Calcific Aortic Valve DiaseaseNCT05806411
Calcific Aortic Valve Disease:the Role of Bacteria as Trigger of a Chronic Inflammation
An observational study of Calcific Aortic Valve Diasease, run by Fondazione IRCCS Policlinico San Matteo di Pavia at 1 site in Italy.
Trial summary
Calcific aoric valve disease (CAVD) is extremely common worldwide, affecting almost 50% of the population over 85 years of age, with a lethality higher than 50% at 2 years for symptomatic patients, unless aortic-valve replacement is performed. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Calcific Aortic Valve Diasease
- What is being tested?
- Analysis of calcific aortic valves
- Type of treatment
- Injection or infusion
- How many people
- 44 participants
- Where
- 1 siteItaly
- Study dates
- 18 Jan 2023to 18 Jan 2025
- 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: Patients with calcific aortic sclerosis (stage III and IV) that are going to be treated with traditional surgery according to International Guidelines will be enrolled as cases.
Who may be able to join
- Age>18 years.
- Calcific aortic sclerosis (stage III and IV)
Who cannot join
- Inability to comply with the requirements of the protocol.
Trial locations and contacts
1 site in 1 country.
Italy1 site, 1 recruiting
- Recruiting
Fondazione IRCCS Policlinico San MAtteo
Pavia, 27100
Elena Seminari, MD, +390382503811, e.seminari@smatteo.pv.it
About this study
Official title: Calcific Aortic Valve Disease: a Multidisciplinary Approach to Investigate the Role of Bacteria as Trigger of a Chronic Inflammation in the Pathogenesis of Calcification
Calcific aoric valve disease (CAVD) is extremely common worldwide, affecting almost 50% of the population over 85 years of age, with a lethality higher than 50% at 2 years for symptomatic patients, unless aortic-valve replacement is performed. CAVD is characterized by slowly progressive fibro-calcific remodelling of the valve leaflets causing aortic stenosis. The spectrum of the disease progression starts with leaflet degeneration and progresses from early lesions to valve stenosis/obstruction, which is initially mild to moderate but eventually becomes severe. Risk factors for CAVD partly overlap those for atherosclerosis but also intake age-related tissue changes and effects of comorbiditiies (e.g. renal failure) in the overall complex mechanisms of valve leaflet degeneration, which is, at present, unpreventable, leaving aortic valve repair the only treatment option for severe aortic stenosis. In the first phase of the disease the valve becomes thickened and mildly calcified, then the disease evolves to severe valve calcification with impaired leaflet motion and vast blood flow obstruction. Calcific AS valves show advanced osteogenic metaplasia with the presence of osteoblast-like cells and chondrocytes associated with dense inflammatory infiltrates. Bacteria have been detected in the absence of diagnosis of acute infective endocarditis, but their role is still unknown. Different bacterial species (C. acnes (59%), E. faecalis (16%), S. aureus (15%), and S. pyogenes (10%)) have been typed and intramural bacterial colonization has been observed in patients with calcified structural valvular heart disease. Indeed, it has been recently demonstrated that bacterial infections can directly affect osteoblast differentiation/activation.
The Authors hypothesized that a subclinical or latent valvular bacterial infiltration facilitates a chronic inflammation and contributes to accelerated structural valve degeneration. An interdisciplinary team has been established to investigate the infective, biochemical and structural features of calcific aortic valve disease.
Read the detailed description
The primary objective of the study is to dissect the bacteria contribution to valve calcification. The Authors hypothesized that a subclinical or latent valvular bacterial infiltration facilitates a chronic inflammation and contributes to accelerated structural valve degeneration. The Authors expect to find a correlation between bacterial detection (as qualitative -positive/negative, quantitative -quantitative PCR) and bone calcification markers on valves. To dissect the bacteria contribution to valve calcification, the osteogenic differentiation capabilities of primary cells obtained from cusp explanted from control and from non-calcified cusp of CAVD patients will be assessed in vitro in absence and in presence of bacterial infection. There are currently no data in the literature that can be referred to for the calculation of the sample size. Cusp calcifications do not equally affect all cusps, considering calcified cusp as cases and non-calcified cusp of the same valve as matched controls, if the probability of bacterial detection among sampled control non calcified cusps is 10% (Cohen, doi: 10.1016/S0003-4975(03)01454-1), a sample of 32 patients (with 32 calcified cusp and 96cusps) can be enrolled. This sample of 96 cusps achieves 81% power to detect an odds ratio of 5.00 versus the alternative of equal odds using a McNemar test with a 0.05 significance level. This calculation is done considering that the probability of bacterial detection in each cusp is almost independent from other cusps of the same valve (intra-valve correlation coefficient= 0.10). The Authors expect a total study duration of 24 months. The Authors estimate to complete recruitment in 12 months. The estimated primary completion is month 15 (3 months after last subject enrollment) and study completion on month 24 (12 months after last patient inclusion)
- Conditions
- Calcific Aortic Valve Diasease
- Being tested
- Analysis of calcific aortic valves
- Keywords
- Calcific aortic valve disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Analysis of calcific aortic valvesDiagnostic test
Microbiologic analysis of calcofic aortic valves
| Study group | Role | What they receive |
|---|---|---|
| Patients | Patients with calcific aortic sclerosis (stage III and IV) that are going to be treated with traditional surgery according to International Guidelines will be enrolled as cases. Receives: Diagnostic Test: Analysis of calcific aortic valves | |
| Controls | Patients that will undergo a cardiac transplantation (for nonvalvular cardiac disease) or patients with aortic valve insufficiency will be enrolled as controls Receives: Diagnostic Test: Analysis of calcific aortic valves |
What is being measured
The primary outcome is the main question the study is designed to answer.
To analyze subclinical or latent valvular bacterial infiltration in patients with calcific aortic disease
Rate of bacterial infiltration in calcified and non calcified cusps and in patients and controls (co-primary endpoint) will be analysed.
Measured: 2 years
To evaluate the correlation between bacterial detection (as qualitative-positive/negative-, quantitative -quantitative PCR-) and bone calcification markers on valves
Rate of expression of osteogenic markers and total calcium valve content in calcified and non-calcified cusps on valves of patients and controls and correlation with bacterial detection
Measured: 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Apr 2023
- Study start18 Jan 2023
- Primary completion18 Jun 2024 (estimated)
- Study completion18 Jan 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Calcific Aortic Valve DiaseaseStudies of the same condition, open and under way.
- More trials run by Fondazione IRCCS Policlinico San Matteo di PaviaThe sponsor's other registered studies.
- 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
- Case-control
- Time perspective
- Prospective
- Enrolment
- 44 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Fondazione IRCCS Policlinico San Matteo di Pavia
- Sponsor type
- University, hospital or other
- Collaborators
- University of Pavia
- Responsible party
- Sponsor
- Investigators
- Elena Seminari, MD, Principal investigator, Fondazione IRCCS Policlinico San MAtteo
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05806411
- Sponsor's protocol ID
- CAvD
- Status last verified
- Mar 2024
- First submitted
- 28 Mar 2023
- Last updated
- 27 Mar 2024
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
Oberbach A, Schlichting N, Friedrich M, Lehmann S, Kullnick Y, Pichlmaier M, Hagl C, Bagaev E; CardiOmics group; Clinical Microbiology group; Clinical Management group. Quantification of Multiple Bacteria in Calcified Structural Valvular Heart Disease. Semin Thorac Cardiovasc Surg. 2020 Summer;32(2):255-263. doi: 10.1053/j.semtcvs.2019.10.003. Epub 2019 Oct 9.
PubMed 31605771Kwon Y, Park C, Lee J, Park DH, Jeong S, Yun CH, Park OJ, Han SH. Regulation of Bone Cell Differentiation and Activation by Microbe-Associated Molecular Patterns. Int J Mol Sci. 2021 May 28;22(11):5805. doi: 10.3390/ijms22115805.
PubMed 34071605Cohen DJ, Malave D, Ghidoni JJ, Iakovidis P, Everett MM, You S, Liu Y, Boyan BD. Role of oral bacterial flora in calcific aortic stenosis: an animal model. Ann Thorac Surg. 2004 Feb;77(2):537-43. doi: 10.1016/S0003-4975(03)01454-1.
PubMed 14759434Freeman RV, Otto CM. Spectrum of calcific aortic valve disease: pathogenesis, disease progression, and treatment strategies. Circulation. 2005 Jun 21;111(24):3316-26. doi: 10.1161/CIRCULATIONAHA.104.486738. No abstract available.
PubMed 15967862
Study at a glance
From the registry record, last updated by the sponsor on 27 Mar 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Calcific Aortic Valve Disease: a Multidisciplinary Approach to Investigate the Role of Bacteria as Trigger of a Chronic Inflammation in the Pathogenesis of Calcification
- ClinicalTrials.gov ID
- NCT05806411
- Acronym / sponsor ID
- CAvD
- Conditions
- Calcific Aortic Valve Diasease
- Keywords
- Calcific aortic valve disease
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 44 participants (estimated)
- Lead sponsor
- Fondazione IRCCS Policlinico San Matteo di PaviaUniversity, hospital or other
- Collaborators
- University of Pavia
- Study start
- 18 Jan 2023 (actual)
- Primary completion
- 18 Jun 2024 (estimated)
- Study completion
- 18 Jan 2025 (estimated)
- First posted
- 10 Apr 2023 (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.
Calcific aoric valve disease (CAVD) is extremely common worldwide, affecting almost 50% of the population over 85 years of age, with a lethality higher than 50% at 2 years for symptomatic patients, unless aortic-valve replacement is performed. CAVD is characterized by slowly progressive fibro-calcific remodelling of the valve leaflets causing aortic stenosis. The spectrum of the disease progression starts with leaflet degeneration and progresses from early lesions to valve stenosis/obstruction, which is initially mild to moderate but eventually becomes severe. Risk factors for CAVD partly overlap those for atherosclerosis but also intake age-related tissue changes and effects of comorbiditiies (e.g. renal failure) in the overall complex mechanisms of valve leaflet degeneration, which is, at present, unpreventable, leaving aortic valve repair the only treatment option for severe aortic stenosis. In the first phase of the disease the valve becomes thickened and mildly calcified, then the disease evolves to severe valve calcification with impaired leaflet motion and vast blood flow obstruction. Calcific AS valves show advanced osteogenic metaplasia with the presence of osteoblast-like cells and chondrocytes associated with dense inflammatory infiltrates. Bacteria have been detected in the absence of diagnosis of acute infective endocarditis, but their role is still unknown. Different bacterial species (C. acnes (59%), E. faecalis (16%), S. aureus (15%), and S. pyogenes (10%)) have been typed and intramural bacterial colonization has been observed in patients with calcified structural valvular heart disease. Indeed, it has been recently demonstrated that bacterial infections can directly affect osteoblast differentiation/activation.
The Authors hypothesized that a subclinical or latent valvular bacterial infiltration facilitates a chronic inflammation and contributes to accelerated structural valve degeneration. An interdisciplinary team has been established to investigate the infective, biochemical and structural features of calcific aortic valve disease.
Detailed description
The primary objective of the study is to dissect the bacteria contribution to valve calcification. The Authors hypothesized that a subclinical or latent valvular bacterial infiltration facilitates a chronic inflammation and contributes to accelerated structural valve degeneration. The Authors expect to find a correlation between bacterial detection (as qualitative -positive/negative, quantitative -quantitative PCR) and bone calcification markers on valves. To dissect the bacteria contribution to valve calcification, the osteogenic differentiation capabilities of primary cells obtained from cusp explanted from control and from non-calcified cusp of CAVD patients will be assessed in vitro in absence and in presence of bacterial infection. There are currently no data in the literature that can be referred to for the calculation of the sample size. Cusp calcifications do not equally affect all cusps, considering calcified cusp as cases and non-calcified cusp of the same valve as matched controls, if the probability of bacterial detection among sampled control non calcified cusps is 10% (Cohen, doi: 10.1016/S0003-4975(03)01454-1), a sample of 32 patients (with 32 calcified cusp and 96cusps) can be enrolled. This sample of 96 cusps achieves 81% power to detect an odds ratio of 5.00 versus the alternative of equal odds using a McNemar test with a 0.05 significance level. This calculation is done considering that the probability of bacterial detection in each cusp is almost independent from other cusps of the same valve (intra-valve correlation coefficient= 0.10). The Authors expect a total study duration of 24 months. The Authors estimate to complete recruitment in 12 months. The estimated primary completion is month 15 (3 months after last subject enrollment) and study completion on month 24 (12 months after last patient inclusion)
Study design
- Observational model
- Case-control
- Time perspective
- Prospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Patients | – | Diagnostic Test: Analysis of calcific aortic valvesPatients with calcific aortic sclerosis (stage III and IV) that are going to be treated with traditional surgery according to International Guidelines will be enrolled as cases. |
| Controls | – | Diagnostic Test: Analysis of calcific aortic valvesPatients that will undergo a cardiac transplantation (for nonvalvular cardiac disease) or patients with aortic valve insufficiency will be enrolled as controls |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Patients with calcific aortic sclerosis (stage III and IV) that are going to be treated with traditional surgery according to International Guidelines will be enrolled as cases.
Key inclusion criteria (2 listed)
- Age>18 years.
- Calcific aortic sclerosis (stage III and IV)
Key exclusion criteria (1 listed)
- Inability to comply with the requirements of the protocol.
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 |
|---|---|---|
| Analysis of calcific aortic valvesMicrobiologic analysis of calcofic aortic valves | Diagnostic test | Controls, Patients |
Primary outcome
To analyze subclinical or latent valvular bacterial infiltration in patients with calcific aortic disease
Time frame: 2 years
Rate of bacterial infiltration in calcified and non calcified cusps and in patients and controls (co-primary endpoint) will be analysed.
To evaluate the correlation between bacterial detection (as qualitative-positive/negative-, quantitative -quantitative PCR-) and bone calcification markers on valves
Time frame: 2 years
Rate of expression of osteogenic markers and total calcium valve content in calcified and non-calcified cusps on valves of patients and controls and correlation with bacterial detection
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Mar 2024.
- Background: PubMed 31605771Oberbach A, Schlichting N, Friedrich M, Lehmann S, Kullnick Y, Pichlmaier M, Hagl C, Bagaev E; CardiOmics group; Clinical Microbiology group; Clinical Management group. Quantification of Multiple Bacteria in Calcified Structural Valvular Heart Disease. Semin Thorac Cardiovasc Surg. 2020 Summer;32(2):255-263. doi: 10.1053/j.semtcvs.2019.10.003. Epub 2019 Oct 9.
- Background: PubMed 34071605Kwon Y, Park C, Lee J, Park DH, Jeong S, Yun CH, Park OJ, Han SH. Regulation of Bone Cell Differentiation and Activation by Microbe-Associated Molecular Patterns. Int J Mol Sci. 2021 May 28;22(11):5805. doi: 10.3390/ijms22115805.
- Background: PubMed 14759434Cohen DJ, Malave D, Ghidoni JJ, Iakovidis P, Everett MM, You S, Liu Y, Boyan BD. Role of oral bacterial flora in calcific aortic stenosis: an animal model. Ann Thorac Surg. 2004 Feb;77(2):537-43. doi: 10.1016/S0003-4975(03)01454-1.
- Results publication: PubMed 15967862Freeman RV, Otto CM. Spectrum of calcific aortic valve disease: pathogenesis, disease progression, and treatment strategies. Circulation. 2005 Jun 21;111(24):3316-26. doi: 10.1161/CIRCULATIONAHA.104.486738. No abstract available.
- Individual participant dataSharing planned: Undecided
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.
Elena Seminari, MD principal investigator
Fondazione IRCCS Policlinico San MAtteo
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 Calcific Aortic Valve Diasease, run by Fondazione IRCCS Policlinico San Matteo di Pavia at 1 site 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 2 inclusion and 1 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 27 Mar 2024. 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 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?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Elena Seminari, MD (+39 0382503811, e.seminari@smatteo.pv.it), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
To analyze subclinical or latent valvular bacterial infiltration in patients with calcific aortic disease (time frame: 2 years). The study lists 2 primary outcomes in all. 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 NCT05806411, which also lists 4 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 27 Mar 2024.