Vitamin K to Attenuate Coronary Artery Calcification in Hemodialysis Patients (iPACK-HD)
Primary Purpose
End-stage Kidney Disease
Status
Completed
Phase
Phase 2
Locations
Canada
Study Type
Interventional
Intervention
Vitamin K1
Microcrystalline Methylcellulose
Sponsored by
About this trial
This is an interventional prevention trial for End-stage Kidney Disease focused on measuring Vitamin K, Chronic Kidney Disease, Vascular Calcification, Hemodialysis, Coronary Artery Calcification
Eligibility Criteria
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
Sites / Locations
- Kingston Health Sciences Centre: Kingston General Hospital Site
- London Health Sciences Centre
- The Ottawa Hospital
Arms of the Study
Arm 1
Arm 2
Arm Type
Placebo Comparator
Active Comparator
Arm Label
Placebo
Vitamin K1
Arm Description
Microcrystalline Methylcellulose
Vitamin K1
Outcomes
Primary Outcome Measures
Recruitment rate
Number of participants recruited per month at each site) and an overall crude average of each site's rate.
Compliance with study medication
Proportion of prescribed doses received.
Dropout rate
Proportion of participants who dropped out from the trial.
Adherence to study protocol
Proportion of participants who adhered to the study protocol.
Rates of eligible patients consented and randomized
Proportion of eligible patients consented and randomized.
Secondary Outcome Measures
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Presence/absence and total hospitalizations
The presence or absence and total hospitalizations will be assessed across the study duration per patient.
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.
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.
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.
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01528800
Brief Title
Vitamin K to Attenuate Coronary Artery Calcification in Hemodialysis Patients
Acronym
iPACK-HD
Official Title
Inhibit Progression of Coronary Artery Calcification With Vitamin K in HemoDialysis Patients: The iPACK-HD Study
Study Type
Interventional
2. Study Status
Record Verification Date
June 2021
Overall Recruitment Status
Completed
Study Start Date
November 2012 (undefined)
Primary Completion Date
December 2019 (Actual)
Study Completion Date
December 2019 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Dr. Rachel Holden
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
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.
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?
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
End-stage Kidney Disease
Keywords
Vitamin K, Chronic Kidney Disease, Vascular Calcification, Hemodialysis, Coronary Artery Calcification
7. Study Design
Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
85 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Microcrystalline Methylcellulose
Arm Title
Vitamin K1
Arm Type
Active Comparator
Arm Description
Vitamin K1
Intervention Type
Drug
Intervention Name(s)
Vitamin K1
Other Intervention Name(s)
Phytonadione, Phylloquinone
Intervention Description
10mg orally three times a week for 12 months
Intervention Type
Drug
Intervention Name(s)
Microcrystalline Methylcellulose
Intervention Description
10mg orally three times a week for 12 months
Primary Outcome Measure Information:
Title
Recruitment rate
Description
Number of participants recruited per month at each site) and an overall crude average of each site's rate.
Time Frame
12 months
Title
Compliance with study medication
Description
Proportion of prescribed doses received.
Time Frame
12 months
Title
Dropout rate
Description
Proportion of participants who dropped out from the trial.
Time Frame
12 months
Title
Adherence to study protocol
Description
Proportion of participants who adhered to the study protocol.
Time Frame
12 months
Title
Rates of eligible patients consented and randomized
Description
Proportion of eligible patients consented and randomized.
Time Frame
12 months
Secondary Outcome Measure Information:
Title
Coronary artery calcification (Agatston calcium scores) progression
Description
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.
Time Frame
12 months
Title
Coronary artery calcification (volume calcium scores) progression
Description
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.
Time Frame
12 months
Title
Coronary artery calcification (Agatston calcium scores) regression
Description
The proportion of participants with a 10% or greater decrease in Agatston calcium scores will be assessed at study exit vs baseline.
Time Frame
12 months
Title
Coronary artery calcification (volume calcium scores) regression
Description
The proportion of participants with a 10% or greater decrease in volume calcium scores will be assessed at study exit vs baseline.
Time Frame
12 months
Title
Aortic valve calcification (Agatston calcium scores) progression
Description
The absolute and percentage change of the Agatston calcium scores (CT scan) will be assessed at study exit vs. baseline.
Time Frame
12 months
Title
Aortic valve calcification (volume calcium scores) progression
Description
The absolute and percentage change of the volume calcium scores (CT scan) will be assessed at study exit vs. baseline.
Time Frame
12 months
Title
Mitral valve calcification (Agatston calcium scores) progression
Description
The absolute and percentage change of the Agatston calcium scores (CT scan) will be assessed at study exit vs. baseline.
Time Frame
12 months
Title
Mitral valve calcification (volume calcium scores) progression
Description
The absolute and percentage change of the volume calcium scores (CT scan) will be assessed at study exit vs. baseline.
Time Frame
12 months
Title
Abdominal aortic calcification (AAC) scores
Description
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.
Time Frame
12 months
Title
Levels of biomarkers of vitamin K status
Description
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.
Time Frame
12 months
Title
Prevalence and incidence of thoracic vertebral fractures
Description
The prevalence and incidence of thoracic vertebral fractures (anterior and lateral radiographs) will be assessed at baseline and study exit.
Time Frame
12 months
Title
Prevalence and incidence of lumbar vertebral fractures
Description
The prevalence and incidence of lumbar vertebral fractures (anterior and lateral radiographs) will be assessed at baseline and study exit.
Time Frame
12 months
Title
Presence/absence and total hospitalizations
Description
The presence or absence and total hospitalizations will be assessed across the study duration per patient.
Time Frame
12 months
Title
Presence/absence and total cardiovascular events
Description
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.
Time Frame
12 months
Title
Presence/absence and total thrombotic events
Description
The presence or absence and total thrombotic events (deep vein thrombosis and pulmonary embolism) will be assessed across the study duration per patient.
Time Frame
12 months
Title
Presence/absence and total hemodialysis access thrombotic events
Description
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.
Time Frame
12 months
Title
Presence/absence and total mortality
Description
The presence or absence and total all-cause and cardiovascular cause mortality will be assessed across the study duration per patient.
Time Frame
12 months
Other Pre-specified Outcome Measures:
Title
Levels of biomarkers of inflammation
Description
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.
Time Frame
12 months
Title
Levels of clinical lab values
Description
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.
Time Frame
12 months
Title
Concomitant medication assessment (presence/absence/dosage)
Description
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.
Time Frame
12 months
Title
Changes in body composition measures
Description
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.
Time Frame
12 months
Title
Levels of vascular inflammation variables
Description
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.
Time Frame
12 months
Title
Levels of vitamin D metabolites
Description
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.
Time Frame
12 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Rachel Holden
Organizational Affiliation
Queens University/Kingston Health Sciences Centre: Kingston General Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Kingston Health Sciences Centre: Kingston General Hospital Site
City
Kingston
State/Province
Ontario
ZIP/Postal Code
K7L 2V7
Country
Canada
Facility Name
London Health Sciences Centre
City
London
State/Province
Ontario
ZIP/Postal Code
N6A 5W9
Country
Canada
Facility Name
The Ottawa Hospital
City
Ottawa
State/Province
Ontario
ZIP/Postal Code
K1H 8L6
Country
Canada
12. IPD Sharing Statement
Citations:
PubMed Identifier
35641194
Citation
Holden RM, Booth SL, Zimmerman D, Moist L, Norman PA, 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-center, pilot trial. Nephrol Dial Transplant. 2023 Feb 28;38(3):746-756. doi: 10.1093/ndt/gfac191.
Results Reference
derived
PubMed Identifier
26075081
Citation
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.
Results Reference
derived
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Vitamin K to Attenuate Coronary Artery Calcification in Hemodialysis Patients
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