Excessive sleepiness (ES), one of the main presenting symptoms of OSA, is estimated to persist in 12% to 65% of individuals receiving CPAP therapy. 1-4 The effect of ES on individuals with OSA includes functional impairment, reduced quality of life, and increased risk for occupational and motor vehicle accidents. 5-9 Solriamfetol (formerly known as JZP-110 and ADX-N05) is a selective dopamine and norepinephrine reuptake inhibitor with robust wake-promoting effects. Its mechanism of action differs from those of amphetamines, modafinil, and armodafinil. 10 Solriamfetol demonstrated significant efficacy relative to placebo for reducing ES and increasing wakefulness in clinical trials of narcolepsy. 11-13 Efficacy for ES in OSA also was demonstrated by solriamfetol in a 12-week randomized, controlled phase III study. 14 This phase III trial evaluated the maintenance of efficacy and safety of solriamfetol administered once daily compared with placebo for the treatment of ES in adults with OSA. Methods Study Design This was a clinical trial from the Treatment of OSA and Narcolepsy Excessive Sleepiness (TONES) phase III program, the TONES 4 study. This phase III, double-blind, placebo-controlled trial was performed from May 2015 to November 2016 in Finland, France, Germany, Sweden, and the United States. An enriched, randomized withdrawal design was used. The study was approved by the appropriate institutional review boards or independent ethics committees (e-Appendix 1) and was conducted in accordance with the amended Declaration of Helsinki; all participants provided written informed consent (ClinicalTrials. gov identifier NCT02348619; EudraCT number 2014-005515-16). FUNDING/SUPPORT: This study was supported by Jazz Pharmaceuticals. In 2014, Jazz Pharmaceuticals acquired a license to develop and commercialize solriamfetol from Aerial Biopharma. Jazz Pharmaceuticals has worldwide development, manufacturing, and commercialization rights to solriamfetol, excluding certain jurisdictions in Asia. SK Biopharmaceuticals, the discoverer of the compound (also known as SKL-N05), maintains rights in 12 Asian markets, including Korea, China and Japan. Editorial assistance in formatting, proofreading, copyediting, and fact-checking was provided by The Curry Rockefeller Group LLC. Jazz Pharmaceuticals provided funding to The Curry Rockefeller Group LLC for writing and editorial support. *Collaborators from the Tones 4 Study Investigators group are listed in the Acknowledgments.

Rationale: Excessive daytime sleepiness in patients with obstructive sleep apnea is associated with substantial burden of illness. Objectives: To assess treatment effects of solriamfetol, a dopamine/norepinephrine reuptake inhibitor, on daily functioning, health-related quality of life, and work productivity in participants with obstructive sleep apnea and excessive daytime sleepiness as additional outcomes in a 12-week phase 3 trial ( www.clinicaltrials.gov identifier NCT02348606). Methods: Participants ( N = 476) were randomized to solriamfetol 37.5, 75, 150, or 300 mg or to placebo. Outcome measures included the Functional Outcomes of Sleep Questionnaire short version, Work Productivity and Activity Impairment Questionnaire: Specific Health Problem, and 36-item Short Form Health Survey version 2. A mixed-effects model with repeated measures was used for comparisons with placebo. Results: Demographics, baseline disease characteristics, daily functioning, health-related quality of life, and work productivity were similar across groups. At Week 12, increased functioning and decreased impairment were observed with solriamfetol 150 and 300 mg (mean difference from placebo [95% confidence interval]) on the basis of Functional Outcomes of Sleep Questionnaire total score (1.22 [0.57 to 1.88] and 1.47 [0.80 to 2.13], respectively), overall work impairment (−11.67 [−19.66 to −3.69] and −11.75 [−19.93 to −3.57], respectively), activity impairment (−10.42 [−16.37 to −4.47] and −10.51 [−16.59 to −4.43], respectively), physical component summary (2.07 [0.42 to 3.72] and 1.91 [0.22 to 3.59], respectively), and mental component summary (150 mg only, 2.05 [0.14 to 3.96]). Common adverse events were headache, nausea, decreased appetite, and anxiety. Conclusions: Solriamfetol improved measures of functioning, quality of life, and work productivity in participants with obstructive sleep apnea and excessive daytime sleepiness. Safety was consistent with previous studies. Clinical trial registered with www.clinicaltrials.gov (NCT02348606).

Background: Increasingly, drug and device clinical trials are tracking activity levels and other quality of life indices as endpoints for therapeutic efficacy. Trials have traditionally required intermittent subject visits to the clinic that are artificial, activity-intensive, and infrequent, making trend and event detection between visits difficult. Thus, there is an unmet need for wearable sensors that produce clinical quality and medical grade physiological data from subjects in the home. The current study was designed to validate the BioStamp nPoint® system (MC10 Inc., Lexington, MA, USA), a new technology designed to meet this need. Objective: To evaluate the accuracy, performance, and ease of use of an end-to-end system called the BioStamp nPoint. The system consists of an investigator portal for design of trials and data review, conformal, low-profile, wearable biosensors that adhere to the skin, a companion technology for wireless data transfer to a proprietary cloud, and algorithms for analyzing physiological, biometric, and contextual data for clinical research. Methods: A prospective, nonrandomized clinical trial was conducted on 30 healthy adult volunteers over the course of two continuous days and nights. Supervised and unsupervised study activities enabled performance validation in clinical and remote (simulated “at home”) environments. System outputs for heart rate (HR), heart rate variability (HRV) (including root mean square of successive differences [RMSSD] and low frequency/high frequency ratio), activity classification during prescribed activities (lying, sitting, standing, walking, stationary biking, and sleep), step count during walking, posture characterization, and sleep metrics including onset/wake times, sleep duration, and respiration rate (RR) during sleep were evaluated. Outputs were compared to FDA-cleared comparator devices for HR, HRV, and RR and to ground truth investigator observations for activity and posture classifications, step count, and sleep events. Results: Thirty participants (77% male, 23% female; mean age 35.9 ± 10.1 years; mean BMI 28.1 ± 3.6) were enrolled in the study. The BioStamp nPoint system accurately measured HR and HRV (correlations: HR = 0.957, HRV RMSSD = 0.965, HRV ratio = 0.861) when compared to Actiheart^TM. The system accurately monitored RR (mean absolute error [MAE] = 1.3 breaths/min) during sleep when compared to a Capnostream35^TM end-tidal CO₂ monitor. When compared with investigator observations, the system correctly classified activities and posture (agreement = 98.7 and 92.9%, respectively), step count (MAE = 14.7, < 3% of actual steps during a 6-min walk), and sleep events (MAE: sleep onset = 6.8 min, wake = 11.5 min, sleep duration = 13.7 min) with high accuracy. Participants indicated “good” to “excellent” usability (average System Usability Scale score of 81.3) and preferred the BioStamp nPoint system over both the Actiheart (86%) and Capnostream (97%) devices. Conclusions: The present study validated the BioSt...

CEP-26401 is a novel orally active, brain-penetrant, high-affinity histamine H3 receptor (H3R) antagonist, with potential therapeutic utility in cognition enhancement. Two randomized, double-blind, placebo-controlled dose escalation studies with single (0.02 to 5 mg) or multiple administration (0.02 to 0.5 mg once daily) of CEP-26401 were conducted in healthy subjects. Plasma and urine samples were collected to investigate CEP-26401 pharmacokinetics. Pharmacodynamic endpoints included a subset of tasks from the Cambridge Neuropsychological Test Automated Battery (CANTAB) and nocturnal polysomnography. Population pharmacokinetic-pharmacodynamic modeling was conducted on one CANTAB and one polysomnography parameter of interest. CEP-26401 was slowly absorbed (median tmax range 3-6 hours) and the mean terminal elimination half-life ranged from 24-60 hours. Steady-state plasma concentrations were achieved within six days of dosing. CEP-26401 exhibits dose- and time-independent pharmacokinetics, and renal excretion is a major elimination pathway. CEP-26401 had a dose-dependent negative effect on sleep, with some positive effects on certain CANTAB cognitive parameters seen at lower concentrations. The derived three compartment population pharmacokinetic model, with first-order absorption and elimination, accurately described the available pharmacokinetic data. CEP-26401 was generally well tolerated up to 0.5 mg/day with most common treatment related adverse events being headache and insomnia. Further clinical studies are required to establish the potential of low-dose CEP-26401 in cognition enhancement.

No abstract