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

Symptomatic Aortic Stenosis

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

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.

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).

Germany, Italy, Netherlands, United States

Participants by arm