Non-clinical and Pre-clinical Testing to Demonstrate Safety of the Barostim Neo Electrode for Activation of Carotid Baroreceptors in Chronic Human Implants.

Seth J Wilks,Erika K Ross,Evan N Nicolai,Seth A Hara,Paul A Pignato,Kip A Ludwig,Adam W Cates

doi:10.3389/fnins.2017.00438

Abstract

The Barostim neo™ electrode was developed by CVRx, Inc.to deliver baroreflex activation therapy (BAT)™ to treat hypertension and heart failure. The neo electrode concept was designed to deliver electrical stimulation to the baroreceptors within the carotid sinus bulb, while minimizing invasiveness of the implant procedure. This device is currently CE marked in Europe, and in a Pivotal (akin to Phase III) Trial in the United States. Here we present the in vitro and in vivo safety testing that was completed in order to obtain necessary regulatory approval prior to conducting human studies in Europe, as well as an FDA Investigational Device Exemption (IDE) to conduct a Pivotal Trial in the United States. Stimulated electrodes (10 mA, 500 μs, 100 Hz) were compared to unstimulated electrodes using optical microscopy and several electrochemical techniques over the course of 27 weeks. Electrode dissolution was evaluated by analyzing trace metal content of solutions in which electrodes were stimulated. Lastly, safety testing under Good Laboratory Practice guidelines was conducted in an ovine animal model over a 12 and 24 week time period, with results processed and evaluated by an independent histopathologist. Long-term stimulation testing indicated that the neo electrode with a sputtered iridium oxide coating can be stimulated at maximal levels for the lifetime of the implant without clinically significant dissolution of platinum or iridium, and without increasing the potential at the electrode interface to cause hydrolysis or significant tissue damage. Histological examination of tissue that was adjacent to the neo electrodes indicated no clinically significant signs of increased inflammation and no arterial stenosis as a result of 6 months of continuous stimulation. The work presented here involved rigorous characterization and evaluation testing of the neo electrode, which was used to support its safety for chronic implantation. The testing strategies discussed provide a starting point and proven framework for testing new neuromodulation electrode concepts to support regulatory approval for clinical studies.

Highlights

Implantable electrodes that are intended to electrically activate the nervous system for therapeutic purposes—commonly referred to as neuromodulation devices, bioelectronic medicines, or electroceuticals (Famm et al, 2013; Birmingham et al, 2014; Reardon, 2014; Olofsson and Tracey, 2017)–are estimated to become between a 6 and 10 billion dollar industry by 2020 (2015; 2016)
The glove design enabled anchoring the fingers of the glove around branches
4.8% of patients received cranial nerve injuries with residual deficits as part of the surgical procedure associated with the dissection around the carotid sinus and implantation

Summary

Introduction

Implantable electrodes that are intended to electrically activate the nervous system for therapeutic purposes—commonly referred to as neuromodulation devices, bioelectronic medicines, or electroceuticals (Famm et al, 2013; Birmingham et al, 2014; Reardon, 2014; Olofsson and Tracey, 2017)–are estimated to become between a 6 and 10 billion dollar industry by 2020 (2015; 2016). A detailed example of a testing strategy to ensure electrical stimulation safety that has led to an FDA IDE and/or approval to conduct human studies through a European notified body would provide a critical frame of reference for the Pre-Submission process. In this manuscript, we describe the stimulation safety testing strategy successfully used to receive CE mark and FDA IDE approval for the second generation baroreflex activation therapy (BAT)TM system. There are only data suggesting that extensive foreign body reaction to the implant could cause a decrease in clinical utility of the implant, subjecting the patients to the surgical risk of the implant without providing as much benefit (Nadol et al, 2014)

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