an existing catheter, and vascular intervention during the study period		18 months

Collaborators and Investigators

• Sponsor: National University Health System, Singapore
• Collaborators: National Medical Research Council (NMRC), Singapore; Nattopharma ASA
• Investigators: Principal Investigator: Sabrina Wong Peixin Haroon, MD MRCP FAMS, National University Health System

Publications and helpful links

General Publications

• Haroon SW, Tai BC, Ling LH, Teo L, Davenport A, Schurgers L, Teo BW, Khatri P, Ong CC, Low S, Yeo XE, Tan JN, Subramanian S, Chua HR, Tan SY, Wong WK, Lau TW. Treatment to reduce vascular calcification in hemodialysis patients using vitamin K (Trevasc-HDK): A study protocol for a randomized controlled trial. Medicine (Baltimore). 2020 Sep 4;99(36):e21906. doi: 10.1097/MD.0000000000021906.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2016
• Primary Completion (Actual): February 1, 2022
• Study Completion (Actual): February 1, 2022

Study Registration Dates

• First Submitted: August 14, 2016
• First Submitted That Met QC Criteria: August 14, 2016
• First Posted (Estimate): August 17, 2016

Study Record Updates

• Last Update Posted (Estimate): January 16, 2023
• Last Update Submitted That Met QC Criteria: January 13, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Hematologic Diseases; Nutrition Disorders; Hemorrhagic Disorders; Avitaminosis; Deficiency Diseases; Malnutrition; Blood Coagulation Disorders; Calcium Metabolism Disorders; Calcinosis; Vascular Calcification; Vitamin K Deficiency; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Fibrin Modulating Agents; Micronutrients; Vitamins; Antifibrinolytic Agents; Hemostatics; Coagulants; Vitamin K; Vitamin K 2; Vitamin MK 7
• Other Study ID Numbers: NHG DSRB Ref: 2015/01000

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Data to be shared with collaborators