Bicuspid Aortic ValveVARNCT02283970
Investigation of Patients With BAV Requiring Valve and/or Aortic Repair (GISSI Outliers VAR)
An observational study of Bicuspid Aortic Valve and Aortic Regurgitation, run by Gruppo di Ricerca GISSI at 10 sites in Italy.
Trial summary
Prospective longitudinal study on four small groups of surgical patients affected by: BAV with isolated regurgitation, BAV associated with aorta dilatation, or both and BAV with isolated stenosis in over 60 year-old patients. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Bicuspid Aortic Valve, Aortic Regurgitation, Aortic Dilatation
- How many people
- 62 participants
- Where
- 10 sitesItaly
- Study dates
- Dec 2012to Jul 2017
- 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: BAV patients eligible for cardiac surgery due to each of these conditions: BAV Regurgitation isolated, ascending aorta aneurysm in normal BAV or both AR and ascending aorta aneurysm, BAV stenosis isolated in over 60 year-old patients.
Who may be able to join
- Men and women over 18 years-old and under the age of 60 (age selection will prevent from enrolling patient with age-related valve and aortic wall degeneration). For the BAV stenosis group there will be considered patients over 60 years-old: including the most frequent form of BAV disease and the commonest age, this group could be used as a control group compared to the outlier ones.
- Echo diagnosis of BAV and indication to surgery:
- BAV with isolated regurgitation, BAV with normal valvular function but associated aorta dilatation, BAV with both valve regurgitation and aortic dilatation BAV with isolated stenosis
- Signed informed consent
Who cannot join
- Patient with a previous cardiac or great vessels surgery
- coexistent coarctation of the aorta
- non-associated cardiac diseases: valve disease (other than aortic), ischemic disease, congenital heart disease.
- Marfan syndrome or other connective tissue disorders involving aortic valve and aortic wall disease (history of disease or clinical signs).
- Other conditions/circumstances likely to lead to poor study adherence (e.g. psychological or organizational reasons).
- Serious disease other than aortic, severely limiting life expectancy.
- Patients who refuse to give informed consent
Trial locations and contacts
10 sites in 1 country.
10 sites in 1 country
Italy10 sites
Casa Di Cura Villa Sant'Anna
Catanzaro, CZ, 88100
Aou Careggi
Florence, FI, 50139
Ospedale Dell'Angelo
Mestre, VE, 30171
Ospedale San Raffaele
Milan, MI, 20132
Centro Cardiologico Monzino
Milan, MI, 20138
Ospedale Niguarda
Milan, MI, 20162
Ospedale San Camillo
Roma, 00152
Irccs Policlinico San Donato
San Donato Milanese, MI, 20097
Azienda Osp. Univ. S. Giovanni Battista
Torino, 10126
Aou Santa Maria Della Misericordia
Udine, UD, 33100
About this study
Official title: Investigation of Patients With BAV Requiring Valve and/or Aortic Repair. Correlation of Surgical and ECO Distinctive Features With Histologic and Genetic Findings in Phenotypically Homogeneous Outlier Cases (GISSI VAR)
Prospective longitudinal study on four small groups of surgical patients affected by: BAV with isolated regurgitation, BAV associated with aorta dilatation, or both and BAV with isolated stenosis in over 60 year-old patients.
The aim of the study is to select homogeneous small groups of surgical patients with the same subtype of BAV and same aortic behaviour and identify markers/predictors of favorable-unfavorable aortic wall evolution to evaluate if there is a BAV phenotype more likely to be considered at high risk for aortic degeneration.
Read the detailed description
The aim of the study is to select homogeneous small groups of surgical patients with the same subtype of BAV and same aortic behaviour and identify markers/predictors of favorable-unfavorable aortic wall evolution to evaluate if there is a BAV phenotype more likely to be considered at high risk for aortic degeneration. The study will focus on multiple aspects of BAV disease. What follows will be considered and combined:
Aortic valve, aorta root and ascending aorta morphology The use of two- (2DE) and three-dimensional (3DE) trans-thoracic (TTE) and/or transoesophageal (TOE) echocardiography can identify all kind of BAV morphology (leaflet position and coronary ostia displacement). It also gives quali- quantitative information about root and ascending aorta morphology and size.
BAV genetics Recently, missense mutations in the NOTCH1 gene have been shown to be associated with calcific aortic valve disease plus BAV. However mutations in the NOTCH1 gene only partially explain the presence of BAV in the absence of other syndromic diseases (i.e. Marfan Syndrome, Loeys Dietz Syndrome type I and II and Ehlers Danlos type IV Syndrome).
BAV Histology In all enrolled patients, during operation, tissue samples will be collected from valve cusps (in case of valve involvement), aortic wall (aortic root, concavity or convexity of ascending aorta) or from both of them. Samples will be analyzed in order to classify medial and intimal disruption and changes.
Study Design and Setting of the Study The first step will consist in enrolling patients with echocardiographic diagnosis of BAV and indication for surgery. From the echo data, aortic valve, as well as aortic root and ascending aorta morphology will be assessed in order to classify patients in each phenotypic pattern. The echo images from participating centres will be sent to an echo core lab for quali- quantitative analysis (see below) and all data will be recorded in a specific database.
The second step will consider first-degree relatives of each enrolled patient. The investigators will ask every first degree relative to perform a screening TTE in order to find out, according to familiar aetiology of BAV, the presence of BAV and/or associated disease (aortic root or ascending aorta enlargement or coronary ostia displacement).
The third step will consist in collecting blood samples from each patient and from any of first-degree relatives with BAV diagnosis. BAV-specific genetic tests will be performed and all data will be recorder in a specific database.
The fourth intraoperative step will consist in :
- performing a 3D TOE in order to study the geometry and the dynamic behaviour of the aortic valve and root and
- in collecting surgical tissue samples: during operation there will be described precisely the anatomy of the valve and the aorta in detail; then, from the usual site of surgery, there will be collected valve and aortic wall samples in order to perform histological, immunohistochemical and genetics tests.
Blood and surgical samples will be stored in a bio-bank for future analysis related to this protocol.
- Medical subject headings
- Bicuspid Aortic Valve Disease, Aortic Valve Insufficiency
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| BAV and aortic regurgitation | BAV Diagnosis, Aortic Regurgitation with surgical indication (according to current clinical guidelines or best clinical practice), normal ascending aorta | |
| BAV and Ascending aorta dilatation | BAV diagnosis, no or trivial Aortic Regurgitation, ascending aorta dilatation with surgical indication (according to current clinical guidelines or best clinical practice) | |
| BAV, aortic regurgitation and dilatation | BAV diagnosis, Aortic Regurgitation and ascending aorta dilatation with surgical indication (according to current clinical guidelines or best clinical practice). | |
| BAV with aortic stenosis in pts>60yrs | BAV diagnosis, Aortic stenosis with surgical indication (according to current clinical guidelines or best clinical practice). Normal ascending aorta |
What is being measured
The primary outcome is the main question the study is designed to answer.
Mutation in NOTCH1 gene
The strongest causative gene associated with BAV is NOTCH1. Its 34 coding exons will be sequenced to search for variants likely to be causative.
The presence of sequence variation will be confirmed using a different method, starting from a new amplification (RFLP or High Resolution Melting-HRM). The pathogeneticity of the mutation will be evaluated screening 500 DNA controls (1000 chromosomes) to estimate the alleles' frequencies (HRM; ABI Prism 7900HT). Finally a familial segregation analysis will be performed to verify the association with the disease.
Measured: Enrollment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Nov 2014 (estimated)
- Study startDec 2012
- Primary completionJul 2014
- Study completionJul 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Bicuspid Aortic ValveStudies 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
- 62 participants (actual)
Sponsor and investigators
- Lead sponsor
- Gruppo di Ricerca GISSI
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Attilio Maseri, MD, Study chair, Dondazione per il Tuo cuore-HCF Onlus
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02283970
- Sponsor's protocol ID
- K11
- Acronym
- VAR
- Status last verified
- Aug 2018
- First submitted
- 17 Oct 2014
- Last updated
- 9 Aug 2018
- Results posted
- No
- Data monitoring committee
- No
Publications
Merlanti B, De Chiara B, Maggioni AP, Moreo A, Pileggi S, Romeo G, Russo CF, Rizzo S, Martinelli L, Maseri A; VAR Study Group. Rationale and design of GISSI OUTLIERS VAR Study in bicuspid aortic valve patients: prospective longitudinal, multicenter study to investigate correlation between surgical, echo distinctive features, histologic and genetic findings in phenotypically homogeneous outlier cases. Int J Cardiol. 2015 Nov 15;199:180-5. doi: 10.1016/j.ijcard.2015.06.182. Epub 2015 Jul 6.
PubMed 26197404
Study at a glance
From the registry record, last updated by the sponsor on 9 Aug 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Investigation of Patients With BAV Requiring Valve and/or Aortic Repair. Correlation of Surgical and ECO Distinctive Features With Histologic and Genetic Findings in Phenotypically Homogeneous Outlier Cases (GISSI VAR)
- ClinicalTrials.gov ID
- NCT02283970
- Acronym / sponsor ID
- VAR / K11
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 62 participants (actual)
- Lead sponsor
- Gruppo di Ricerca GISSIUniversity, hospital or other
- Study start
- Dec 2012
- Primary completion
- Jul 2014 (actual)
- Study completion
- Jul 2017 (actual)
- First posted
- 5 Nov 2014 (estimated)
- 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.
Prospective longitudinal study on four small groups of surgical patients affected by: BAV with isolated regurgitation, BAV associated with aorta dilatation, or both and BAV with isolated stenosis in over 60 year-old patients.
The aim of the study is to select homogeneous small groups of surgical patients with the same subtype of BAV and same aortic behaviour and identify markers/predictors of favorable-unfavorable aortic wall evolution to evaluate if there is a BAV phenotype more likely to be considered at high risk for aortic degeneration.
Detailed description
The aim of the study is to select homogeneous small groups of surgical patients with the same subtype of BAV and same aortic behaviour and identify markers/predictors of favorable-unfavorable aortic wall evolution to evaluate if there is a BAV phenotype more likely to be considered at high risk for aortic degeneration. The study will focus on multiple aspects of BAV disease. What follows will be considered and combined:
Aortic valve, aorta root and ascending aorta morphology The use of two- (2DE) and three-dimensional (3DE) trans-thoracic (TTE) and/or transoesophageal (TOE) echocardiography can identify all kind of BAV morphology (leaflet position and coronary ostia displacement). It also gives quali- quantitative information about root and ascending aorta morphology and size.
BAV genetics Recently, missense mutations in the NOTCH1 gene have been shown to be associated with calcific aortic valve disease plus BAV. However mutations in the NOTCH1 gene only partially explain the presence of BAV in the absence of other syndromic diseases (i.e. Marfan Syndrome, Loeys Dietz Syndrome type I and II and Ehlers Danlos type IV Syndrome).
BAV Histology In all enrolled patients, during operation, tissue samples will be collected from valve cusps (in case of valve involvement), aortic wall (aortic root, concavity or convexity of ascending aorta) or from both of them. Samples will be analyzed in order to classify medial and intimal disruption and changes.
Study Design and Setting of the Study The first step will consist in enrolling patients with echocardiographic diagnosis of BAV and indication for surgery. From the echo data, aortic valve, as well as aortic root and ascending aorta morphology will be assessed in order to classify patients in each phenotypic pattern. The echo images from participating centres will be sent to an echo core lab for quali- quantitative analysis (see below) and all data will be recorded in a specific database.
The second step will consider first-degree relatives of each enrolled patient. The investigators will ask every first degree relative to perform a screening TTE in order to find out, according to familiar aetiology of BAV, the presence of BAV and/or associated disease (aortic root or ascending aorta enlargement or coronary ostia displacement).
The third step will consist in collecting blood samples from each patient and from any of first-degree relatives with BAV diagnosis. BAV-specific genetic tests will be performed and all data will be recorder in a specific database.
The fourth intraoperative step will consist in :
- performing a 3D TOE in order to study the geometry and the dynamic behaviour of the aortic valve and root and
- in collecting surgical tissue samples: during operation there will be described precisely the anatomy of the valve and the aorta in detail; then, from the usual site of surgery, there will be collected valve and aortic wall samples in order to perform histological, immunohistochemical and genetics tests.
Blood and surgical samples will be stored in a bio-bank for future analysis related to this protocol.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| BAV and aortic regurgitation | – | –BAV Diagnosis, Aortic Regurgitation with surgical indication (according to current clinical guidelines or best clinical practice), normal ascending aorta |
| BAV and Ascending aorta dilatation | – | –BAV diagnosis, no or trivial Aortic Regurgitation, ascending aorta dilatation with surgical indication (according to current clinical guidelines or best clinical practice) |
| BAV, aortic regurgitation and dilatation | – | –BAV diagnosis, Aortic Regurgitation and ascending aorta dilatation with surgical indication (according to current clinical guidelines or best clinical practice). |
| BAV with aortic stenosis in pts>60yrs | – | –BAV diagnosis, Aortic stenosis with surgical indication (according to current clinical guidelines or best clinical practice). Normal ascending aorta |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- BAV patients eligible for cardiac surgery due to each of these conditions: BAV Regurgitation isolated, ascending aorta aneurysm in normal BAV or both AR and ascending aorta aneurysm, BAV stenosis isolated in over 60 year-old patients.
Key inclusion criteria (4 listed)
- Men and women over 18 years-old and under the age of 60 (age selection will prevent from enrolling patient with age-related valve and aortic wall degeneration). For the BAV stenosis group there will be considered patients over 60 years-old: including the most frequent form of BAV disease and the commonest age, this group could be used as a control group compared to the outlier ones.
- Echo diagnosis of BAV and indication to surgery:
- BAV with isolated regurgitation, BAV with normal valvular function but associated aorta dilatation, BAV with both valve regurgitation and aortic dilatation BAV with isolated stenosis
- Signed informed consent
Key exclusion criteria (7 listed)
- Patient with a previous cardiac or great vessels surgery
- coexistent coarctation of the aorta
- non-associated cardiac diseases: valve disease (other than aortic), ischemic disease, congenital heart disease.
- Marfan syndrome or other connective tissue disorders involving aortic valve and aortic wall disease (history of disease or clinical signs).
- Other conditions/circumstances likely to lead to poor study adherence (e.g. psychological or organizational reasons).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Mutation in NOTCH1 gene
Time frame: Enrollment
The strongest causative gene associated with BAV is NOTCH1. Its 34 coding exons will be sequenced to search for variants likely to be causative. The presence of sequence variation will be confirmed using a different method, starting from a new amplification (RFLP or High Resolution Melting-HRM). The pathogeneticity of the mutation will be evaluated screening 500 DNA controls (1000 chromosomes) to estimate the alleles' frequencies (HRM; ABI Prism 7900HT). Finally a familial segregation analysis will be performed to verify the association with the disease.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Aug 2018.
- Background: PubMed 26197404Merlanti B, De Chiara B, Maggioni AP, Moreo A, Pileggi S, Romeo G, Russo CF, Rizzo S, Martinelli L, Maseri A; VAR Study Group. Rationale and design of GISSI OUTLIERS VAR Study in bicuspid aortic valve patients: prospective longitudinal, multicenter study to investigate correlation between surgical, echo distinctive features, histologic and genetic findings in phenotypically homogeneous outlier cases. Int J Cardiol. 2015 Nov 15;199:180-5. doi: 10.1016/j.ijcard.2015.06.182. Epub 2015 Jul 6.
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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.
Attilio Maseri, MD study chair
Dondazione per il Tuo cuore-HCF Onlus
10 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Bicuspid Aortic Valve and Aortic Regurgitation, run by Gruppo di Ricerca GISSI at 10 sites in Italy.
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 4 inclusion and 7 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: finished, as of the sponsor's last update on 9 Aug 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 10 sites in Italy. 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?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Mutation in NOTCH1 gene (time frame: Enrollment). 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 NCT02283970, which also lists 1 linked publication.
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 9 Aug 2018; AzTrials last refreshed its copy on 8 Nov 2026.