Medtronic plc has kicked off two clinical trials of its Evolut transcatheter aortic valve replacement (TAVR) system. One study will pit the self-expanding Evolut Pro and Pro+TAVR systems against Edwards Lifesciences Corp.’s balloon-expandable Sapien 3 and Sapien 3 Ultra transcatheter heart valves in small annulus patients. The Dublin-based med-tech giant also has begun a feasibility study to assess TAVR in patients with symptomatic moderate and asymptomatic severe aortic stenosis.

SMART clinical trial

The prospective, multicenter, international Small Annuli Randomized To Evolut or Sapien (SMART) postmarket trial will compare the safety and performance of the Evolut devices vs. the Sapien valves in about 700 patients with small annuli and those who are candidates for TAV-in-SAV procedures – situations in which a transcatheter valve is implanted inside a failed surgical valve. According to Medtronic, this population represents more than 40% of the global TAVR market. The company expects the SMART trial to include predominantly women, who have been underrepresented in TAVR studies.

The two cohorts of the study – small annuli and TAV-in-SAV – will be analyzed separately.

The native aortic stenosis study will randomize up to 600 patients at about 90 sites, currently targeting the U.S., Canada and EMEA region. The co-primary outcome measures will be superiority of bioprosthetic valve dysfunction (BVD) and noninferiority of clinical outcomes – a composite of mortality, disabling stroke or rehospitalization – at 12 months.

The TAV-in-SAV study will randomize 150 patients, with a primary endpoint of BVD at 12 months. Patients in both groups will be followed for five years.

“Hemodynamic performance is particularly important in many patients with aortic stenosis, including those with small annuli, surgical aortic valves needing a TAV-in-SAV procedure, patients with left ventricular dysfunction, and those who are young and most active. For many of these and other TAVR patients, valve design matters,” said Howard Hermann, the John Winthrop Bryfogle professor of cardiovascular diseases and director of interventional cardiology in the Perelman School of Medicine at the University of Pennsylvania and principal investigator and steering committee chair of the SMART trial. “The outcome of this important head-to-head study will allow heart teams to more selectively tailor clinical decision-making to ensure the right valve is selected for the right patient.”

The first enrollment in the SMART trial is planned for early 2021.

Feasibility study

The Evolut EXPAND TAVR I feasibility study seeks to explore TAVR use in two populations that are outside current guidelines and indications for aortic valve replacement – patients with symptomatic moderate and asymptomatic severe aortic stenosis.

This prospective, multicenter study aims to enroll 150 patients at up to 25 cites in the U.S., Canada, Europe, Israel, Australia and New Zealand to assess the use of TAVR before signs of left ventricular dysfunction are seen. The study also will assess the clinical and hemodynamic performance of the Evolut TAVR system to inform clinical work, the company said.

Safety endpoints for the feasibility study include all-cause mortality, all stroke, valve-related dysfunction requiring repeat procedure and new permanent pacemaker implant – all at 30 days and six months. The primary efficacy outcomes are cardiovascular and heart failure hospitalizations and heart failure events at 30 days and six months. Additional efficacy measures include changes in Kansas City Cardiomyopathy Questionnaire and six-minute walk test at six months and change in cardiac function by echocardiogram at six months.

“Moderate aortic stenosis, if left untreated, can be just as deadly for patients as the more severe form of the disease,” said Jeffrey Popma, chief medical officer and vice president of medical affairs for Medtronic’s Structural Heart business, part of the Cardiac and Vascular Group. “Limited clinical research has shown that early intervention may reduce the high rates of mortality often seen in these patients as the disease progresses further down the road. The outcomes observed in this study will help shape our clinical strategy to pursue expansion of the therapy to new populations who may benefit.”

Medtronic has submitted the study to the U.S. FDA for IDE approval. “Once approved, we anticipate enrollment to begin over the next few months,” Joey Lomicky, a Medtronic spokesperson, told BioWorld.

Medtronic and Edwards have vied for supremacy in the TAVR space in recent years. Results of the FRANCE-TAVI registry study, released last fall, suggested that the Edwards line of devices provide better outcomes on moderate or worse paravalvular regurgitation and in-hospital mortality. The study compared Sapien XT and Sapien 3 to the Corevalve Evolut platform.

Medtronic challenged the study’s conclusion, noting the FRANCE-TAVI trial was a nonrandomized, retrospective analysis and attempts to compare performance of the devices can be difficult and misleading.

“As rigorous as the retrospective analysis might be, the lack of randomization introduces device selection practices as a confounder for drawing conclusions on differences between devices,” Lomicky said. The propensity score matching analysis also lacked key elements for device selection, such as left ventricular outflow tract calcification and small and large annuli.

“The Corevalve Evolut platform has demonstrated excellent outcomes in large randomized trials in comparison to the surgical standard of care. They also compared favorably against Sapien in the prospective, randomized CHOICE and SOLVE-TAVI studies,” Lomicky said.

He added that Medtronic has maintained market leadership in TAVR in Europe over multiple years despite new entrants and is committed to grabbing the lion’s share of the global market.

“We continue to see strong adoption of our latest generation Evolut Pro+ system globally and … will continue to invest in product innovation with future improvements to the overall procedural experience, including enhancements in deliverability, implant visibility and deployment stability.”

Mitral valve initiative

Separately, Medtronic disclosed a three-year-old partnership with The Foundry LLC – a California-based med-tech incubator – to invest in and create a medical device company to develop a novel transcatheter mitral valve repair (TMVr) technology.

The collaboration calls for Medtronic and The Foundry to make structured investment tranches into the initiative and gives Medtronic an exclusive right to acquire the ensuing company, known as Half Moon Medical Inc., upon completion of certain technical and clinical milestones.

Half Moon Medical, which is based in Menlo Park, Calif., recently got the FDA’s nod for an early feasibility study in patients with severe, symptomatic mitral regurgitation. The experimental TMVr device fills the regurgitant orifice in a diseased mitral valve to restore function. It can be repositioned and recovered during deployment using a transfemoral delivery catheter, which helps physicians traverse the vasculature and position the device in the compromised mitral valve.

Half Moon Medical has tested nearly three dozen early concepts and design iterations and expects to implant the first TMVr devices in the coming weeks under the IDE.

“We have been encouraged by Half Moon’s deployment to date, leveraging Medtronic’s investment and intellectual property coupled with decades of mitral valve therapy experience at The Foundry through their development of repair and replacement technologies,” said Nina Goodheart, president of the Coronary & Structural Heart division within Medtronic’s Cardiac and Vascular Group. “We believe this technology is promising and differentiated from other approaches to mitral valve repair.”

The Half Moon TMVr technology could complement Medtronic’s minimally invasive Intrepid Transcatheter Valve Replacement System, which is being evaluated in the APOLLO pivotal trial for transcatheter mitral valve replacement. Medtronic also is recruiting patients in early feasibility studies of its Intrepid Transfemoral System to assess transseptal/transfemoral access in patients with severe, symptomatic mitral or tricuspid valve regurgitation.

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