The HALT Biomarker Study

Study Overview
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Brief Summary
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The purpose of the HALT Biomarkers study are to identify a panel of circulating proteins that discriminates between patients with and without Hypo-Attenuated Leaflet Thickening (HALT) and can be used to supplement the diagnosis of HALT; to characterize changes in circulating proteins after treatment of HALT with systemic anticoagulation; and to identify circulating proteins that predict the occurrence of HALT. The study population will be adult patients undergoing transfemoral transcatheter aortic valve replacement (TAVR) for severe aortic stenosis (AS) or bioprosthetic valve degeneration. Enrollment will continue until 30 patients with HALT are identified for completion of phase 1. Based on a HALT incidence rate of 10%, we anticipate enrolling 300 patients. Patients are enrolled prior to undergoing transfemoral TAVR. Blood samples, clinical data and echocardiograms will be collected at the following timepoints: baseline (pre-TAVR, T0), post-TAVR (pre-discharge, T1), 30-day follow-up (window 3-9 weeks, T2), and 6-month follow-up (T3). Cardiac 4D CT will be performed at the 30-day follow-up visit to screen for the occurrence of HALT. Patients with HALT will be treated with systemic anticoagulation for 5-6 months, at which point a follow-up CT scan and blood sample will be obtained. Control subjects will also undergo a 6-month study visit with blood sample collection. The study will be conducted within two phases. Phase 1 will serve as a derivation / discovery study in which candidate protein biomarkers of HALT will be identified. Once this is successfully completed, a second cohort will be enrolled within phase 2. Phase 2 will be performed under the auspices a future contract or amendment and will seek to cross-validate the initial study findings.

Official Title
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Circulating Biomarkers of Hypo-Attenuated Leaflet Thickening After Transcatheter Aortic Valve Replacement

Conditions
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Aortic Stenosis, Hypo-attenuated Leaflet Thickening, Bioprosthetic Valve Degeneration

Intervention / Treatment
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* Diagnostic Test: Proteomics Analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 65 years Subject with severe native AS or severe bioprosthetic valve degeneration Subject undergoing transfemoral TAVR using a Medtronic Evolut R, Evolut Pro or Evolut Pro+ transcatheter heart valve Exclusion Criteria: Chronic anticoagulation therapy Contraindication to systemic oral anticoagulation therapy Chronic kidney disease with EGFR<30 ml/min Bleeding diathesis or known coagulopathy Hypercoagulable state Life-expectancy <12 months due to other medical conditions (e.g., malignancy, severe Alzheimer's disease, etc.) The patient is currently participating in another investigational device or drug study that has not reached its primary objective/endpoint Pregnant, lactating, or planning pregnancy within next 12 months

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: HALT Cohort<br>Patients who develop HALT | Diagnostic Test: Proteomics Analysis<br>* Determine a panel of circulating proteins that discriminates between patients with and without Hypo-Attenuated Leaflet Thickening (HALT)<br>|
| Other: Control Group<br>Patients who do not develop HALT | Diagnostic Test: Proteomics Analysis<br>* Determine a panel of circulating proteins that discriminates between patients with and without Hypo-Attenuated Leaflet Thickening (HALT)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Derivation of the panel of circulating proteins indicative of HALT | 1. Establish the incidence of similar proteomic profiles and the rate to which the profile occurs in TAVR recipients with HALT via a high-throughput precision proteomics platform which utilizes the proximity extension assay (PEA). PEA merges a dual-recognition antibody-based immunoassay with quantitative real-time PCR that allows for the simultaneous quantification of 92 proteins. We will focus on the 5 highest yield panels for the current investigation: cardiovascular II, cardiovascular III, cardiometabolic, inflammation, and oncology II panels. These panels will allow for the assessment of 460 circulating proteins. | 6 months | 
| Establish the rate at which these characteristics indicative of future HALT | Using data analysis of baseline patient characteristics to establish the rate that they are indicative of future HALT in patients with aortic stenosis. The sampling frame assumes the sequencing of 460 proteins; a 5% False Discovery Rate; a 10% prognostic prevalence; a minimum fold change of 2; and a normalization ratio of 1. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cross-validation of the panel of circulating proteins indicative of HALT | 3. Using 20 matched pairs of subjects with and without HALT, the derivation of the HALT indicative panel of circulating proteins gathered through PEA will be cross-validated using data analysis to establish the rate to which the panel is present in both cohorts. This rate will be used to determine if the proteomic profile of a patient can be used as a diagnostic test for the presence of HALT. | 6 months |