PROJECT SUMMARY / ABSTRACT Stroke affects over 7.5 million patients in the U.S, with an estimated 795,000 additional cases of stroke occurring each year. Over 30% of stroke survivors have spasticity, a disorder of muscle tone that can cause striking impairments in functional movement. Pharmacological, surgical and physical treatments to manage spasticity have, at best, short-term efficacy and are confounded by side effects. In this NINDS CREATE Device project, we propose translational activities that will advance through multi-site Phase II clinical trials and regulatory submission a recently developed neuromodulation device that non-invasively treats spasticity using a novel approach that combines trans-spinal direct current stimulation (tsDCS) with simultaneous peripheral nerve stimulation. The implications of the current project are far-reaching changes in clinical practice for treating spasticity using an entirely novel approach based on non-invasive neuromodulation. PathMaker Neurosystems Inc. is a clinical-stage neuromodulation company developing a first-in-class treatment for treating stroke patients with spasticity. Our objective for this NINDS CREATE Device project is to carry out key translational activities that will be essential for advancing this technology through multi-site Phase II clinical trials and regulatory approval as a safe and efficacious new treatment for spasticity. The project consists of 5 Specific Aims: In Specific Aim 1, we will implement a GMP-compliant version of the device (MyoRegulator) for use in a Phase II pivotal clinical study in stroke. In Specific Aim 2, we will implement a compliant Quality Management System (QMS). In Specific Aim 3, we will complete preparations for a Phase II clinical study. In Specific Aim 4, we will complete a multi-site double-blind controlled human clinical study. In Specific Aim 5, we will submit De Novo 510(k) for regulatory approval for MyoRegulator. These Specific Aims will lay the essential groundwork allowing our novel, NIH-funded technology to move rapidly through human clinical trials and to regulatory approval. As our company works to translate the groundbreaking academic studies that have resulted in a novel approach to the treatment of spasticity, NINDS CREATE Device support will advance this breakthrough treatment towards the market and enable an entirely new treatment option for stroke patients with spasticity.