The HALT Biomarker Study (HALT)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Aortic Stenosis; Hypo-attenuated Leaflet Thickening; Bioprosthetic Valve Degeneration
• Intervention / Treatment: Diagnostic test: Proteomics Analysis

• Study Type: Interventional
• Enrollment (Anticipated): 300
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Roukoz Abou Karam; Email: raboukaram@mgh.harvard.edu
• Study Contact Backup: Name: Paris J Jamiel, BS; Phone Number: (617) 726-0996; Email: pjamiel@mgh.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Recruiting
      • Massachusetts General Hospital
      • Contact: Email: SELMARIAH@mgh.harvard.edu
      • Principal Investigator: Sammy Elmariah, MD
  • Minnesota
    • Minneapolis, Minnesota, United States, 55407
      • Not yet recruiting
      • Minneapolis Heart Institute
      • Contact: Email: Santiago.Garcia@allina.com
      • Principal Investigator: Santiago Garcia, MD
  • New Hampshire
    • Manchester, New Hampshire, United States, 03103
      • Recruiting
      • Catholic Medical Center
      • Contact: Email: fahad.gilani@cmc-nh.org
      • Principal Investigator: Fahad S Gilani

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 65 years and older (Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age > 65 years
2. Subject with severe native AS or severe bioprosthetic valve degeneration
3. Subject undergoing transfemoral TAVR using a Medtronic Evolut R, Evolut Pro or Evolut Pro+ transcatheter heart valve

Exclusion Criteria:

1. Chronic anticoagulation therapy
2. Contraindication to systemic oral anticoagulation therapy
3. Chronic kidney disease with EGFR<30 ml/min
4. Bleeding diathesis or known coagulopathy
5. Hypercoagulable state
6. Life-expectancy <12 months due to other medical conditions (e.g., malignancy, severe Alzheimer's disease, etc.)
7. The patient is currently participating in another investigational device or drug study that has not reached its primary objective/endpoint
8. Pregnant, lactating, or planning pregnancy within next 12 months

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: Medtronic; Minneapolis Heart Institute; Catholic Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): June 22, 2020
• Primary Completion (Anticipated): June 22, 2030
• Study Completion (Anticipated): June 22, 2035

Study Registration Dates

• First Submitted: August 28, 2020
• First Submitted That Met QC Criteria: September 11, 2020
• First Posted (Actual): September 17, 2020

Study Record Updates

• Last Update Posted (Actual): November 10, 2021
• Last Update Submitted That Met QC Criteria: November 2, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Aortic Valve Disease; Heart Valve Diseases; Ventricular Outflow Obstruction; Aortic Valve Stenosis
• Other Study ID Numbers: 2020P001793

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No