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Highlights This prospective study is one of the largest clinical trials in essential tremor to date. Study findings suggest that individualized non-invasive neuromodulation therapy used repeatedly at home over three months results in safe and effective hand tremor reduction and improves quality of life for many essential tremor patients. Background: Two previous randomized, controlled, single-session trials demonstrated efficacy of non-invasive neuromodulation therapy targeting the median and radial nerves for reducing hand tremor. This current study evaluated efficacy and safety of the therapy over three months of repeated home use. Methods: This was a prospective, open-label, post-clearance, single-arm study with 263 patients enrolled across 26 sites. Patients were instructed to use the therapy twice daily for three months. Pre-specified co-primary endpoints were improvements on clinician-rated Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS) and patient-rated Bain & Findley Activities of Daily Living (BF-ADL) dominant hand scores. Other endpoints included improvement in the tremor power detected by an accelerometer on the therapeutic device, Clinical and Patient Global Impression scores (CGI-I, PGI-I), and Quality of Life in Essential Tremor (QUEST) survey. Results: 205 patients completed the study. The co-primary endpoints were met (p≪0.0001), with 62% (TET-RAS) and 68% (BF-ADL) of 'severe' or 'moderate' patients improving to 'mild' or 'slight'. Clinicians (CGI-I) reported improvement in 68% of patients, 60% (PGI-I) of patients reported improvement, and QUEST improved (p = 0.0019). Wrist-worn accelerometer recordings before and after 21,806 therapy sessions showed that 92% of patients improved, and 54% of patients experienced ≥50% improvement in tremor power. Device-related adverse events (e.g., wrist discomfort, skin irritation, pain) occurred in 18% of patients. No device-related serious adverse events were reported. Discussion: This study suggests that non-invasive neuromodulation therapy used repeatedly at home over three months results in safe and effective hand tremor reduction in many essential tremor patients.

Objective: To assess the antipsychotic efficacy and safety of a combination of olanzapine and samidorphan (OLZ/SAM). Methods: This 4-week, phase 3, randomized, double-blind, placeboand olanzapine-controlled study was conducted from December 2015 to June 2017 in adults with schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria who were experiencing an acute exacerbation. Patients were randomized 1:1:1 to OLZ/SAM, olanzapine monotherapy, or placebo. The primary and key secondary efficacy endpoint assessed was the change in Positive and Negative Syndrome Scale (PANSS) total score and Clinical Global Impressions-Severity of Illness Scale (CGI-S) score between baseline and week 4, respectively, for OLZ/SAM versus placebo. Safety monitoring occurred throughout. Results: 401 patients received ≥ 1 dose of study drug; 352 completed treatment. Treatment with OLZ/SAM resulted in significant improvements versus placebo in PANSS total and CGI-S scores from baseline to week 4 (least squares [LS] mean ± SE: −6.4 ± 1.8 [P < .001] and −0.38 ± 0.12 [P = .002], respectively). Olanzapine treatment resulted in similar improvements (PANSS and CGI-S LS mean ± SE of −5.3 ± 1.84 [P = .004] and −0.44 ± 0.12 [P < .001], respectively). Adverse events (AEs) occurred in 54.5%, 54.9%, and 44.8% of patients on OLZ/SAM, olanzapine, and placebo, respectively. Weight gain, somnolence, dry mouth, anxiety, and headache were the most common AEs (ie, ≥ 5%) with active treatment. Conclusions: OLZ/SAM treatment resulted in statistically and clinically significant efficacy improvements over 4 weeks versus placebo in adults with acutely exacerbated schizophrenia. Improvements were similar to those observed with olanzapine. OLZ/SAM was well tolerated, with a safety profile similar to that of olanzapine.