Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT04312139 |
| Other study ID # |
?2???-01683 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
March 1, 2020 |
| Est. completion date |
September 2025 |
Study information
| Verified date |
October 2022 |
| Source |
National and Kapodistrian University of Athens |
| Contact |
Nikolaos Anousakis-Vlachochristou, MD |
| Phone |
00302132088099 |
| Email |
anousakisvn[@]med.uoa.gr |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
AthenaValve aims to develop and initial validate a novel serum diagnostic kit, for the
assessment of severity and prognosis of progression of aortic valve stenosis (AS, a
devastating disease without early diagnosis and medical treatment). Two independent clinical
cohorts of patients will provide serum samples, along with tissue and serum of a validated
animal model of the disease for evaluation of the early stages, in order to develop and
validate a multiplexed Enzyme-linked Immunosorbent Assay kit (multiplex ELISA). Advanced
bioinformatics analysis will facilitate the selection of the most promising molecules from
integrated proteomics-transcriptomics-metabolomics data. The novel biomarkers will help
clinicians to early diagnose patients at high risk and will pave the way for the experimental
implementation of promising pharmaceutical therapies.
Moreover, AthenaValve aims to shed light on the systemic cellular interplay of the same
patients, by analyzing the circulating immune cell phenotypes of the subgroups of rapid and
slow progression patients
Description:
The deposition of calcium salts in the arterial wall and the heart valves is a commonly
occurring phenomenon associated with increasing age and various pathological factors. A
particular case is the calcification of the aortic valve, which is accompanied by gradual
stenosis leading to heart failure. As a result, causes significant morbidity and a dramatic
increase in mortality if not treated surgically or via transcatheter intervention. It affects
approximately 2% of the population over the age of 65, being the third cause of death in this
population. It numbers about 100 surgeries per 100,000 person-years in the decade and 180000
patients each year are candidates for percutaneous aortic valve implantation (TAVI) in the
US, Canada, and European Union.
Characteristic of the disease is that it remains even today without a diagnosis at the
critical early stages and all existing therapies have failed to slow or reverse the damage
when applied in the final stages. Previous experimental studies suggested that existing drugs
may be more effective if given early in the disease course. At the time when the aortic
stenosis becomes evident on echocardiography or Computerized Tomography (CT), underlying
biochemical and molecular lesions have already developed. Moreover, among the aortic valve
stenosis patients, it is unknown who will rapidly evolve to a dynamic narrowing of the valve
and previous research studies report significantly diverse progression rates among patients,
with approximately 20-25% demonstrating more than double rates. Thus, the Achilles heel of
the therapeutic management of patients is the lack of early diagnosis and disease progression
prognosis.
Under a combination of pathological effects by factors such as hypertension, diabetes
mellitus and dyslipidemia in patients with a possible genetic predisposition, impairment of
the normal structure and function of endothelium occurs, which progressively leads to the
disease of the underlying valve tissue. Local acidosis and accumulation of oxidative oxygen
radicals cause damage to membrane phospholipids, oxidation of cholesterol and proteins, which
lose their normal quaternary structure and degrade. The gradual deposition of phosphate and
calcium carbonate salts over the pathological proteins leads to calcification of the valve
tissue. Intense inflammatory reaction with activation of bone marrow and infiltration of
tissue with immunocompetent cells accompanies the damage: macrophages, B and T lymphocytes,
mast cells infiltrate and actively contribute to the disease. Within this environment,
inflammatory cytokines secreted from the inflammatory cells lead to activation of embryonic
cell pathways that help to further enhance the calcification through the conversion of
resident fibroblasts to active osteoblasts, which actively deposit calcium salts through
extracellular vesicles.
In the disease, multiple cell types and distant organs are involved (liver - cholesterol
metabolism, spleen and bone marrow - immune response activation) and the damage is expected
to release fragments of biological and biochemical substances in the blood circulation.
Hence, the disease is expected to be reflected in changes in serum protein. It is possible to
detect proteins and metabolites in the blood serum in appropriately selected patients,
prospectively enrolled and monitored through the course of aortic valve stenosis. An optimal
subgroup description of patients with rapid or slow disease progression can reveal important
information for future clinical diagnostic and prognostic use. Moreover, the disease is
characterized by cellular infiltration of a plethora of known and unknown immune cells that
contribute to the disease. Thus, the discovery of novel cellular phenotypes linked to disease
progression can help delineate important clinical aspects.
The purposes of Athena Valve are:
(A) Collection of data on the progression of calcification and aortic valve stenosis,
description of subpopulations with rapid and slow progression and record of clinical events.
(B) The bioinformatics analysis of data from combined transcriptomics-metabolomics-proteomics
of diseased animal model aortic valve tissue in the early, intermediate and final stages, in
comparison with existing patient multi-omics databases, in order to investigate candidate
molecules - "drivers" of the damage with a causal relationship.
(C) The differential proteomic analysis of patient sera samples with severe aortic valve
stenosis, retrospectively defined as rapid versus slow disease progressors and control group
of individuals without aortic valve stenosis and severe calcification.
(D) The differential metabolomic analysis of patient sera samples with severe aortic valve
stenosis, retrospectively defined as rapid versus slow disease progressors and control group
of individuals without aortic valve stenosis and severe calcification.
(E) To obtain the differential profile of circulating immune cells among patients.
(F) The integrated bioinformatics data analysis of differential patient serum proteome and
metabolome enriched with the results of the animal model and existing databases from other
patients, to determine the most probable - causally related molecules with disease
progression in a molecular network.
(G) Utilization of the more important protein targets for the development of a novel
detection assay for multiple protein targets in blood serum by multiplex ELISA based on the
results of the bioinformatics analysis.
(H) Application of the new assay multiplex ELISA in paired serum samples of patients with
moderate to severe aortic stenosis and control group of individuals without aortic valve
stenosis and severe calcification, prospectively enrolled and monitored, initial validation
of the assay and review of its diagnostic performance.
Brief Methodology:
Two independent clinical cohorts will provide necessary data and serum samples. The first, a
retrospective cohort of patients with severe aortic valve stenosis will define serum,
echocardiographic and clinical differences among subgroups with different progression rates.
The second cohort, prospectively developed, will confirm the retrospectively obtained
clinical and echocardiographic data and provide baseline and follow-up measurements of aortic
valve calcification (CT calcium score). Paired baseline and follow-up serum samples will
validate serum targets from the retrospective cohort. Patients will be assessed with
echocardiography annually and with follow-up CT at 2 and 5 years from enrollment.
Retrospective proteomics will be done with untargeted Liquid Chromatography/Mass Spectrometry
(LC/MS) and metabolomics with untargeted Liquid Chromatography-tandem Mass Spectrometry
(LC-MS/MS) in Serial Reaction Monitoring (SRM) mode. Prospective proteomics and metabolomics
will be quantitative and targeted. Blood samples will be immediately frozen and stored to -80
C.
Moreover, peripheral blood mononuclear cells will be isolated and cryopreserved at -80 C with
differential density centrifugation. Cell populations will be analyzed utilizing mass
cytometry, flow cytometry, cell sorting, and molecular methods.
For pathophysiological enrichment, a modified New Zealand rabbit model for aortic stenosis
will be used in a longitudinal protocol of tissue harvesting in the early, intermediate and
late-stage disease (corresponding to inflammation - calcification and subsequent valve
stenosis).
