Emphysema or COPDNCT03285100
The Effects of Discontinuation of Vitamin K Antagonists on the Rate of Elastin Degradation
An observational study of Emphysema or COPD and Aneurysm, run by Canisius-Wilhelmina Hospital at 1 site in Netherlands.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Emphysema or COPD, Aneurysm, Cystic Fibrosis
- What is being tested?
- Venipuncture
- How many people
- 30 participants
- Where
- 1 siteNetherlands
- Study dates
- 31 Oct 2017to 1 Oct 2018
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
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
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
Netherlands1 site, 1 recruiting
- Recruiting
Canisius Wilhelmina Hospital
Nijmegen, 6532SZ
Rob Janssen, MD, PhD, +31-24-3658755, rob.janssen@cwz.nl
Rob Janssen, MD, PhD
About this study
Official title: Pilot Study to Assess the Effects of Discontinuation of Vitamin K Antagonists on the Rate of Elastin Degradation
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.
Read more
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.
- Being tested
- Venipuncture
- Medical subject headings
- Emphysema, Pulmonary Disease, Chronic Obstructive, Aneurysm, Cystic Fibrosis, alpha 1-Antitrypsin Deficiency
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
VenipunctureDiagnostic 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.
What is being measured
The primary outcome is the main question the study is designed to answer.
Difference in elastin degradation rate
Difference in elastin degradation rate before and after discontinuation of VKAs, quantified by the change in plasma desmosine levels
Measured: Plasma desmosine is measured at baseline and 6 months after discontinuation of VKAs
Secondary outcomes (3)
Difference in vitamin K status
Difference in vitamin K status before and after discontinuation of VKAs, quantified by the change in dp-ucMGP, discontinuation of VKAs.
Measured: Plasma dp-ucMGP is measured at baseline and 6 months after discontinuation of VKAs
Association between desmosine and dp-ucMGP
Association between desmosine and dp-ucMGP both in patients who use VKAs and do not use VKAs.
Measured: 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
Levels of dp-ucMGP and desmosine levels of subjects with different VKORC1 polymorphisms are compared, both during the use of VKAs and after discontinuation.
Measured: 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.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Sep 2017
- Study start31 Oct 2017
- Primary completion1 Oct 2018 (estimated)
- Study completion1 Oct 2018 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (11)Papers the sponsor has linked to this study.
- Other trials for Emphysema or COPDStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 30 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Canisius-Wilhelmina Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- Maastricht University Medical Center
- Responsible party
- Principal investigator, Rob Janssen, Canisius-Wilhelmina Hospital
- Investigators
- Rob Janssen, MD, PhD, Principal investigator, Canisius-Wilhelmina Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03285100
- Sponsor's protocol ID
- NL60536.091.17
- Status last verified
- Jan 2018
- First submitted
- 13 Sep 2017
- Last updated
- 25 Jan 2018
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
Mithieux SM, Weiss AS. Elastin. Adv Protein Chem. 2005;70:437-61. doi: 10.1016/S0065-3233(05)70013-9.
PubMed 15837523Robert 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.
PubMed 18175202Bouvet 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.
PubMed 18292396Basalyga 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.
PubMed 15545515Turino 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.
PubMed 21757624Maclay 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.
PubMed 22374923Williams 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.
PubMed 24473329Geleijnse 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.
PubMed 15514282Knapen 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.
PubMed 25694037Patillon 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.
PubMed 23285254Rabinovich 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.
PubMed 27009168
Study at a glance
From the registry record, last updated by the sponsor on 25 Jan 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pilot Study to Assess the Effects of Discontinuation of Vitamin K Antagonists on the Rate of Elastin Degradation
- ClinicalTrials.gov ID
- NCT03285100
- Acronym / sponsor ID
- NL60536.091.17
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 30 participants (estimated)
- Lead sponsor
- Canisius-Wilhelmina HospitalUniversity, hospital or other
- Collaborators
- Maastricht University Medical Center
- Study start
- 31 Oct 2017 (actual)
- Primary completion
- 1 Oct 2018 (estimated)
- Study completion
- 1 Oct 2018 (estimated)
- First posted
- 15 Sep 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- 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
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (4 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Venipuncture* 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. | Diagnostic test | – |
Primary outcome
Difference in elastin degradation rate
Time frame: Plasma desmosine is measured at baseline and 6 months after discontinuation of VKAs
Difference in elastin degradation rate before and after discontinuation of VKAs, quantified by the change in plasma desmosine levels
3 secondary outcomes
Difference in vitamin K status
Time frame: Plasma dp-ucMGP is measured at baseline and 6 months after discontinuation of VKAs
Association between desmosine and dp-ucMGP
Time frame: 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
Time frame: 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.
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Jan 2018.
- Background: PubMed 15837523Mithieux SM, Weiss AS. Elastin. Adv Protein Chem. 2005;70:437-61. doi: 10.1016/S0065-3233(05)70013-9.
- Background: PubMed 18175202Robert 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.
- Background: PubMed 18292396Bouvet 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.
- Background: PubMed 15545515Basalyga 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.
- Background: PubMed 21757624Turino 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.
- Background: PubMed 22374923Maclay 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.
- Background: PubMed 24473329Williams 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.
- Background: PubMed 15514282Geleijnse 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.
- Background: PubMed 25694037Knapen 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.
- Background: PubMed 23285254Patillon 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.
- Background: PubMed 27009168Rabinovich 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.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Rob Janssen, MD, PhD principal investigator
Canisius-Wilhelmina Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Emphysema or COPD and Aneurysm, run by Canisius-Wilhelmina Hospital at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 25 Jan 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Rob Janssen, MD, PhD (+31-24-3658755, rob.janssen@cwz.nl), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Difference in elastin degradation rate (time frame: Plasma desmosine is measured at baseline and 6 months after discontinuation of VKAs). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03285100, which also lists 11 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Jan 2018.