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

Primary Purpose

Symptomatic Aortic Stenosis

Status

Completed

Phase

Not Applicable

Locations

International

Study Type

Interventional

Intervention

Embolic Protection Device

Transcatheter aortic valve implantation (TAVI)

About this trial

This is an interventional prevention trial for Symptomatic Aortic Stenosis focused on measuring Aortic stenosis, TAVI, TriGUARD, Keystone Heart, Cerebral Embolic Protection

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Subjects must meet ALL of the following criteria:

General Inclusion Criteria

The patient is a male or non-pregnant female ≥18 years of age
The patient meets indications for transcatheter aortic valve implantation (TAVI)
The patient is willing to comply with protocol-specified follow-up evaluations
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:

General Exclusion Criteria

Patients undergoing transcatheter aortic valve implantation (TAVI) via the trans-axillary, trans-subclavian, or trans-aortic route
Patients undergoing transcatheter aortic valve implantation (TAVI) via the transapical approach due to friable or mobile atherosclerotic plaque in the aortic arch
Patients with a previously implanted prosthetic aortic valve (i.e., planned valve-in-valve transcatheter aortic valve implantation (TAVI))
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
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
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
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
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
Patients with a history of a stroke or transient ischemic attack (TIA) within the prior 6 months
Patients with renal failure (estimated Glomerular Filtration Rate [eGFR] <30 mL/min, calculated from serum creatinine by the Cockcroft-Gault formula)
Patients with hepatic failure (Child-Pugh class C)
Patients with hypercoagulable states that cannot be corrected by additional periprocedural heparin
Patients presenting with cardiogenic shock at the time of the index procedure
Patients with severe peripheral arterial, abdominal aortic, or thoracic aortic disease that precludes delivery sheath vascular access
Patients in whom the aortic arch, innominate artery ostium, or proximal innominate artery is heavily calcified, severely atheromatous, or severely tortuous
Patients with an innominate artery ostium diameter <10 mm or >25 mm
Patients with a transverse aortic diameter >43
Patients with anatomic irregularities of the innominate artery that could prevent positioning of the TriGuard upper stabilizer and compromise stability of the device
Patients with any other condition that would prevent adherence to the TriGuard HDH Instructions for Use
Patients with contraindication to cerebral MRI
Patients who have a planned treatment with any other investigational device or procedure during the study period
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

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Intervention

Control Arm

Arm Description

Embolic Protection with transcatheter aortic valve implantation (TAVI)

Transcatheter aortic valve implantation (TAVI) without embolic protection

Outcomes

Primary Outcome Measures

Primary Safety Endpoint - Composite Safety Endpoint Based on MACCE

Combined safety endpoint at 30 days defined according to VARC-2 ("TAVI early safety") as a composite of: All-cause mortality - number of patients that expired All stroke (disabling and non-disabling) - defined by VARC-2 scale Life-threatening or disabled bleeding - BARC bleeding scale - 5 point scale ranging from no bleeding to fatal Acute kidney injury - Stage 2 or 3 (including renal replacement therapy) Coronary artery obstruction requiring intervention Major vascular complication, and Valve-related dysfunction requiring repeat procedure (BAV, TAVI, or SAVR) - number of patients in whom a valve related dysfunction occurred It was pre-specified to combine all participants that received the device in the andomized Intervention and Roll-in Arms/Groups for this Outcome Measure.

Primary Efficacy Endpoint

Hierarchical composite efficacy endpt, determined by pair-wise comparisons among subjects according to hierarchy: mortality or any stroke [30 days] death/stroke time to event analysis by days determine win stroke at same day the comparison moves to next tier NIHSS worsening [2-5 days post] Freedom from lesions detected by DW-MRI 2-5 days post Total volume lesions detected by DW-MRI 2-5 days post Each subj in intervention compared with each subj from control based on hierarchy according to Finkelstein-Schoenfeld method. If Subj A dies or has stroke &Subj B survives free of stroke to 30 days, Subj B wins(score+1) &Subj A loses (score-1). Both die or have stroke, patient with later event wins. Both have death/stroke on same day is equilibrium (score 0). Both are alive & have stroke on same day, comparison moves to next tier. Both stroke-free to 30 days, comparison moves to the next tier. Scores summed to cumulative score for each subj, &outcomes between groups are compared.

Secondary Outcome Measures

Full Information

NCT ID

NCT02536196

First Posted

August 26, 2015

Last Updated

February 16, 2021

Sponsor

Keystone Heart

1. Study Identification

Unique Protocol Identification Number

NCT02536196

Brief Title

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

Official Title

A Randomized Evaluation of the TriGuard Embolic Deflection Device to Reduce the Impact of Cerebral Embolic Lesions After Transcatheter Aortic Valve Implantation

Study Type

Interventional

2. Study Status

Record Verification Date

February 2021

Overall Recruitment Status

Completed

Study Start Date

June 2016 (Actual)

Primary Completion Date

May 2019 (Actual)

Study Completion Date

June 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Keystone Heart

4. Oversight

Data Monitoring Committee

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Symptomatic Aortic Stenosis

Keywords

Aortic stenosis, TAVI, TriGUARD, Keystone Heart, Cerebral Embolic Protection

7. Study Design

Primary Purpose

Prevention

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

Masking

Outcomes Assessor

Allocation

Randomized

Enrollment

478 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Intervention

Arm Type

Experimental

Arm Description

Embolic Protection with transcatheter aortic valve implantation (TAVI)

Arm Title

Control Arm

Arm Type

Active Comparator

Arm Description

Transcatheter aortic valve implantation (TAVI) without embolic protection

Intervention Type

Device

Intervention Name(s)

Embolic Protection Device

Intervention Description

Embolic protection

Intervention Type

Procedure

Intervention Name(s)

Transcatheter aortic valve implantation (TAVI)

Intervention Description

Transcatheter aortic valve implantation (TAVI)

Primary Outcome Measure Information:

Title

Primary Safety Endpoint - Composite Safety Endpoint Based on MACCE

Description

Time Frame

30 Days

Title

Primary Efficacy Endpoint

Description

Time Frame

Pre-discharge through 30-days

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Subjects must meet ALL of the following criteria: General Inclusion Criteria The patient is a male or non-pregnant female ≥18 years of age The patient meets indications for transcatheter aortic valve implantation (TAVI) The patient is willing to comply with protocol-specified follow-up evaluations 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: General Exclusion Criteria Patients undergoing transcatheter aortic valve implantation (TAVI) via the trans-axillary, trans-subclavian, or trans-aortic route Patients undergoing transcatheter aortic valve implantation (TAVI) via the transapical approach due to friable or mobile atherosclerotic plaque in the aortic arch Patients with a previously implanted prosthetic aortic valve (i.e., planned valve-in-valve transcatheter aortic valve implantation (TAVI)) 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 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 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 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 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 Patients with a history of a stroke or transient ischemic attack (TIA) within the prior 6 months Patients with renal failure (estimated Glomerular Filtration Rate [eGFR] <30 mL/min, calculated from serum creatinine by the Cockcroft-Gault formula) Patients with hepatic failure (Child-Pugh class C) Patients with hypercoagulable states that cannot be corrected by additional periprocedural heparin Patients presenting with cardiogenic shock at the time of the index procedure Patients with severe peripheral arterial, abdominal aortic, or thoracic aortic disease that precludes delivery sheath vascular access Patients in whom the aortic arch, innominate artery ostium, or proximal innominate artery is heavily calcified, severely atheromatous, or severely tortuous Patients with an innominate artery ostium diameter <10 mm or >25 mm Patients with a transverse aortic diameter >43 Patients with anatomic irregularities of the innominate artery that could prevent positioning of the TriGuard upper stabilizer and compromise stability of the device Patients with any other condition that would prevent adherence to the TriGuard HDH Instructions for Use Patients with contraindication to cerebral MRI Patients who have a planned treatment with any other investigational device or procedure during the study period 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Alexandra J Lansky, MD

Organizational Affiliation

alexandra.lansky@yale.edu

Official's Role

Principal Investigator

Facility Information:

Facility Name

Cedars-Sinai Medical Center

City

Los Angeles

State/Province

California

ZIP/Postal Code

90048

Country

United States

Facility Name

Foundation for Cardiovascular Medicine

City

San Diego

State/Province

California

ZIP/Postal Code

92122

Country

United States

Facility Name

Yale New Haven Hospital

City

New Haven

State/Province

Connecticut

ZIP/Postal Code

06510

Country

United States

Facility Name

MedStar Washington Hospital Center

City

Washington

State/Province

District of Columbia

ZIP/Postal Code

20010

Country

United States

Facility Name

Morton Plant Hospital

City

Clearwater

State/Province

Florida

ZIP/Postal Code

33756

Country

United States

Facility Name

Delray Medical Center

City

Hialeah

State/Province

Florida

ZIP/Postal Code

33016

Country

United States

Facility Name

Piedmont Hospital

City

Atlanta

State/Province

Georgia

ZIP/Postal Code

30309

Country

United States

Facility Name

Northwestern University

City

Evanston

State/Province

Illinois

ZIP/Postal Code

60208

Country

United States

Facility Name

University of Iowa

City

Iowa City

State/Province

Iowa

ZIP/Postal Code

52242

Country

United States

Facility Name

Cardiovascular Institute of the South

City

Houma

State/Province

Louisiana

ZIP/Postal Code

70360

Country

United States

Facility Name

Morristown Medical Center

City

Morristown

State/Province

New Jersey

ZIP/Postal Code

07960

Country

United States

Facility Name

New York University

City

New York

State/Province

New York

ZIP/Postal Code

10016

Country

United States

Facility Name

Columbia University Medical Center/NYPH

City

New York

State/Province

New York

ZIP/Postal Code

10032

Country

United States

Facility Name

St. Francis Hospital

City

Roslyn

State/Province

New York

ZIP/Postal Code

11576

Country

United States

Facility Name

Cleveland Clinic

City

Cleveland

State/Province

Ohio

ZIP/Postal Code

44195

Country

United States

Facility Name

Pinnacle Health

City

Harrisburg

State/Province

Pennsylvania

ZIP/Postal Code

17101

Country

United States

Facility Name

University of Pennsylvania

City

Philadelphia

State/Province

Pennsylvania

ZIP/Postal Code

19104

Country

United States

Facility Name

Baylor Heart and Vascular HospitalBaylor Heart and Vascular

City

Dallas

State/Province

Texas

ZIP/Postal Code

75201

Country

United States

Facility Name

Houston Methodist Hospital

City

Houston

State/Province

Texas

ZIP/Postal Code

77030

Country

United States

Facility Name

University of Texas

City

Houston

State/Province

Texas

ZIP/Postal Code

77030

Country

United States

Facility Name

Baylor Research Center

City

Plano

State/Province

Texas

ZIP/Postal Code

75093

Country

United States

Facility Name

University of Virginia

City

Charlottesville

State/Province

Virginia

ZIP/Postal Code

22903

Country

United States

Facility Name

Swedish Medical Center

City

Seattle

State/Province

Washington

ZIP/Postal Code

98122

Country

United States

Facility Name

University of Bonn

City

Bonn

Country

Germany

Facility Name

Universitats-Herzzentrum Freiburg

City

Freiburg

Country

Germany

Facility Name

Hamburg Univeristy Cardiovascular Center

City

Hamburg

Country

Germany

Facility Name

Leipzig Heart Institute

City

Leipzig

Country

Germany

Facility Name

San Donato Hospital

City

Milano

Country

Italy

Facility Name

San Rafeele Hospital

City

Milano

Country

Italy

Facility Name

UMC Utrecht

City

Utrecht

Country

Netherlands

12. IPD Sharing Statement

Learn more about this trial

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

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

Symptomatic Aortic Stenosis

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial