The REFLECT Trial: Cerebral Protection to Reduce Cerebral Embolic Lesions After Transcatheter Aortic Valve Implantation

NCT ID: NCT02536196

Last Updated: 2021-02-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 478 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-06-30
• Study Completion Date: 2019-06-30

Brief Summary

The Keystone Heart TriGuard™ HDH is an aortic embolism deflection device intended to reduce the amount of embolic material that may enter the carotid, subclavian, and vertebral arteries during transcatheter heart valve implantation.

The objective of the study is to assess the safety and efficacy of the TriGuard™ HDH embolic deflection device in patients undergoing transcatheter aortic valve implantation (TAVI), in comparison with an active control group of patients undergoing unprotected TAVI.

Subjects with indications for TAVI and who meet study eligibility criteria will be randomized 2:1 to one of two treatment arms: 1) Intervention: Embolic protection device (TriGuard™) with transcatheter aortic valve implantation or 2) Control: Unprotected transcatheter aortic valve implantation.

Detailed Description

This prospective, single-blind, three arm, randomized, (2 device: 1 control), multicenter safety and efficacy trial is designed to enroll up to 603 total subjects in two consecutive phases: Phase I enrolled 258 subjects (including 54 Roll-Ins) and utilized the TriGuard HDH and Phase II will enroll up to 345 subjects (including 40-50 Roll-Ins) and will utilize the TriGUARD 3 (Figure 3b shows the patient flow/disposition).

Phase I In phase I, a total of 204 evaluable subjects and 54 roll-in subjects were enrolled at 26 total investigational sites in the United States, Europe, and Israel, of which 20 sites were in the United States. A minimum of 50% of subjects were planned to be enrolled at US sites, and no single site was permitted to enroll more than 20% of all subjects.

Subjects with indications for TAVI and who met study eligibility criteria were randomized 2:1 (stratified by study site) to one of two treatment arms:

• Intervention (Phase 1 Cohort) - TAVI with the TriGuard HDH CEPD
• Control - standard unprotected TAVI At sites where the investigator did not have prior experience with the TriGuard device (minimum of 2 prior cases), up to 3 roll-in subjects were enrolled. Roll-in subjects were not randomized, but underwent TAVI with the TriGuard HDH device. These cases were proctored by a Sponsor representative. Investigational sites with ≥2 prior TriGuard cases were allowed to enroll 1 roll-in subject at the discretion of the site principal investigator.

All subjects were to be followed clinically in-hospital and at 30 and 90 days, and to undergo diffusion-weighted MR imaging 2 to 5 days post-procedure, and neurologic and neuropsychological testing pre-procedure, post-procedure (2-5 days post-procedure), and at 30 and 90 days.

The initial randomized cohort expected to enroll up to 285 subjects. Note: Enrollment in Phase I has been halted after enrolling a total of 258 subjects (54 roll-ins and 204 randomized subjects including 63 controls) based on the recommendation of the Data Monitoring Committee following a review of interim 30-day data on 90 subjects at the prespecified interim analysis time point. A next iteration device designed for increased efficacy, ease of use, and improved safety will be tested in Phase II (below).

Phase II In Phase II, up to 295 randomized subjects and 40-50 roll-in subjects will be enrolled at up to 25 sites in the United States (inclusive of sites enrolling subjects in Phase I). No single site will be permitted to enroll more than 20% of all randomized subjects in Phase II.

Subjects with indications for TAVI and who meet study eligibility criteria will be randomized 2:1 (stratified by study site) to one of two treatment arms:

• Intervention - TAVI with the TriGUARD 3 CEPD
• Control - standard unprotected TAVI. Randomization will be stratified by implanted valve type (Medtronic vs. Edwards).

No single valve type will be implanted in more than approximately 70% of randomized patients (phase II).

Roll-in subjects (a minimum of 2 and a maximum of 3 Roll-ins per-site) will not be randomized, but will undergo TAVI with the TriGUARD 3 device. These cases will be proctored by a Sponsor representative.

All subjects will be followed clinically in-hospital and at 30 days, undergo diffusion-weighted MR imaging 2 to 5 days post-procedure, and undergo neurologic (NIHSS) testing pre-procedure, post-procedure (2-5 days post-procedure), and at 30 days. A follow-up phone-call to assess the occurrence of death or stroke will be done at 90 days.

The initial randomized cohort will consist of up to 225 subjects. After at least 50% of the initial randomized cohort (approximately 112 subjects) have reached the 30 day primary efficacy endpoint evaluation time point, a sample size reestimation will be performed in case the conditional power of the trial (assessed by the independent biostatistician) is >40% but <80%, subject to approval by the Sponsor. If this analysis determines that more than 225 randomized subjects will be required to ensure adequate study power, enrollment may continue until the required number of subjects have been enrolled, or until the total subject limit for the study has been reached (whichever occurs first).

Conditions

Symptomatic Aortic Stenosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: SINGLE

Study Groups

Intervention

Embolic Protection with transcatheter aortic valve implantation (TAVI)

Group Type: EXPERIMENTAL

Embolic Protection Device

Intervention Type: DEVICE

Embolic protection

Transcatheter aortic valve implantation (TAVI)

Intervention Type: PROCEDURE

Transcatheter aortic valve implantation (TAVI)

Control Arm

Transcatheter aortic valve implantation (TAVI) without embolic protection

Group Type: ACTIVE_COMPARATOR

Transcatheter aortic valve implantation (TAVI)

Intervention Type: PROCEDURE

Transcatheter aortic valve implantation (TAVI)

Interventions

Embolic Protection Device

Embolic protection

Intervention Type: DEVICE

Transcatheter aortic valve implantation (TAVI)

Transcatheter aortic valve implantation (TAVI)

Intervention Type: PROCEDURE

Eligibility Criteria

Inclusion Criteria

1. The patient is a male or non-pregnant female ≥18 years of age

2. The patient meets indications for transcatheter aortic valve implantation (TAVI)

3. The patient is willing to comply with protocol-specified follow-up evaluations

4. The patient, or legally authorized representative, has been informed of the nature of the study, agrees to its provisions and has provided written informed consent, approved by the appropriate Institutional Review Board (IRB) or Ethics Committee (EC).

Potential Subjects will be excluded if ANY of the following criteria apply:

Exclusion Criteria

1. Patients undergoing transcatheter aortic valve implantation (TAVI) via the trans-axillary, trans-subclavian, or trans-aortic route

2. Patients undergoing transcatheter aortic valve implantation (TAVI) via the transapical approach due to friable or mobile atherosclerotic plaque in the aortic arch

3. Patients with a previously implanted prosthetic aortic valve (i.e., planned valve-in-valve transcatheter aortic valve implantation (TAVI))

4. Pregnant or nursing subjects and those who plan pregnancy in the period up to 1 year following index procedure. Female subjects of child-bearing potential must have a negative pregnancy test done within 14 days prior to index procedure per site standard test

5. Patients with known diagnosis of acute myocardial infarction (AMI) within 72 hours preceding the index procedure (according to definition) or AMI >72 hours preceding the index procedure, in whom Creatine Kinase (CK) and CK-MB have not returned to within normal limits at the time of procedure, or patients who are currently experiencing clinical symptoms consistent with new-onset AMI, such as nitrate-unresponsive prolonged chest pain

6. Patients with a history of bleeding diathesis or coagulopathy or patients in whom anti-platelet and/or anticoagulant therapy is contraindicated, patients who will refuse transfusion, or patients with an active peptic ulcer or history of upper gastrointestinal (GI) bleeding within the prior 3 months

7. Patients with known mental or physical illness or known history of substance abuse that may cause non-compliance with the protocol, confound the data interpretation, or is associated with a life expectancy of less than one year

8. Patients with severe allergy or known hypersensitivity or contraindication to aspirin, heparin/bivalirudin, clopidogrel, nitinol, stainless steel alloy, and/or contrast sensitivity that cannot be adequately pre-medicated

9. Patients with a history of a stroke or transient ischemic attack (TIA) within the prior 6 months

10. Patients with renal failure (estimated Glomerular Filtration Rate [eGFR] <30 mL/min, calculated from serum creatinine by the Cockcroft-Gault formula)

11. Patients with hepatic failure (Child-Pugh class C)

12. Patients with hypercoagulable states that cannot be corrected by additional periprocedural heparin

13. Patients presenting with cardiogenic shock at the time of the index procedure

14. Patients with severe peripheral arterial, abdominal aortic, or thoracic aortic disease that precludes delivery sheath vascular access

15. Patients in whom the aortic arch, innominate artery ostium, or proximal innominate artery is heavily calcified, severely atheromatous, or severely tortuous

16. Patients with an innominate artery ostium diameter <10 mm or >25 mm

17. Patients with a transverse aortic diameter >43

18. Patients with anatomic irregularities of the innominate artery that could prevent positioning of the TriGuard upper stabilizer and compromise stability of the device

19. Patients with any other condition that would prevent adherence to the TriGuard HDH Instructions for Use

20. Patients with contraindication to cerebral MRI

21. Patients who have a planned treatment with any other investigational device or procedure during the study period

22. Patients planned to undergo any other cardiac surgical or interventional procedure (e.g., concurrent coronary revascularization) during the TAVI procedure or within 10 days prior to the TAVI procedure. NOTE: Diagnostic cardiac catheterization is permitted within 10 day prior to the TAVI procedure

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Keystone Heart

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Alexandra J Lansky, MD

Role: PRINCIPAL_INVESTIGATOR

alexandra.lansky@yale.edu

Locations

Cedars-Sinai Medical Center

Los Angeles, California, United States

Foundation for Cardiovascular Medicine

San Diego, California, United States

Yale New Haven Hospital

New Haven, Connecticut, United States

MedStar Washington Hospital Center

Washington D.C., District of Columbia, United States

Morton Plant Hospital

Clearwater, Florida, United States

Delray Medical Center

Hialeah, Florida, United States

Piedmont Hospital

Atlanta, Georgia, United States

Northwestern University

Evanston, Illinois, United States

University of Iowa

Iowa City, Iowa, United States

Cardiovascular Institute of the South

Houma, Louisiana, United States

Morristown Medical Center

Morristown, New Jersey, United States

New York University

New York, New York, United States

Columbia University Medical Center/NYPH

New York, New York, United States

St. Francis Hospital

Roslyn, New York, United States

Cleveland Clinic

Cleveland, Ohio, United States

Pinnacle Health

Harrisburg, Pennsylvania, United States

University of Pennsylvania

Philadelphia, Pennsylvania, United States

Baylor Heart and Vascular HospitalBaylor Heart and Vascular

Dallas, Texas, United States

Houston Methodist Hospital

Houston, Texas, United States

University of Texas

Houston, Texas, United States

Baylor Research Center

Plano, Texas, United States

University of Virginia

Charlottesville, Virginia, United States

Swedish Medical Center

Seattle, Washington, United States

University of Bonn

Bonn, , Germany

Universitats-Herzzentrum Freiburg

Freiburg im Breisgau, , Germany

Hamburg Univeristy Cardiovascular Center

Hamburg, , Germany

Leipzig Heart Institute

Leipzig, , Germany

San Donato Hospital

Milan, , Italy

San Rafeele Hospital

Milan, , Italy

UMC Utrecht

Utrecht, , Netherlands

Countries

United States; Germany; Italy; Netherlands

References

Lansky AJ, Grubman D, Dwyer MG 3rd, Zivadinov R, Parise H, Moses JW, Shah T, Pietras C, Tirziu D, Gambone L, Leon MB, Nazif TM, Messe SR. Clinical Significance of Diffusion-Weighted Brain MRI Lesions After TAVR: Results of a Patient-Level Pooled Analysis. J Am Coll Cardiol. 2024 Aug 20;84(8):712-722. doi: 10.1016/j.jacc.2024.05.055.

Reference Type: DERIVED

PMID: 39142725 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

REFLECT

Identifier Type: -

Identifier Source: org_study_id