The Effects of Discontinuation of Vitamin K Antagonists on the Rate of Elastin Degradation

NCT03285100 | Unknown

• 1 other identifier: NL60536.091.17
• Study Type: observational
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

Background: Elastin is a unique protein providing elasticity, resilience and deformability to dynamic tissues, such as lungs and vasculature. Elastin fibers are characterized by their high affinity for calcium. However, calcified elastin is more prone to the degrading effects of proteases and, in turn, partially degraded elastin has an even higher affinity for calcium. A disturbed balance between proteases and anti-proteases is a major underlying mechanism in the development of chronic obstructive pulmonary disease (COPD). Virtually the only protein that can protect elastin from calcification is matrix Gla-protein (MGP), which needs vitamin K for its activation. In COPD patients, a lower vitamin K status is found when compared to control subjects and an inverse association exists between vitamin K status and elastin degradation. In addition, vitamin K status is lower and elastin degradation is accelerated in Vitamin K antagonist (VKA) users. VKAs are widely used. Nowadays, an increasing number of patients uses direct oral anticoagulants (DOACs), which do not influence vitamin K status. The hypothesis of this study is that discontinuation of VKAs results in an improved vitamin K status and deceleration of elastin degradation. In order to test this hypothesis, an observational pilot study will be conducted in which the change in elastin degradation- quantified by plasma desmosine concentrations - in patients who discontinue use of VKAs will be used as primary endpoint. Study design: Observational study. Study population: A total of 30 VKA users who will discontinue the use of VKAs. Elastin degradation rate (quantified by plasma desmosine levels) and vitamin K status (quantified by measuring plasma levels of dephosphorylated uncarboxylated (dp-uc)MGP) will be measured during the use of VKAs and approximately 6 months after discontinuation of VKAs. Furthermore, the VKORC1 polymorphisms will be determined. Main study parameters: The primary endpoint is the change in the rate of elastin degradation quantified by the plasma desmosine assay. Secondary endpoints are the change in vitamin K status quantified by measuring plasma levels of dp-ucMGP, the relation between desmosine and dp-ucMGP and differences of desmosine and dp-ucMGP levels among subjects with different polymorphisms of the vitamin K 2,3-epoxide reductase complex 1 (VKORC1) gene.

Conditions

Emphysema or COPD; Aneurysm; Cystic Fibrosis; Alpha 1-Antitrypsin Deficiency

Outcome Measures

Primary Outcomes (1)

• Difference in elastin degradation rate

  Difference in elastin degradation rate before and after discontinuation of VKAs, quantified by the change in plasma desmosine levels

  Plasma desmosine is measured at baseline and 6 months after discontinuation of VKAs

Secondary Outcomes (3)

• Difference in vitamin K status

  Plasma dp-ucMGP is measured at baseline and 6 months after discontinuation of VKAs

• Association between desmosine and dp-ucMGP

  Desmosine and dp-ucMGP are determined before discontinuation of VKAs and 6 months after discontinuation of VKAs

• Differences in desmosine and dp-ucMGP levels between different VKORC1 polymorphisms

  Desmosine and dp-ucMGP are determined, both before discontinuation of VKAs and 6 months after discontinuation of VKAs. VKORC1 polymorphisms are determined before discontinuation of VKAs.

Interventions

Venipuncture DIAGNOSTIC_TEST

* Approximately 6 months after discontinuation of VKAs one additional venipuncture will be performed for determination of dp-ucMGP and desmosine. * At baseline two additional blood collection tubes will be drawn for determination of dp-ucMGP, desmosine and VKORC1 polymorphisms. Since this is during one of the last regular International Normalized Ratio (INR) testing at the anticoagulation clinic, no additional venipuncture has to be performed at this moment.

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

30 VKA users from the anticoagulant clinic in the Canisius Wilhelmina Hospital, who are going to discontinue the use of VKAs at short time

You may qualify if:

• Use of VKAs for at least 3 months
• Stop VKAs at short time
• Written informed consent
• Age ≥18 years
• Ability to comply with all study requirements

You may not qualify if:

• Active malignancy or cured malignancy \<12 months prior to enrollment
• Use of maintenance dose oral corticosteroids
• Serious mental impairment
• Life expectation of less than 6 months on the basis of concurrent disease

Sponsors & Collaborators

• Canisius-Wilhelmina Hospital: lead
• Maastricht University Medical Center: collaborator

Study Sites (1)

Canisius Wilhelmina Hospital

Nijmegen, 6532SZ, Netherlands

RECRUITING

Related Publications (11)

• Mithieux SM, Weiss AS. Elastin. Adv Protein Chem. 2005;70:437-61. doi: 10.1016/S0065-3233(05)70013-9.

  PMID: 15837523 BACKGROUND

• Robert L, Robert AM, Fulop T. Rapid increase in human life expectancy: will it soon be limited by the aging of elastin? Biogerontology. 2008 Apr;9(2):119-33. doi: 10.1007/s10522-007-9122-6. Epub 2008 Jan 4.

  PMID: 18175202 BACKGROUND

• Bouvet C, Moreau S, Blanchette J, de Blois D, Moreau P. Sequential activation of matrix metalloproteinase 9 and transforming growth factor beta in arterial elastocalcinosis. Arterioscler Thromb Vasc Biol. 2008 May;28(5):856-62. doi: 10.1161/ATVBAHA.107.153056. Epub 2008 Feb 21.

  PMID: 18292396 BACKGROUND

• Basalyga DM, Simionescu DT, Xiong W, Baxter BT, Starcher BC, Vyavahare NR. Elastin degradation and calcification in an abdominal aorta injury model: role of matrix metalloproteinases. Circulation. 2004 Nov 30;110(22):3480-7. doi: 10.1161/01.CIR.0000148367.08413.E9. Epub 2004 Nov 15.

  PMID: 15545515 BACKGROUND

• Turino GM, Ma S, Lin YY, Cantor JO, Luisetti M. Matrix elastin: a promising biomarker for chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2011 Sep 15;184(6):637-41. doi: 10.1164/rccm.201103-0450PP.

  PMID: 21757624 BACKGROUND

• Maclay JD, McAllister DA, Rabinovich R, Haq I, Maxwell S, Hartland S, Connell M, Murchison JT, van Beek EJ, Gray RD, Mills NL, Macnee W. Systemic elastin degradation in chronic obstructive pulmonary disease. Thorax. 2012 Jul;67(7):606-12. doi: 10.1136/thoraxjnl-2011-200949. Epub 2012 Feb 28.

  PMID: 22374923 BACKGROUND

• Williams MC, Murchison JT, Edwards LD, Agusti A, Bakke P, Calverley PM, Celli B, Coxson HO, Crim C, Lomas DA, Miller BE, Rennard S, Silverman EK, Tal-Singer R, Vestbo J, Wouters E, Yates JC, van Beek EJ, Newby DE, MacNee W; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) investigators. Coronary artery calcification is increased in patients with COPD and associated with increased morbidity and mortality. Thorax. 2014 Aug;69(8):718-23. doi: 10.1136/thoraxjnl-2012-203151. Epub 2014 Jan 28.

  PMID: 24473329 BACKGROUND

• Geleijnse JM, Vermeer C, Grobbee DE, Schurgers LJ, Knapen MH, van der Meer IM, Hofman A, Witteman JC. Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study. J Nutr. 2004 Nov;134(11):3100-5. doi: 10.1093/jn/134.11.3100.

  PMID: 15514282 BACKGROUND

• Knapen MH, Braam LA, Drummen NE, Bekers O, Hoeks AP, Vermeer C. Menaquinone-7 supplementation improves arterial stiffness in healthy postmenopausal women. A double-blind randomised clinical trial. Thromb Haemost. 2015 May;113(5):1135-44. doi: 10.1160/TH14-08-0675. Epub 2015 Feb 19.

  PMID: 25694037 BACKGROUND

• Patillon B, Luisi P, Blanche H, Patin E, Cann HM, Genin E, Sabbagh A. Positive selection in the chromosome 16 VKORC1 genomic region has contributed to the variability of anticoagulant response in humans. PLoS One. 2012;7(12):e53049. doi: 10.1371/journal.pone.0053049. Epub 2012 Dec 28.

  PMID: 23285254 BACKGROUND

• Rabinovich RA, Miller BE, Wrobel K, Ranjit K, Williams MC, Drost E, Edwards LD, Lomas DA, Rennard SI, Agusti A, Tal-Singer R, Vestbo J, Wouters EF, John M, van Beek EJ, Murchison JT, Bolton CE, MacNee W, Huang JT; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators. Circulating desmosine levels do not predict emphysema progression but are associated with cardiovascular risk and mortality in COPD. Eur Respir J. 2016 May;47(5):1365-73. doi: 10.1183/13993003.01824-2015. Epub 2016 Mar 23.

  PMID: 27009168 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

* at baseline: blood sample of 15mL (EDTA-plasma), divided in four two portions (one for determination of dp-ucMGP and one for desmosine) * at baseline: blood sample of 10mL (EDTA-plasma). DNA will be isolated from these samples for determination of the VKORC1 polymorphisms * after six months: blood sample of 15mL (EDTA-plasma), divided in four two portions (one for determination of dp-ucMGP and one for desmosine)

MeSH Terms

Conditions

Emphysema; Pulmonary Disease, Chronic Obstructive; Aneurysm; Cystic Fibrosis; alpha 1-Antitrypsin Deficiency

Interventions

Phlebotomy

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms; Lung Diseases, Obstructive; Lung Diseases; Respiratory Tract Diseases; Chronic Disease; Disease Attributes; Vascular Diseases; Cardiovascular Diseases; Pancreatic Diseases; Digestive System Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Infant, Newborn, Diseases; Liver Diseases; Subcutaneous Emphysema

Intervention Hierarchy (Ancestors)

Blood Specimen Collection; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Therapeutics; Surgical Procedures, Operative; Investigative Techniques

Study Officials

• Rob Janssen, MD, PhD

  Canisius-Wilhelmina Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Rob Janssen, MD, PhD

CONTACT

+31-24-3658755; rob.janssen@cwz.nl

Ianthe Piscaer, MD

CONTACT

+31-43-3875051; ianthe.piscaer@mumc.nl

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, PhD

Study Record Dates

• First Submitted: September 13, 2017
• First Posted: September 15, 2017
• Study Start: October 31, 2017
• Primary Completion: October 1, 2018
• Study Completion: October 1, 2018
• Last Updated: January 25, 2018

Record last verified: 2018-01

Locations

NL (1)