The REDUCE FMR study was the first double-blinded trial of a percutaneous heart valve therapy, achieved its primary endpoint, and demonstrated favorable reverse LV remodeling. A median 22% reduction in regurgitant volume was demonstrated, as assessed by a blinded, independent echo core lab. The results of The REDUCE FMR study are consistent with the prior Carillon device studies.
REDUCE FMR was the first ever double-blinded, randomized, parallel, sham-controlled RCT of a percutaneous heart valve therapy. The objective was to assess the safety and effectiveness of the Carillon Mitral Contour System for treatment of secondary (functional) mitral regurgitation (FMR) associated with heart failure. Key eligibility criteria were similar to the prior trials of the Carillon system including NYHA class II-IV, MR grade 2+ to 4+, LVEDD >55mm and an ejection fraction <50%, despite the use of stable guideline-directed medical therapy. The primary endpoint was change in regurgitant volume (RV) at 1 year by intention-to-treat analysis. Being double-blind, the study was of the highest scientific rigor – patients and assessors were blinded throughout follow-up and the independent echo core lab not only was blinded to treatment and the timing of the images but also read the images in random order.
In total, 120 patients were randomly allocated to treatment (87) or the sham-control (33) arm at 31 sites in Europe, Australia and New Zealand.
Echocardiographic evaluation was performed at the site prior to enrollment, and 35 patients (29.2%) were later judged by the echo core laboratory to have had MR 1+ at baseline. In 14 (16%) of those allocated to treatment, no device was implanted, due most commonly to coronary impingement (n=8) which resolved following device removal in all cases. The average device implant time was 64.2±34.8 minutes and total procedure time averaged 102.7±54.9 minutes. Freedom from device-related major adverse events (MAE) was 98.9%, with no device embolizations, device fractures, cardiac perforations or intra-procedural ischemic events. There were two deaths within 30 days, both in implanted patients attributed to progressive cardio-renal deterioration. The incidence of MAE at 1 year was not statistically different between the treatment and control groups (16.1% in treatment group vs. 18.2% in control group).
The primary endpoint was met with a statistically significant reduction in mitral RV in the treatment group as compared to the control group (decrease of 7.1 mL/beat vs. an increase of 3.3 mL/beat, p=0.049). A secondary analysis of patients with more severe FMR (MR grade ≥3+) demonstrated a similar pattern of changes. Patients in the treatment group (n=15) experienced a reduction in mitral RV of 12.8 mL/beat whereas patients in the control group (n=8) experienced an increase of 0.6 mL/beat (p=0.14). In addition to improvements in RV, favorable reverse LV remodeling was demonstrated, with a significant reduction in LV volumes in patients receiving the device vs. the control group.
Patients in the treatment group also experienced a significant improvement in 6-minute walk distance at 12 months compared with their baseline (p=0.002), whereas patients allocated to the control group did not (p=0.29). Likewise, the treatment group had a significant improvement in NYHA class at 12 months compared with baseline (p=0.002) whereas patients allocated to the control group did not (p=0.75).
With REDUCE FMR, the Carillon system became the first TMVr therapy to demonstrate significant favorable reverse LV remodeling at 1 year and significant reduction in RV in a blinded, randomized, sham-controlled trial.
The TITAN II study achieved its endpoint and showed significant improvements in echo parameters and patient function.
TITAN II was a single-arm study designed to assess the safety and efficacy of an updated version of the Carillon system. Inclusion and exclusion criteria were similar to those in TITAN. Patients had symptomatic congestive heart failure (NYHA class ≥2), MR grade 2+ to 4+, a dilated LV (LVEDD >55 mm) and an ejection fraction <40%. Quantitative assessments of MR were performed by an independent core echo laboratory, and MAE were reviewed by an independent data and safety monitoring board. In total, 36 patients were enrolled; 30 received a permanent implant.
The TITAN study met its endpoint and showed the Carillon device can significantly and safely reduce FMR severity in heart failure patients, resulting in significant favorable reverse LV remodeling over 12 months and improved measures of clinical outcomes over 24 months.
The TITAN study was a prospective, non-randomized multi-center European study. The objective of the study was to determine if the Carillon device could safely and effectively reduce FMR and yield a durable long-term clinical benefit. Follow-up included typical clinical and echo assessments through 1 year and implanted patients had an additional clinical follow-up assessment at 2 years. The study was rigorously conducted with oversight by independent parties including an echo core lab, clinical events committee, and a data and safety monitoring board. Key inclusion criteria included MR grade 2+ to 4+, NYHA Class II-IV and LVEF <40%.
Of the 53 patients enrolled in the study, 36 underwent permanent implant of the device. In 17 patients, the device was recaptured (due to transient coronary impingement (n=8) or <1 grade FMR reduction (n=9). These non-implant patients were followed as a comparator group.
The first-in-human AMADEUS study met its endpoint and demonstrated successful deployment of the Carillon device and a significant reduction in FMR.
AMADEUS was a single-arm, first-in-human study designed to evaluate the safety and feasibility of the Carillon system. The study utilized several independent bodies to minimize bias and increase rigor, including a blinded echo core lab, clinical events committee, and data and safety monitoring board. Key inclusion criteria included moderate to severe FMR, NYHA class II-IV, LVEDD >55mm, and ejection fraction <40% receiving sustained stable and optimal HF medication regimen. The study enrolled 48 patients with the device successfully implanted in 30 patients. At six months, the degree of FMR reduction among five different quantitative echo measures ranged from 22-32%.