Randomized Trials

The company’s cerebral protection system is being studied during TAVI procedures in three randomized trials: CLEAN-TAVI, MISTRAL-C, and SENTINEL.

CLEAN-TAVI TRIAL
CLEAN-TAVI: The First RCT to Study Cerebral Protection During TAVI

Claret Medical co-funded the landmark CLEAN-TAVI clinical trial, a prospective, blinded, 1:1 randomized controlled trial of 100 patients receiving a Medtronic CoreValve. This is the first randomized controlled trial to study the use of cerebral protection during TAVI. First results were revealed in September 2014 at the Transcatheter Cardiovascular Therapeutics (TCT) scientific symposium in Washington, D.C. as a Late Breaking Clinical Trial presentation, which demonstrated the effectiveness of the company’s cerebral protection system.

The study hypothesis was that the use of Claret Medical’s cerebral protection technology would reduce the number of cerebral emboli by 50% as evaluated by diffusion-weighted MRI two days post-procedure. Other endpoints included evaluation at 7, 30 and 365 days, neurological evaluation, neurocognitive assessment, periprocedural transcranial Doppler assessment, and histopathological analysis of captured debris.

Clinical Results

The study met its primary endpoint and demonstrated that the use of Claret Medical technology significantly reduced the number and volume of cerebral lesions, with a 65% reduction in the total volume of new brain lesions and a 57% reduction in the number of new brain lesions 7 days after the procedure.

The patients protected by the Claret Medical technology showed a significantly lower ataxia* rate when compared to the control group (9% vs. 24%, respectively) in a “Per Protocol” analysis at 2 days post-procedure, which indicates the potential of the device to improve neurological outcomes.

Neurological deficit was observed in 28% of patients that did not receive cerebral protection during TAVI as evaluated by a neurologist 2 days post-procedure in the “Intent to Treat” analysis, demonstrating that the incidence of brain infarcts is higher than previously reported when serial neurological assessment is performed.

Of particular importance, no additional safety issues were experienced as a result of using Claret Medical’s cerebral protection system in conjunction with the TAVI procedure.

*Ataxia is a lack of coordination and steadiness of muscle movement most often associated with damage to the brain.

References:

  1. Haussig, et al. JAMA, 2016
  2. Van Mieghem, et al. EuroIntervention, 2016
MISTRAL-C TRIAL
MISTRAL-C: The First Study to Show Definitive Neurocognitive Benefit for TAVI Patients Protected by Sentinel CPS

MISTRAL-C is a multi-center, randomized, controlled trial of 65 patients enrolled at four centers in the Netherlands that underwent TAVI using both self-expanding and balloon-expandable valves, with and without the use of the Sentinel CPS. Results were presented in October 2015 in an oral presentation at the Transcatheter Cardiovascular Therapeutics (TCT) scientific symposium in San Francisco.

The study compared the median total new lesion volume as detected by DW-MRI at five days post-procedure to pre-procedural baseline cerebral scans. It also included a detailed neurological and cognitive assessment of patients five days post-procedure.

Clinical Results

MISTRAL-C showed encouraging cognitive benefit from use of the Sentinel™ Cerebral Protection System (CPS) during TAVI. Data show that unprotected patients have a statistically significant (p=0.017) worsening in cognition when compared to Sentinel-protected patients at five days post-TAVI, when assessed using the Mini Mental State Exam (MMSE).

MISTRAL-C also validated findings from the landmark CLEAN-TAVI study that showed the use of a Claret Medical cerebral protection system reduced the number and volume of brain lesions in TAVI patients.2 MISTRAL-C showed a 52 percent reduction in the median total new lesion volume at 5 days post-procedure as assessed using highly sensitive 3-Tesla brain MRI. None of the protected patients had National Institute of Health Stroke Scale (NIHSS) deterioration at 5 days post-procedure, while 5% of unprotected patients showed deterioration.

References:

  1. van Mieghem N. MISTRAL C: MRI Investigation in TAVI with Claret. Transcatheter Cardiovascular Therapeutics (TCT). 2015
  2. Linke A. CLEAN-TAVI: A Prospective, Randomized Trial of Cerebral Embolic Protection in High Risk Patients with Aortic Stenosis Undergoing Transcatheter Aortic Valve Replacement. Transcatheter Cardiovascular Therapeutics (TCT). 2014
SENTINEL TRIAL
SENTINEL: The first randomized clinical trial approved by the FDA evaluating cerebral protection in TAVI

The SENTINEL clinical trial was a prospective, multi-center, randomized, controlled trial of 363 patients enrolled at 19 centers in the U.S. and Germany that underwent TAVI using all commercially available TAVI valves, with and without the use of the Sentinel.

The purpose of the study was to assess the safety and efficacy of the Claret Medical Sentinel used with TAVI (protected TAVI) compared to unprotected TAVI.

The primary safety endpoint was the occurrence of all Major Adverse Cardiac and Cerebrovascular Events (MACCE) at 30 days compared to a historical performance goal, with MACCE defined as all death, all stroke, and all Class 3 Acute Kidney Injury (AKI).

The primary efficacy endpoint was the reduction in median total new lesion volume in protected territories between the Imaging Arms (Test and Control) as assessed by weighted magnetic resonance imaging (DW-MRI) at Day 2-7 post-procedure. The FDA mandated observational success criteria was to demonstrate the true treatment effect by showing the observed ratio of the median total new lesion volume is ≥ 30% in favor of the Test Arm having a lower median new lesion volume in the protected territories as compared to the Control Arm.

Clinical Results

SENTINEL met its primary safety endpoint with a 30-day MACCE rate of 7.3% which is non-inferior to the performance goal of 18.3% and numerically lower than the concurrent control arm of 9.9%. The study demonstrated no additional overall risk of using the Sentinel Cerebral Protection System (CPS), with 99.6% safe and successful delivery and retrieval of at least one Sentinel filter, and a low 0.4% Sentinel access site complication rate.

Of particular importance, the adjudicated 30-day stroke rate for the control arm (unprotected TAVI) was 9.1%, and a majority of the strokes (61%) were identified within 72 hours of the TAVI procedure. The use of the Sentinel CPS was found to reduce strokes by 63% in the first 72 hours after TAVI – when most strokes occur.

Cerebral debris, which included valve tissue, arterial wall, calcium and thrombus material from catheters used during the TAVI procedure, was captured and retrieved in 99% of patients protected with the Sentinel.

SENTINEL confirms findings from the CLEAN-TAVI1 and MISTRAL-C2 randomized trials, showing a strong treatment effect in reducing cerebral infarcts with the use of the Sentinel CPS.

The Sentinel CPS has received the CE Mark and is commercially available in Europe.