The Combination of Aroxybutynin and Atomoxetine in the Treatment of Obstructive Sleep Apnea (MARIPOSA): A Randomized Controlled Trial.

Rationale: Obstructive sleep apnea (OSA) is a common sleep disorder for which the principal treatment option, continuous positive airway pressure, is often poorly tolerated. There is currently no approved pharmacotherapy for OSA. However, recent studies have demonstrated improvement in OSA with combined antimuscarinic and noradrenergic drugs. Objectives: The aim of this study was to evaluate the efficacy and safety of AD109, a combination of the novel antimuscarinic agent aroxybutynin and the norepinephrine reuptake inhibitor atomoxetine, in the treatment of OSA. Methods: Phase II randomized, double-blind, placebo-controlled, parallel-group, 4-week trial comparing AD109 2.5/75 mg, AD109 5/75 mg, atomoxetine 75 mg alone, and placebo (www.clinicaltrials.gov identifier NCT05071612). Measurements and Main Results: Of 211 randomized patients, 181 were included in the prespecified efficacy analyses. Sleep was assessed by two baseline and two treatment polysomnograms. Apnea-hypopnea index with a 4% desaturation criterion (primary outcome) was reduced from a median (IQR) of 20.5 (12.3-27.2) to 10.8 (5.6-18.5) in the AD109 2.5/75 mg arm (-47.1%), from 19.4 (13.7-26.4) to 9.5 (6.1-19.3) in the AD109 5/75 mg arm (-42.9%; both P < 0.0001 vs. placebo), and from 19.0 (11.8-28.8) to 11.8 (5.5-21.5) with atomoxetine alone (-38.8%; P < 0.01 vs. placebo). Apnea-hypopnea index with a 4% desaturation criterion decreased from 20.1 (11.9-25.9) to 16.3 (11.1-28.9) in the placebo arm. Subjectively, there was improvement in fatigue with AD109 2.5/75 mg (P < 0.05 vs. placebo and atomoxetine). Atomoxetine taken alone decreased total sleep time (P < 0.05 vs. AD109 and placebo). The most common adverse events were dry mouth, insomnia, and urinary hesitancy. Conclusions: AD109 showed clinically meaningful improvement in OSA, suggesting that further development of the compound is warranted. Clinical trial registered with www.clinicaltrials.gov (NCT05071612).

Efficacy of atomoxetine plus oxybutynin in the treatment of obstructive sleep apnea with moderate pharyngeal collapsibility.

PURPOSE: Preliminary studies have shown a significant decrease in severity of obstructive sleep apnea (OSA) with the use of a combination of atomoxetine and oxybutynin, with patients having moderate pharyngeal collapsibility during sleep more likely to respond. This study evaluated the efficacy and safety of AD036 (atomoxetine 80 mg and oxybutynin 5 mg) in the treatment of OSA. METHODS: This trial was a phase 2, randomized, placebo-controlled crossover study comparing AD036, atomoxetine 80 mg alone, and placebo during three home sleep studies, each separated by about 1 week. The trial included patients with OSA and moderate pharyngeal collapsibility as defined by a higher proportion of hypopneas to apneas and mild oxygen desaturation. RESULTS: Of 62 patients who were randomized, 60 were included in efficacy analyses. The apnea-hypopnea index (AHI) from a median (interquartile range) of 14.2 (5.4 to 22.3) events/h on placebo to 6.2 (2.8 to 13.6) with AD036 and 4.8 (1.4 to 11.6) with atomoxetine alone (p < .0001). Both drugs also decreased the oxygen desaturation index (ODI) and the hypoxic burden (p < .0001). AD036, but not atomoxetine alone, reduced the respiratory arousal index and improved ventilation at the respiratory arousal threshold (greater Vactive). There was a trend for total sleep time to be decreased more with atomoxetine alone than with AD036. The most common adverse event was insomnia (12% with AD036, 18% with atomoxetine). CONCLUSION: AD036 significantly improved OSA severity in patients with moderate pharyngeal collapsibility. Atomoxetine may account for the majority of improvement in OSA severity, while the addition of oxybutynin may mitigate the disruptive effect of atomoxetine on sleep and further improve ventilation. TRIAL REGISTRATION: Clinical trial registered with www. CLINICALTRIALS: gov (NCT04445688).

Proteomic Biomarkers of the Apnea Hypopnea Index and Obstructive Sleep Apnea: Insights into the Pathophysiology of Presence, Severity, and Treatment Response.

Obstructive sleep apnea (OSA), a disease associated with excessive sleepiness and increased cardiovascular risk, affects an estimated 1 billion people worldwide. The present study examined proteomic biomarkers indicative of presence, severity, and treatment response in OSA. Participants (n = 1391) of the Stanford Technology Analytics and Genomics in Sleep study had blood collected and completed an overnight polysomnography for scoring the apnea−hypopnea index (AHI). A highly multiplexed aptamer-based array (SomaScan) was used to quantify 5000 proteins in all plasma samples. Two separate intervention-based cohorts with sleep apnea (n = 41) provided samples pre- and post-continuous/positive airway pressure (CPAP/PAP). Multivariate analyses identified 84 proteins (47 positively, 37 negatively) associated with AHI after correction for multiple testing. Of the top 15 features from a machine learning classifier for AHI ≥ 15 vs. AHI < 15 (Area Under the Curve (AUC) = 0.74), 8 were significant markers of both AHI and OSA from multivariate analyses. Exploration of pre- and post-intervention analysis identified 5 of the 84 proteins to be significantly decreased following CPAP/PAP treatment, with pathways involving endothelial function, blood coagulation, and inflammatory response. The present study identified PAI-1, tPA, and sE-Selectin as key biomarkers and suggests that endothelial dysfunction and increased coagulopathy are important consequences of OSA, which may explain the association with cardiovascular disease and stroke.

Solriamfetol for Excessive Daytime Sleepiness in Parkinson's Disease: Phase 2 Proof-of-Concept Trial.

BACKGROUND: Solriamfetol is approved (US and EU) for excessive daytime sleepiness (EDS) in narcolepsy and obstructive sleep apnea. OBJECTIVES: Evaluate solriamfetol safety/efficacy for EDS in Parkinson's disease (PD). METHODS: Phase 2, double-blind, 4-week, crossover trial: adults with PD and EDS were randomized to sequence A (placebo, solriamfetol 75, 150, 300 mg/d), B (solriamfetol 75, 150, 300 mg/d, placebo), or C (placebo). Outcomes (safety/tolerability [primary]; Epworth Sleepiness Scale [ESS]; Maintenance of Wakefulness Test [MWT]) were assessed weekly. P values are nominal. RESULTS: Common adverse events (n = 66): nausea (10.7%), dizziness (7.1%), dry mouth (7.1%), headache (7.1%), anxiety (5.4%), constipation (5.4%), dyspepsia (5.4%). ESS decreased both placebo (-4.78) and solriamfetol (-4.82 to -5.72; P > 0.05). MWT improved dose-dependently with solriamfetol, increasing by 5.05 minutes with 300 mg relative to placebo (P = 0.0098). CONCLUSIONS: Safety/tolerability was consistent with solriamfetol's known profile. There were no significant improvements on ESS; MWT results suggest possible benefit with solriamfetol in PD. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Solriamfetol for Excessive Sleepiness in Obstructive Sleep Apnea (TONES 3). A Randomized Controlled Trial.

Rationale: Primary treatment of obstructive sleep apnea can be accompanied by a persistence of excessive sleepiness despite adherence. Furthermore, effectiveness of sleep apnea treatment is limited by poor adherence. Currently available pharmacologic options for the treatment of sleepiness in this population are limited. Objectives: To evaluate the efficacy and safety of solriamfetol (JZP-110), a selective dopamine and norepinephrine reuptake inhibitor with robust wake-promoting effects, for the treatment of excessive sleepiness in participants with obstructive sleep apnea with current or prior sleep apnea treatment. Methods: This was a double-blind, randomized, placebo-controlled, parallel-group, 12-week trial comparing solriamfetol, 37.5, 75, 150, and 300 mg, with placebo. Measurements and Main Results: Of 476 randomized participants, 459 were included in the prespecified efficacy analyses. Coprimary endpoints (Maintenance of Wakefulness Test sleep latency and Epworth Sleepiness Scale score) were met at all solriamfetol doses (P < 0.05), with dose-dependent effects observed at Week 1 maintained over the study duration. All doses except 37.5 mg resulted in higher percentages of participants reporting improvement on Patient Global Impression of Change (key secondary endpoint; P < 0.05). Adverse events were reported in 47.9% of placebo- and 67.9% of solriamfetol-treated participants; five participants experienced serious adverse events (two [1.7%] placebo, three [0.8%] solriamfetol); none were deemed related to study drug. The most common adverse events with solriamfetol were headache (10.1%), nausea (7.9%), decreased appetite (7.6%), anxiety (7.0%), and nasopharyngitis (5.1%). Conclusions: Solriamfetol significantly increased wakefulness and reduced sleepiness in participants with obstructive sleep apnea and excessive sleepiness; most adverse events were mild or moderate in severity. Clinical trial registered with www.clinicaltrials.gov (NCT02348606) and www.eudract.ema.europa.eu (EudraCT 2014-005514-31).

Proteomic insights into the pathophysiology of periodic limb movements and restless legs syndrome.

OBJECTIVES: We used a high-throughput assay of 5000 plasma proteins to identify biomarkers associated with periodic limb movements (PLM) and restless legs syndrome (RLS) in adults. METHODS: Participants (n = 1410) of the Stanford Technology Analytics and Genomics in Sleep (STAGES) study had blood collected, completed a sleep questionnaire, and underwent overnight polysomnography with the scoring of PLMs. An aptamer-based array (SomaScan) was used to quantify 5000 proteins in plasma. A second cohort (n = 697) that had serum assayed using a previous iteration of SomaScan (1300 proteins) was used for replication and in a combined analysis (n = 2107). A 5% false discovery rate was used to assess significance. RESULTS: Multivariate analyses in STAGES identified 68 proteins associated with the PLM index after correction for multiple testing (ie, base model). Most significantly decreased proteins were iron-related and included Hepcidin (LEAP-1), Ferritin, and Ferritin light chain. Most significantly increased proteins included RANTES, Cathepsin A, and SULT 1A3. Of 68 proteins significant in the base model, 17 were present in the 1300 panel, and 15 of 17 were replicated. The most significant proteins in the combined model were Hepcidin (LEAP-1), Cathepsin A, Ferritin, and RANTES. Exploration of proteins in RLS versus non-RLS identified Cathepsin Z, Heme oxygenase 2 (HO-2), Interleukin-17A (upregulated in the combined cohort), and Megalin (upregulated in STAGES only) although results were less significant than for proteins associated with PLM index. CONCLUSIONS: These results confirm the association of PLM with low iron status and suggest the involvement of catabolic enzymes in PLM/RLS.

Incidence and duration of common early-onset adverse events in randomized controlled trials of solriamfetol for treatment of excessive daytime sleepiness in obstructive sleep apnea and narcolepsy.

STUDY OBJECTIVES: This post hoc analysis characterized the weekly incidence and overall duration of common early-onset, treatment-emergent adverse events (TEAEs) during solriamfetol treatment. METHODS: Participants (obstructive sleep apnea [OSA], n = 474; narcolepsy, n = 236) were randomized to 12 weeks of placebo or solriamfetol 37.5 (OSA only), 75, 150, or 300 mg. For common early-onset TEAEs (those occurring in ≥ 5% of participants in any solriamfetol dose group and with a higher incidence than that observed in placebo-treated participants during week 1), the incidence of new occurrence or change in severity over time was calculated for each subsequent study week. Data were analyzed separately for each study and summarized by placebo and combined solriamfetol groups. RESULTS: Common early-onset TEAEs (at doses ≤ 150 mg; ie, approved doses) included headache (OSA, 5.1%; narcolepsy, 8.5%), nausea (OSA, 2.5%; narcolepsy, 4.2%), decreased appetite (OSA, 4.2%; narcolepsy, 5.9%), as well as anxiety (2.1%), insomnia (1.3%), and feeling jittery (3.0%) in OSA and dry mouth (4.2%) in narcolepsy. Incidence of common early-onset TEAEs was highest at week 1 and decreased over time. In OSA at doses ≤ 150 mg, headache, nausea, and feeling jittery had median durations ≤ 8 days, whereas decreased appetite, anxiety, and insomnia had longer durations. In narcolepsy at doses ≤ 150 mg, headache and nausea had median durations ≤ 8 days, whereas decreased appetite and dry mouth had longer durations. Most TEAEs were mild to moderate in severity. CONCLUSIONS: Common early-onset TEAEs with solriamfetol are limited in duration, with the majority subsiding during the first week of treatment. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Twelve-week Study of the Safety and Efficacy of JZP-110 in the Treatment of Excessive Sleepiness in Narcolepsy; URL: https://clinicaltrials.gov/ct2/show/NCT02348593; Identifier: NCT02348593; and Name: Twelve-week Study of the Safety and Efficacy of JZP-110 in the Treatment of Excessive Sleepiness in OSA; URL: https://clinicaltrials.gov/ct2/show/NCT02348606; Identifier: NCT02348606. CITATION: Rosenberg R, Thorpy MJ, Dauvilliers Y, et al. Incidence and duration of common early-onset adverse events in randomized controlled trials of solriamfetol for treatment of excessive daytime sleepiness in obstructive sleep apnea and narcolepsy. J Clin Sleep Med. 2022;18(1):235-244.

Solriamfetol treatment of excessive daytime sleepiness in participants with narcolepsy or obstructive sleep apnea with a history of depression.

Given the high rate of depression associated with narcolepsy or obstructive sleep apnea (OSA), this analysis compared effects of solriamfetol treatment of excessive daytime sleepiness (EDS) in participants with/without a history of depression (DHx+/DHx-). This secondary analysis included data from two randomized, controlled trials in which participants were randomized to 12 weeks placebo or solriamfetol 37.5 (OSA only), 75, 150, or 300 mg/day. Efficacy/safety (combined solriamfetol doses) was summarized for DHx+/DHx-subgroups. 27.5% (65/236) with narcolepsy and 23.4% (111/474) with OSA were DHx+. In narcolepsy (DHx+ and DHx-), 40-min Maintenance of Wakefulness Test (MWT40) mean sleep latency increased (5.4 and 7.0 min), Epworth Sleepiness Scale (ESS) score decreased (3.8 and 3.5 points), and percentage of participants improved on Patient Global Impression of Change (PGI-C) was higher (31.7% and 39.4%) relative to placebo. In OSA (DHx+ and DHx-), MWT40 mean sleep latency increased (7.7 and 10.7 min), ESS decreased (3.5 and 3.7 points), and percentage of participants improved on PGI-C was higher (41.1% and 29.4%) relative to placebo. Common treatment-emergent adverse events (headache, decreased appetite, nausea, anxiety) were similar in DHx+/DHx-. This study suggests that safety and efficacy of solriamfetol for treating EDS in narcolepsy and OSA are not affected by depression history. Moreover, the findings emphasize the high prevalence of depression in people with sleep disorders and suggest that increased awareness of this association may have clinical significance.

Residual excessive daytime sleepiness in patients treated for obstructive sleep apnea: guidance for assessment, diagnosis, and management.

Excessive daytime sleepiness (EDS) affects approximately half of patients with obstructive sleep apnea (OSA) and can persist in some despite normalization of breathing, oxygenation, and sleep quality with primary OSA therapy, such as continuous positive airway pressure (CPAP). EDS is often overlooked and under discussed in the primary care setting and in the follow-up of CPAP-treated patients due to difficult assessment of such a multi-dimensional symptom. This review aims to provide suggestions for procedures that can be implemented into routine clinical practice to identify, evaluate, and manage EDS in patients treated for OSA, including how to appropriately use various self-report and objective assessments along the clinical pathway and options for pharmacotherapy. In addition, examples of when it is appropriate to refer a patient to a sleep specialist for evaluation are discussed.

Randomized Controlled Trial of Solriamfetol for Excessive Daytime Sleepiness in OSA: An Analysis of Subgroups Adherent or Nonadherent to OSA Treatment.

BACKGROUND: Solriamfetol, a dopamine-norepinephrine reuptake inhibitor, is approved in the United States to improve wakefulness in adults with excessive daytime sleepiness (EDS) associated with OSA (37.5-150 mg/d). RESEARCH QUESTION: Does solriamfetol have differential effects on EDS based on adherence to primary OSA therapy and does solriamfetol affect primary OSA therapy use? STUDY DESIGN AND METHODS: Participants were randomized to 12 weeks of placebo or solriamfetol 37.5, 75, 150, or 300 mg/d (stratified by primary OSA therapy adherence). Coprimary end points were week 12 change from baseline in 40-min Maintenance of Wakefulness Test (MWT) and Epworth Sleepiness Scale (ESS) in the modified intention-to-treat population. Primary OSA therapy use (hours per night, % nights) and safety were evaluated. RESULTS: At baseline, 324 participants (70.6%) adhered to OSA therapy (positive airway pressure use ≥ 4 h/night on ≥ 70% nights, surgical intervention, or oral appliance use on ≥ 70% nights) and 135 participants (29.4%) did not adhere. Least squares (LS) mean differences from placebo in MWT sleep latency (minutes) in the 37.5-, 75-, 150-, and 300-mg/d groups among adherent participants were 4.8 (95% CI, 0.6-9.0), 8.4 (95% CI, 4.3-12.5), 10.2 (95% CI, 6.8-13.6), and 12.5 (95% CI, 9.0-15.9) and among nonadherent participants were 3.7 (95% CI, -2.0 to 9.4), 9.9 (95% CI, 4.4-15.4), 11.9 (95% CI, 7.5-16.3), and 13.5 (95% CI, 8.8-18.3). On ESS, LS mean differences from placebo in the 37.5-, 75-, 150-, and 300-mg/d groups among adherent participants were -2.4 (95% CI, -4.2 to -0.5), -1.3 (95% CI, -3.1 to 0.5), -4.2 (95% CI, -5.7 to -2.7), and -4.7 (95% CI, -6.1 to -3.2) and among nonadherent participants were -0.7 (95% CI, -3.5 to 2.1), -2.6 (95% CI, -5.4 to 0.1), -5.0 (95% CI, -7.2 to -2.9), and -4.6 (95% CI, -7.0 to -2.3). Common adverse events included headache, nausea, anxiety, decreased appetite, nasopharyngitis, and diarrhea. No clinically meaningful changes were seen in primary OSA therapy use with solriamfetol. INTERPRETATION: Solriamfetol improved EDS in OSA regardless of primary OSA therapy adherence. Primary OSA therapy use was unaffected with solriamfetol. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02348606; URL: www.clinicaltrials.gov; EU Clinical Trials Register; No.: EudraCT2014-005514-31; URL: www.clinicaltrialsregister.eu.

Effects of solriamfetol in a long-term trial of participants with obstructive sleep apnea who are adherent or nonadherent to airway therapy.

STUDY OBJECTIVES: Solriamfetol, a dopamine/norepinephrine reuptake inhibitor, is approved in the United States and European Union to treat excessive daytime sleepiness in patients with obstructive sleep apnea (OSA) (37.5-150 mg/day) and narcolepsy (75-150 mg/day). This analysis evaluated solriamfetol's efficacy in subgroups of participants with OSA who were adherent or nonadherent to primary OSA therapy at baseline and examined whether solriamfetol affected the use of primary therapy in an open-label extension trial. METHODS: Participants with OSA who completed prior solriamfetol studies received solriamfetol 75, 150, or 300 mg/day for ≤ 52 weeks. The main efficacy outcome was the Epworth Sleepiness Scale score. Primary therapy use was summarized as the percentage of nights, the number of hours/night, and the percentage of nights with use ≥ 50%/night (%). Efficacy and primary therapy use are reported for participants who directly enrolled from a previous 12-week study and had ≤ 40 weeks of open-label treatment (n = 333). Safety data are reported for all participants (n = 417). RESULTS: Mean ESS scores in adherent (n = 255) and nonadherent (n = 78) subgroups, respectively, were 15.0 and 15.8 at baseline (of 12-week study) and 6.5 and 6.8 at week 40. For participants using an airway therapy, mean use at baseline was 90% of nights, 6.6 hours/night, and use ≥ 50%/night on 90% of nights; changes from baseline to week 40 were minimal (0.9%, -0.8 hours, and 6.5%, respectively). Common adverse events (both subgroups) included headache, nasopharyngitis, insomnia, dry mouth, nausea, anxiety, and upper respiratory tract infection. CONCLUSIONS: Long-term efficacy and safety of solriamfetol were similar regardless of adherence to primary OSA therapy. Solriamfetol did not affect primary therapy use. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: A Long-Term Safety Study of JZP-110 in the Treatment of Excessive Sleepiness in Subjects with Narcolepsy or OSA; URL: https://clinicaltrials.gov/ct2/show/NCT02348632; Identifier: NCT02348632 and Registry: EU Clinical Trials Register; Identifier: 2014-005489-31; URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2014-005489-31..

Enhancing slow wave sleep with sodium oxybate reduces the behavioral and physiological impact of sleep loss.

STUDY OBJECTIVES: To investigate whether enhancement of slow wave sleep (SWS) with sodium oxybate reduces the impact of sleep deprivation. DESIGN: Double-blind, parallel group, placebo-controlled design SETTING: Sleep research laboratory PARTICIPANTS: Fifty-eight healthy adults (28 placebo, 30 sodium oxybate), ages 18-50 years. INTERVENTIONS: A 5-day protocol included 2 screening/baseline nights and days, 2 sleep deprivation nights, each followed by a 3-h daytime (08:00-11:00) sleep opportunity and a recovery night. Sodium oxybate or placebo was administered prior to each daytime sleep period. Multiple sleep latency test (MSLT), psychomotor vigilance test (PVT), Karolinska Sleepiness Scale (KSS), and Profile of Mood States were administered during waking hours. MEASUREMENTS AND RESULTS: During daytime sleep, the sodium oxybate group had more SWS, more EEG spectral power in the 1-9 Hz range, and less REM. Mean MSLT latency was longer for the sodium oxybate group on the night following the first daytime sleep period and on the day following the second day sleep period. Median PVT reaction time was faster in the sodium oxybate group following the second day sleep period. The change from baseline in SWS was positively correlated with the change in MSLT and KSS. During recovery sleep the sodium oxybate group had less TST, SWS, REM, and slow wave activity (SWA) than the placebo group. CONCLUSIONS: Pharmacological enhancement of SWS with sodium oxybate resulted in a reduced response to sleep loss on measures of alertness and attention. In addition, SWS enhancement during sleep restriction appears to result in a reduced homeostatic response to sleep loss.

Comparing two measures of sleep depth/intensity.

STUDY OBJECTIVES: To compare delta spectral power (delta) and odds ratio product (ORP) as measures of sleep depth during sleep restriction with placebo or a drug that increases delta. METHODS: This is a secondary analysis of data from a study of 41 healthy participants randomized to receive placebo or gaboxadol 15 mg during sleep restriction. Participants underwent in-laboratory sleep studies on two baseline, four sleep restriction (5-h), and two recovery nights. Relation between delta or ORP and sleep depth was operationally defined as the degree of association of each metric to the probability of arousal or awakening occurring during the next 30 s (arousability). RESULTS: ORP values in wake, N1, N2, N3, and REM were significantly different. Delta differed between both N2 and N3 and other sleep stages but not between wake and N1 or N1 and REM. Epoch-by-epoch and individual correlations between ORP and delta power were modest or insignificant. The relation between ORP and arousability was linear across the entire ORP range. Delta also changed with arousability but only when delta values were less than 300 µV2. Receiver-operating-characteristic analysis found the ability to predict imminent arousal to be significantly greater with ORP than with log delta power for all experimental conditions. Changes in ORP, but not log delta, across the night correlated with next-day physiologic sleep tendency. CONCLUSIONS: Compared to delta power, ORP is more discriminating among sleep stages, more sensitive to sleep restriction, and more closely associated with arousability. This evidence supports ORP as a measure of sleep depth/intensity.

NightBalance Sleep Position Treatment Device Versus Auto-Adjusting Positive Airway Pressure for Treatment of Positional Obstructive Sleep Apnea.

STUDY OBJECTIVES: Compare treatment efficacy and objective adherence between the NightBalance sleep position treatment (SPT) device and auto-adjusting positive airway pressure (APAP) in patients with exclusive positional obstructive sleep apnea (ePOSA) defined as a supine apnea-hypopnea index (sAHI) ≥ 2 times the nonsupine AHI (nsAHI) and a nsAHI < 10 events/h. METHODS: This prospective multicenter randomized crossover trial enrolled treatment naive participants with ePOSA (AHI ≥ 15 events/h and nsAHI < 10 events/h) or (AHI > 10 and < 15 events/h with daytime sleepiness and nsAH < 5 events/h). Polysomnography and objective adherence determination (device data) were performed at the end of each 6-week treatment. Patient device preference was determined at the end of the study. RESULTS: A total of 117 participants were randomized (58 SPT first, 59 APAP first). Of these, 112 started treatment with the second device (adherence cohort) and 110 completed the study (AHI cohort). The AHI on SPT was higher (mean ± standard deviation, 7.29 ± 6.8 versus 3.71 ± 5.1 events/h, P < .001). The mean AHI difference (SPT-APAP) was 3.58 events/h with a one sided 95% confidence interval upper bound of 4.96 events/h (< the prestudy noninferiority margin of 5 events/h). The average nightly adherence (all nights) was greater on SPT (345.3 ± 111.22 versus 286.98 ± 128.9 minutes, P < .0001). Participants found the SPT to be more comfortable and easier to use and 53% reported a preference for SPT assuming both devices were equally effective. CONCLUSIONS: Treatment with SPT resulted in non-inferior treatment efficacy and greater adherence compared to APAP in ePOSA suggesting that SPT is an effective treatment for this group. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Title: The POSAtive Study: Study for the Treatment of Positional Obstructive Sleep Apnea; Identifier: NCT03061071; URL: https://clinicaltrials.gov/ct2/show/NCT03061071.

Slow wave sleep enhancement with gaboxadol reduces daytime sleepiness during sleep restriction.

STUDY OBJECTIVES: To evaluate the impact of enhanced slow wave sleep (SWS) on behavioral, psychological, and physiological changes resulting from sleep restriction. DESIGN: A double-blind, parallel group, placebo-controlled design was used to compare gaboxadol (GBX) 15 mg, a SWS-enhancing drug, to placebo during 4 nights of sleep restriction (5 h/night). Behavioral, psychological, and physiological measures of the impact of sleep restriction were assessed in both groups at baseline, during sleep restriction and following recovery sleep. SETTING: Sleep research laboratory. PARTICIPANTS: Forty-one healthy adults; 9 males and 12 females (mean age: 32.0 +/- 9.9 y) in the placebo group and 10 males and 10 females (mean age: 31.9 +/- 10.2 y) in the GBX group. INTERVENTIONS: Both experimental groups underwent 4 nights of sleep restriction. Each group received either GBX 15 mg or placebo on all sleep restriction nights, and both groups received placebo on baseline and recovery nights. MEASUREMENTS AND RESULTS: Polysomnography documented a SWS-enhancing effect of GBX with no group difference in total sleep time during sleep restriction. The placebo group displayed the predicted deficits due to sleep restriction on the multiple sleep latency test (MSLT) and on introspective measures of sleepiness and fatigue. Compared to placebo, the GBX group showed significantly less physiological sleepiness on the MSLT and lower levels of introspective sleepiness and fatigue during sleep restriction. There were no differences between groups on the psychomotor vigilance task (PVT) and a cognitive test battery, but these measures were minimally affected by sleep restriction in this study. The correlation between change from baseline in MSLT on Day 6 and change from baseline in SWS on Night 6 was significant in the GBX group and in both group combined. CONCLUSIONS: The results of this study are consistent with the hypothesis that enhanced SWS, in this study produced by GBX, reduces physiological sleep tendency and introspective sleepiness and fatigue which typically result from sleep restriction.

Neural network analysis of sleep stages enables efficient diagnosis of narcolepsy.

Analysis of sleep for the diagnosis of sleep disorders such as Type-1 Narcolepsy (T1N) currently requires visual inspection of polysomnography records by trained scoring technicians. Here, we used neural networks in approximately 3,000 normal and abnormal sleep recordings to automate sleep stage scoring, producing a hypnodensity graph-a probability distribution conveying more information than classical hypnograms. Accuracy of sleep stage scoring was validated in 70 subjects assessed by six scorers. The best model performed better than any individual scorer (87% versus consensus). It also reliably scores sleep down to 5 s instead of 30 s scoring epochs. A T1N marker based on unusual sleep stage overlaps achieved a specificity of 96% and a sensitivity of 91%, validated in independent datasets. Addition of HLA-DQB1*06:02 typing increased specificity to 99%. Our method can reduce time spent in sleep clinics and automates T1N diagnosis. It also opens the possibility of diagnosing T1N using home sleep studies.

Laboratory and field studies of naps and caffeine as practical countermeasures for sleep-wake problems associated with night work.

STUDY OBJECTIVES: To evaluate the effects of napping, caffeine, and napping plus caffeine on performance and alertness in both laboratory and field settings. DESIGN: (1) Laboratory Study: parallel-groups design with random assignment to 1 of 4 experimental conditions. (2) Field Study: crossover design. SETTING: Sleep laboratory and field settings. PARTICIPANTS: (1) Laboratory Study: 68 healthy individuals; (2) Field Study: 53 shiftworkers who worked nights or rotating shifts. INTERVENTIONS: (1) Laboratory Study: an evening nap opportunity before the first 2 of 4 consecutive simulated night shifts plus placebo taken all 4 nights, caffeine taken nightly, the combination of the nap and caffeine conditions, or placebo. (2) Field Study: an evening nap on the first 2 of 4 consecutive night shifts plus caffeine taken nightly versus placebo taken nightly without naps. MEASUREMENTS AND RESULTS: (1) Laboratory Study: Napping, caffeine, and their combination all improved alertness and performance as measured by Maintenance of Wakefulness Test and Psychomotor Vigilance Task, but the combination of napping and caffeine was best in improving alertness. (2) Field Study: Napping plus caffeine improved performance as measured by Psychomotor Vigilance Test and decreased subjective sleepiness in individuals working the night shift. CONCLUSIONS: Napping plus caffeine helps improve performance and alertness of night-shift workers.

Tiagabine is associated with sustained attention during sleep restriction: evidence for the value of slow-wave sleep enhancement?

STUDY OBJECTIVES: To evaluate the impact of enhanced slow-wave sleep (SWS) on behavioral, psychological, and physiologic changes resulting from sleep restriction DESIGN: A double-blind, parallel-group, placebo-controlled design was used to compare tiagabine, 8 mg, (a SWS-enhancing drug) to placebo during 4 nights of sleep restriction (time in bed = 5 hours per night). Behavioral, psychological, and physiologic measures of the impact of sleep restriction were compared between groups at baseline, during sleep restriction, and following recovery sleep. SETTING: Two sleep research laboratories. PARTICIPANTS: Thirty-eight healthy adults; 9 men and 10 women (mean age: 26.0 +/- 6.1 years) in the placebo group and 8 men and 11 women (mean age: 26.7 +/- 8.1 years) in the tiagabine 8 mg group INTERVENTIONS: Both experimental groups underwent 4 nights of sleep restriction. Each group received either tiagabine 8 mg or placebo on all sleep-restriction nights, and both groups received placebo on baseline and recovery nights. MEASUREMENTS AND RESULTS: Polysomnography documented a SWS-enhancing effect of tiagabine. The placebo group displayed the predicted deficits due to sleep restriction on the Psychomotor Vigilance Task and the Multiple Sleep Latency Test. Compared with placebo, the tiagabine group did not demonstrate impairment in sustained attention on the Psychomotor Vigilance Test, performed better on the Wisconsin Card Sorting Task, reported more restorative sleep, and had less of an increase in afternoon-evening salivary free cortisol. Multiple Sleep Latency Test, ratings of sleepiness, recovery sleep, and other measures did not differ between groups. CONCLUSIONS: To our knowledge these findings are the first to be consistent with the hypothesis that pharmacologic SWS enhancement reduces selective aspects of the behavioral, psychological, and physiologic impact of sleep restriction.

Tiagabine enhances slow wave sleep and sleep maintenance in primary insomnia.

BACKGROUND AND PURPOSE: To evaluate the effect of tiagabine on sleep and next-morning alertness and performance in adult patients with primary insomnia. PATIENTS AND METHODS: Patients with primary insomnia, as defined by Diagnostic and Statistical Manual of Mental Disorders--Fourth Edition (DSM-IV), received tiagabine 4, 8, 12, 16 mg, and placebo in a randomized, double-blind, five-period, Latin square, crossover study. Efficacy was assessed using polysomnographic and self-report techniques; residual effects were evaluated using the Digit Symbol Substitution Test (DSST) and the Rey Auditory Verbal Learning Test (RAVLT). RESULTS: Fifty-eight patients (40f, 18m; mean age 46.6+/-8.0 years) were randomized. Results showed a significant dose-dependent increase in slow wave sleep percentage with all tiagabine doses, a trend toward a dose-dependent increase in total sleep time, and no effect on latency to persistent sleep. Wake after sleep onset also decreased in a dose-dependent manner, with the 16-mg dose differing significantly from placebo. The tolerability profiles of tiagabine 4 and 8 mg were similar to placebo. The most common adverse events reported following tiagabine 12 and 16 mg were dizziness and nausea. Residual effects were only apparent at 12- and 16-mg doses. CONCLUSIONS: Tiagabine increased slow wave sleep and reduced wake after sleep onset in a dose-dependent manner. Tiagabine dosages up to 8 mg did not compromise next-morning alertness and psychomotor performance in adult patients with primary insomnia. Further investigation of tiagabine doses up to 8 mg is warranted.