Vitamin K to Attenuate Coronary Artery Calcification in Hemodialysis Patients (iPACK-HD)

Inhibit Progression of Coronary Artery Calcification With Vitamin K in HemoDialysis Patients: The iPACK-HD Study

The purpose of this study is to see if vitamin K supplementation three times per week reduces the progression of coronary artery calcification over 12 months in dialysis patients compared to placebo.

Study Overview

• Status: Completed
• Conditions: End-stage Kidney Disease
• Intervention / Treatment: Drug: Microcrystalline Methylcellulose; Drug: Vitamin K1

Detailed Description

At every stage of chronic kidney disease (CKD), the leading cause of mortality is cardiovascular disease. This is due, in part, to vascular calcification (VC) of the coronary arteries. The extent of VC in the coronary arteries of patients with CKD is commonly determined by high resolution CT scan. The total coronary artery calcium (CAC) score, measured in Agatston units (AUs), reflects the calcium burden in the three major coronary arteries and is the current standard for determining extent of vascular calcification in hemodialysis patients. Matrix Gla protein (MGP), a vitamin K dependent protein, is a key inhibitor of vascular calcification and is present in the arterial wall. It is established that MGP becomes up-regulated adjacent to sites of calcification and that vitamin K is critical to its function. Therefore vitamin K status may be critical to the extent of vascular calcification in this patient group. However, to date, no trial has examined whether vitamin K supplementation prevents the progression of coronary artery calcification in patients with kidney failure, a group in which high risk has been established. Therefore, our primary research question is: Does vitamin K supplementation with 10 mg of phylloquinone thrice weekly reduce the progression of coronary artery calcification (as measured by CAC score) over 12 months in prevalent hemodialysis patients with a baseline CAC score of ≥ 30 Agatston Units compared to placebo?

• Study Type: Interventional
• Enrollment (Actual): 85
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Kingston, Ontario, Canada, K7L 2V7
      • Kingston Health Sciences Centre: Kingston General Hospital Site
    • London, Ontario, Canada, N6A 5W9
      • London Health Sciences Centre
    • Ottawa, Ontario, Canada, K1H 8L6
      • The Ottawa Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Able to provide signed informed consent
• ≥18 years of age
• Expected to survive one year
• Have end-stage kidney disease and require hemodialysis
• Have a baseline coronary artery calcification score ≥30 Agatston units (AUs)

Exclusion Criteria:

• Have a medical condition that requires warfarin
• Require hemodialysis for acute kidney injury
• Are Pregnant
• Have other severe co-morbid conditions (e.g. malignancy, disabling stroke) with life expectancy less than one year
• Have undergone coronary artery bypass grafting or have stents placed in their coronary arteries
• Are currently enrolled in another interventional trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo; Microcrystalline Methylcellulose	Drug: Microcrystalline Methylcellulose; 10mg orally three times a week for 12 months
ACTIVE_COMPARATOR: Vitamin K1	Drug: Vitamin K1; 10mg orally three times a week for 12 months; Other Names: Phylloquinone; Phytonadione

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recruitment rate	Number of participants recruited per month at each site) and an overall crude average of each site's rate.	12 months
Compliance with study medication	Proportion of prescribed doses received.	12 months
Dropout rate	Proportion of participants who dropped out from the trial.	12 months
Adherence to study protocol	Proportion of participants who adhered to the study protocol.	12 months
Rates of eligible patients consented and randomized	Proportion of eligible patients consented and randomized.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Coronary artery calcification (Agatston calcium scores) progression	A)The percent and absolute change of the Agatston calcium scores (CT scan) will be assessed at study exit vs. baseline. Included measures will be: Total CAC, Left Main CAC, Right Coronary Artery CAC, Left Anterior Descending CAC, Circumflex CAC, and Posterior Descending Artery CAC. B) The proportion of participants with a 15% or greater increase in Agatston calcium scores will be assessed at study exit vs baseline.	12 months
Coronary artery calcification (volume calcium scores) progression	A) The percent and absolute change of the volume calcium scores (CT scan) will be assessed at study exit vs. baseline. Included measures will be: Total CAC, Left Main CAC, Right Coronary Artery CAC, Left Anterior Descending CAC, Circumflex CAC, and Posterior Descending Artery CAC. B) The proportion of participants with a 15% or greater increase in volume calcium scores will be assessed at study exit vs baseline.	12 months
Coronary artery calcification (Agatston calcium scores) regression	The proportion of participants with a 10% or greater decrease in Agatston calcium scores will be assessed at study exit vs baseline.	12 months
Coronary artery calcification (volume calcium scores) regression	The proportion of participants with a 10% or greater decrease in volume calcium scores will be assessed at study exit vs baseline.	12 months
Aortic valve calcification (Agatston calcium scores) progression	The absolute and percentage change of the Agatston calcium scores (CT scan) will be assessed at study exit vs. baseline.	12 months
Aortic valve calcification (volume calcium scores) progression	The absolute and percentage change of the volume calcium scores (CT scan) will be assessed at study exit vs. baseline.	12 months
Mitral valve calcification (Agatston calcium scores) progression	The absolute and percentage change of the Agatston calcium scores (CT scan) will be assessed at study exit vs. baseline.	12 months
Mitral valve calcification (volume calcium scores) progression	The absolute and percentage change of the volume calcium scores (CT scan) will be assessed at study exit vs. baseline.	12 months
Abdominal aortic calcification (AAC) scores	The AAC score (mean score in L1-L4, mean number of positive segments, mean total severity using lateral lumbar spine radiographs) will be assessed at study exit vs. baseline.	12 months
Levels of biomarkers of vitamin K status	Gas6, PK, MK4, osteocalcin Gla, osteocalcin Glu, osteocalcin Gla to Glu ratio, percent of osteocalcin undercarboxylated, and dpucMGP will be assessed at baseline, four, eight and study exit. Protein induced by vitamin K absence or antagonist II (PIVKA-II) will be assessed at baseline and study exit.	12 months
Prevalence and incidence of thoracic vertebral fractures	The prevalence and incidence of thoracic vertebral fractures (anterior and lateral radiographs) will be assessed at baseline and study exit.	12 months
Prevalence and incidence of lumbar vertebral fractures	The prevalence and incidence of lumbar vertebral fractures (anterior and lateral radiographs) will be assessed at baseline and study exit.	12 months
Presence/absence and total hospitalizations	The presence or absence and total hospitalizations will be assessed across the study duration per patient.	12 months
Presence/absence and total cardiovascular events	The presence or absence and total cardiovascular events (acute coronary syndrome, congestive heart failure, stroke, transient ischemic attack, amputation, and cardiac [symptom-driven] [cerebral or peripheral] revascularization procedure, or cardiac arrest) will be assessed across the study duration per patient.	12 months
Presence/absence and total thrombotic events	The presence or absence and total thrombotic events (deep vein thrombosis and pulmonary embolism) will be assessed across the study duration per patient.	12 months
Presence/absence and total hemodialysis access thrombotic events	The presence or absence and total hemodialysis access thrombotic events (fistula and/or graft thrombosis or dialysis catheter thrombosis) will be assessed across the study duration per patient.	12 months
Presence/absence and total mortality	The presence or absence and total all-cause and cardiovascular cause mortality will be assessed across the study duration per patient.	12 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Levels of biomarkers of inflammation	C-reactive protein (CRP), interleukin 6 (IL-6), leptin, insulin, glucose, homeostasis model assessment-insulin resistance (HOMA-IR) will be assessed at baseline, four months, eight months, and study exit.	12 months
Levels of clinical lab values	Hemoglobin, albumin, Kt/V, creatinine, lipid profile (HDL, LDL, triglycerides, and total cholesterol), and parameters of mineral metabolism (phosphate, calcium, PTH, and ALP) will be assessed monthly. Serum FGF-23 will be assessed at baseline, four months, eight, and study exit.	12 months
Concomitant medication assessment (presence/absence/dosage)	Prescription of concomitant medications (listed below) will be assessed monthly.; Calcium-based phosphate binders; Non-calcium-based phosphate binders; Calcitriol; Vitamin D Calcimimetic; HMG-CoA reductase inhibitors; Angiotensin converting enzyme inhibitors; Angiotensin II receptor blockers; Anti-platelet therapy: acetylsalicylic acid, clopidogrel bisulfate, and dipyridamole Average dosage and total exposure across study exit will be assessed for calcitriol, other vitamin D drugs, and calcium-based phosphate binders.	12 months
Changes in body composition measures	Muscle atrophy and adipose tissue will be assessed using an L3 slice (CT scan) at study exit vs. baseline. Specifically, muscle, normalized muscle, intermuscular adipose tissue (IMAT), visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and total adipose tissue (TAT) cross-sectional area (cm2 or cm2/m2) and muscle, IMAT, VAT and SAT radiodensity (HUs) measurements will be included.	12 months
Levels of vascular inflammation variables	Myoglobin, calciprotectin, neutrophil gelatinase-associated lipocalin, matrix-metalloproteinase 2, osteopontin, myeloperoxidase, serum amyloid A, insulin-like growth factor binding protein-4, intercellular adhesion molecule 1, vascular cell adhesion protein 1, matrix-metalloproteinase 9, and cystatin C will be assessed at baseline, four months, eight months and study exit.	12 months
Levels of vitamin D metabolites	1,25-OH-D3, 25-OH-D2, percent 25D that is D2, Total 25D, 24,25(OH)2D3, 25D3:24,25D3, 24,25D3:25D3, 3epi25-OH-D3, 3epi25-OH-D3(%), 1,25(OH)2D3, 1,24,25(OH)3D3, 1,25(OH)2D3:1,24,25(OH)3D3, 1,25(OH)2D3:1,24,25(OH)3D3 will be assessed at baseline, four months, eight months and study exit.	12 months

Collaborators and Investigators

• Sponsor: Dr. Rachel Holden
• Investigators: Principal Investigator: Rachel Holden, Queens University/Kingston Health Sciences Centre: Kingston General Hospital

Publications and helpful links

General Publications

• Holden RM, Booth SL, Zimmerman D, Moist L, Norman P, Day AG, Menard A, Fu X, Shea MK, Babiolakis CS, Nolan R, Turner ME, Ward E, Kaufmann M, Adams MA, Heyland DK. Inhibit progression of coronary artery calcification with vitamin k in hemodialysis patients (the iPACK-HD study): a randomized, placebo-controlled multi-centre, pilot trial. Nephrol Dial Transplant. 2022 May 31:gfac191. doi: 10.1093/ndt/gfac191. Online ahead of print.
• Holden RM, Booth SL, Day AG, Clase CM, Zimmerman D, Moist L, Shea MK, McCabe KM, Jamal SA, Tobe S, Weinstein J, Madhumathi R, Adams MA, Heyland DK. Inhibiting the progression of arterial calcification with vitamin K in HemoDialysis patients (iPACK-HD) trial: rationale and study design for a randomized trial of vitamin K in patients with end stage kidney disease. Can J Kidney Health Dis. 2015 May 1;2:17. doi: 10.1186/s40697-015-0053-x. eCollection 2015.

Study record dates

Study Major Dates

• Study Start: November 1, 2012
• Primary Completion (ACTUAL): December 1, 2019
• Study Completion (ACTUAL): December 1, 2019

Study Registration Dates

• First Submitted: February 6, 2012
• First Submitted That Met QC Criteria: February 7, 2012
• First Posted (ESTIMATE): February 8, 2012

Study Record Updates

• Last Update Posted (ACTUAL): June 28, 2021
• Last Update Submitted That Met QC Criteria: June 24, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: Chronic Kidney Disease; Hemodialysis; Coronary Artery Calcification; Vascular Calcification; Vitamin K
• Additional Relevant MeSH Terms: Metabolic Diseases; Urologic Diseases; Renal Insufficiency; Renal Insufficiency, Chronic; Calcium Metabolism Disorders; Kidney Diseases; Kidney Failure, Chronic; Calcinosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Fibrin Modulating Agents; Micronutrients; Vitamins; Antifibrinolytic Agents; Hemostatics; Coagulants; Vitamin K; Vitamin K 1
• Other Study ID Numbers: iPACK-HD