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

• ClinicalTrials.gov Identifier: NCT01528800
• Recruitment Status: Completed
• First Posted: February 8, 2012
• Last Update Posted: June 28, 2021
• Sponsor: Dr. Rachel Holden
• Information provided by (Responsible Party): Dr. Rachel Holden, Clinical Evaluation Research Unit at Kingston General Hospital

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.

Condition or disease	Intervention/treatment	Phase
End-stage Kidney Disease	Drug: Vitamin K1; Drug: Microcrystalline Methylcellulose	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 85 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Inhibit Progression of Coronary Artery Calcification With Vitamin K in HemoDialysis Patients: The iPACK-HD Study
• Study Start Date: November 2012
• Actual Primary Completion Date: December 2019
• Actual Study Completion Date: December 2019

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Placebo; Microcrystalline Methylcellulose	Drug: Microcrystalline Methylcellulose; 10mg orally three times a week for 12 months
Active Comparator: Vitamin K1; Vitamin K1	Drug: Vitamin K1; 10mg orally three times a week for 12 months; Other Names: Phytonadione; Phylloquinone

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Coronary artery calcification (Agatston calcium scores) progression [ Time Frame: 12 months ]

   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.

2. Coronary artery calcification (volume calcium scores) progression [ Time Frame: 12 months ]

   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.

3. Coronary artery calcification (Agatston calcium scores) regression [ Time Frame: 12 months ]
   The proportion of participants with a 10% or greater decrease in Agatston calcium scores will be assessed at study exit vs baseline.
4. Coronary artery calcification (volume calcium scores) regression [ Time Frame: 12 months ]
   The proportion of participants with a 10% or greater decrease in volume calcium scores will be assessed at study exit vs baseline.
5. Aortic valve calcification (Agatston calcium scores) progression [ Time Frame: 12 months ]
   The absolute and percentage change of the Agatston calcium scores (CT scan) will be assessed at study exit vs. baseline.
6. Aortic valve calcification (volume calcium scores) progression [ Time Frame: 12 months ]
   The absolute and percentage change of the volume calcium scores (CT scan) will be assessed at study exit vs. baseline.
7. Mitral valve calcification (Agatston calcium scores) progression [ Time Frame: 12 months ]
   The absolute and percentage change of the Agatston calcium scores (CT scan) will be assessed at study exit vs. baseline.
8. Mitral valve calcification (volume calcium scores) progression [ Time Frame: 12 months ]
   The absolute and percentage change of the volume calcium scores (CT scan) will be assessed at study exit vs. baseline.
9. Abdominal aortic calcification (AAC) scores [ Time Frame: 12 months ]
   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.
10. Levels of biomarkers of vitamin K status [ Time Frame: 12 months ]
    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.
11. Prevalence and incidence of thoracic vertebral fractures [ Time Frame: 12 months ]
    The prevalence and incidence of thoracic vertebral fractures (anterior and lateral radiographs) will be assessed at baseline and study exit.
12. Prevalence and incidence of lumbar vertebral fractures [ Time Frame: 12 months ]
    The prevalence and incidence of lumbar vertebral fractures (anterior and lateral radiographs) will be assessed at baseline and study exit.
13. Presence/absence and total hospitalizations [ Time Frame: 12 months ]
    The presence or absence and total hospitalizations will be assessed across the study duration per patient.
14. Presence/absence and total cardiovascular events [ Time Frame: 12 months ]
    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.
15. Presence/absence and total thrombotic events [ Time Frame: 12 months ]
    The presence or absence and total thrombotic events (deep vein thrombosis and pulmonary embolism) will be assessed across the study duration per patient.
16. Presence/absence and total hemodialysis access thrombotic events [ Time Frame: 12 months ]
    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.
17. Presence/absence and total mortality [ Time Frame: 12 months ]
    The presence or absence and total all-cause and cardiovascular cause mortality will be assessed across the study duration per patient.

Other Outcome Measures:

1. Levels of biomarkers of inflammation [ Time Frame: 12 months ]
   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.
2. Levels of clinical lab values [ Time Frame: 12 months ]
   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.
3. Concomitant medication assessment (presence/absence/dosage) [ Time Frame: 12 months ]

   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.

4. Changes in body composition measures [ Time Frame: 12 months ]
   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.
5. Levels of vascular inflammation variables [ Time Frame: 12 months ]
   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.
6. Levels of vitamin D metabolites [ Time Frame: 12 months ]
   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.

Eligibility Criteria

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

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

Contacts and Locations

Locations

Canada, Ontario

Kingston Health Sciences Centre: Kingston General Hospital Site

Kingston, Ontario, Canada, K7L 2V7

London Health Sciences Centre

London, Ontario, Canada, N6A 5W9

The Ottawa Hospital

Ottawa, Ontario, Canada, K1H 8L6

Sponsors and Collaborators

Dr. Rachel Holden

Investigators

• Principal Investigator: Rachel Holden; Queens University/Kingston Health Sciences Centre: Kingston General Hospital

  Study Documents (Full-Text)

Documents provided by Dr. Rachel Holden, Clinical Evaluation Research Unit at Kingston General Hospital:

Statistical Analysis Plan  [PDF] June 21, 2021

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

• Responsible Party: Dr. Rachel Holden, Professor of Medicine Queen's University, Clinical Evaluation Research Unit at Kingston General Hospital
• ClinicalTrials.gov Identifier: NCT01528800
• Other Study ID Numbers: iPACK-HD
• First Posted: February 8, 2012
• Last Update Posted: June 28, 2021
• Last Verified: June 2021

Keywords provided by Dr. Rachel Holden, Clinical Evaluation Research Unit at Kingston General Hospital:

Vitamin K; Chronic Kidney Disease; Vascular Calcification; Hemodialysis; Coronary Artery Calcification

Additional relevant MeSH terms:

Kidney Diseases; Kidney Failure, Chronic; Calcinosis; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Calcium Metabolism Disorders; Metabolic Diseases; Renal Insufficiency, Chronic; Renal Insufficiency; Chronic Disease; Disease Attributes; Pathologic Processes; Vitamin K; Vitamin K 1; Vitamins; Micronutrients; Physiological Effects of Drugs; Antifibrinolytic Agents; Fibrin Modulating Agents; Molecular Mechanisms of Pharmacological Action; Hemostatics; Coagulants