Clinical trial NCT02278692: Evaluation of Vitamin K Supplementation for Calcific Uremic Arteriolopathy
Official title: Evaluation of Vitamin K Supplementation for Calcific Uremic Arteriolopathy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Calciphylaxis
Calcific Uremic Arteriolopathy
Keywords: Vitamin K
Calciphylaxis
Calcific uremic arteriolopathy
Dialysis
End-stage renal disease
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
Collaborators: name: National Kidney Foundation, United States
name: American Heart Association
name: Harvard University
First posted: 2014-10-30
Enrollment: 26
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Calcific uremic arteriolopathy a.k.a. calciphylaxis is a vascular calcification disorder seen in dialysis patients. Calcific uremic arteriolopathy has 60-80% one-year mortality and significant morbidity associated with non-healing and extremely painful skin lesions. At present, there is no effective treatment for calcific uremic arteriolopathy.

Vitamin K is an important vitamin for inhibiting vascular calcification. It is known to increase the circulating levels of carboxylated Matrix Gla Protein, a potent inhibitor of vascular calcification. However, the effects of vitamin K supplementation in patients with calcific uremic arteriolopathy are unknown.

The purpose of this study is to conduct a pilot randomized controlled trial to examine the effects of oral vitamin K supplementation on circulating levels of anti-calcification factor (carboxylated Matrix Gla Protein) and clinical outcomes in patients with calcific uremic arteriolopathy.

Detailed description: Calcific uremic arteriolopathy (CUA), also known as calciphylaxis, is a vascular calcification disorder associated with 60-80% one-year mortality and significant morbidity. CUA predominantly affects end-stage renal disease (ESRD) patients and presents with painful skin lesions. Although rare (prevalence: 4% in dialysis patients), the incidence of CUA is on the rise as shown by us and others. Mural calcification of dermal arterioles is the hallmark histological finding of CUA. However, there are significant gaps in the understanding of the pathophysiology and risk factors for CUA and there are no effective therapies.

In animal models, vitamin K prevents vascular calcification by serving as a co-factor for Matrix Gla Protein (MGP) carboxylation, a process that converts decarboxylated-MGP (dc-MGP) to carboxylated-MGP (c-MGP). By inhibiting pro-calcification Bone Morphogenic Protein (BMP) ligands, c-MGP acts as a potent vascular calcification inhibitor. uc-MGP is inactive with no vascular calcification inhibitory properties. However, the effects of vitamin K administration on CUA remain unknown.

Aim: To conduct a pilot randomized controlled trial (RCT) of oral vitamin K in CUA.

The investigators will examine the following hypotheses:

Hypothesis 1: Vitamin K therapy, when compared to placebo, reduces uncarboxylated Matrix Gla Protein in chronic hemodialysis patients with CUA.

Hypothesis 2: Vitamin K therapy can be safely administered in chronic hemodialysis patients with CUA.

Hypothesis 3: Vitamin K therapy leads to improvement in CUA pain and average lesion size when compared to placebo in chronic hemodialysis patients.

Study population and procedures: Twenty patients will be enrolled in this pilot RCT over the 2-year study period.

Study Procedures: Patients meeting the eligibility criteria will be consented and randomized to receive either vitamin K (phylloquinone) 10 mg orally three times a week for a total of 12 weeks or identical appearing placebo. Follow-up will occur every 4 weeks during which information will be obtained regarding pain severity, number and size of CUA lesion (s), and adverse events. Blood samples will be taken at baseline and at 12-week follow-up.

Sample processing and assays: Blood samples (plasma and serum, total 30 mL) will be taken at baseline and at 12-week follow-up.

Eligibility criteria: Inclusion Criteria:

* Calcific uremic arteriolopathy (a.k.a. calciphylaxis)

Exclusion Criteria:

* Warfarin discontinuation contra-indicated (e.g. mechanical heart valve)
* Prior allergic reaction to vitamin K
* Prior history of venous thromboembolism\*
* Pregnancy and lactation

(\*Patients with prior history of thrombosis who are treated with non-warfarin anticoagulant agents (e.g. apixaban, enoxaparin, etc) will be considered for inclusion)

Primary outcomes:
measure: Change from baseline in circulating MGP level at 12 weeks
timeFrame: Baseline and 12 weeks
Secondary outcomes:
measure: Change from baseline in largest lesion size at 12 weeks
timeFrame: Baseline and every month for 3 months
measure: Change from baseline in combined area of all lesions at 12 weeks
timeFrame: Baseline and every month for 3 months
measure: Change from baseline in pain at 12 weeks
timeFrame: Baseline and every month for 3 months
Other outcomes:
measure: Adverse events
timeFrame: Baseline and every month for 3 months
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
Study officials:
affiliation: Massachusetts General Hospital
name: Sagar Nigwekar, MD, MMSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: Nigwekar SU, Brunelli SM, Meade D, Wang W, Hymes J, Lacson E Jr. Sodium thiosulfate therapy for calcific uremic arteriolopathy. Clin J Am Soc Nephrol. 2013 Jul;8(7):1162-70. doi: 10.2215/CJN.09880912. Epub 2013 Mar 21.
citation: Nigwekar SU, Bhan I, Turchin A, Skentzos SC, Hajhosseiny R, Steele D, Nazarian RM, Wenger J, Parikh S, Karumanchi A, Thadhani R. Statin use and calcific uremic arteriolopathy: a matched case-control study. Am J Nephrol. 2013;37(4):325-32. doi: 10.1159/000348806. Epub 2013 Mar 21.
citation: Nigwekar SU, Bloch DB, Nazarian RM, Vermeer C, Booth SL, Xu D, Thadhani RI, Malhotra R. Vitamin K-Dependent Carboxylation of Matrix Gla Protein Influences the Risk of Calciphylaxis. J Am Soc Nephrol. 2017 Jun;28(6):1717-1722. doi: 10.1681/ASN.2016060651. Epub 2017 Jan 3.
citation: Nigwekar SU, Zhao S, Wenger J, Hymes JL, Maddux FW, Thadhani RI, Chan KE. A Nationally Representative Study of Calcific Uremic Arteriolopathy Risk Factors. J Am Soc Nephrol. 2016 Nov;27(11):3421-3429. doi: 10.1681/ASN.2015091065. Epub 2016 Apr 14.
citation: Cozzolino M, Mangano M, Galassi A, Ciceri P, Messa P, Nigwekar S. Vitamin K in Chronic Kidney Disease. Nutrients. 2019 Jan 14;11(1):168. doi: 10.3390/nu11010168.