bluuebunny/crossref_metadata_2025_split huggingface dataset:
0453 Lemborexant Exposure Is Independent of Race
Authors: Rawal Sumit , Landry Ishani , Lalovic Bojan , Nakai Kenya , Kubota Naoki , Moline Margaret 
Published: May 2022

Abstract

Introduction
Some hypnotic treatments for insomnia require dosing consideration due to exposure differences based on patient characteristics. Lemborexant (LEM) is a dual orexin receptor antagonist approved in multiple countries for the treatment of adult insomnia. LEM is not associated with exposure differences based on sex, age, or BMI that impact dosing. The potential impact of race on exposure was determined in two stand-alone pharmacokinetic (PK) studies and by modeling data from studies comprising the LEM clinical development program, which included healthy subjects and insomnia patients.

Methods
Study 003 (NCT02039089) was a single-center, multiple-dose, randomized, double-blind, placebo-controlled, parallel-group study in healthy Japanese and White subjects. Study 014 (NCT04555733) was a phase 1, single center, open-label, single and multiple oral dose study in healthy Chinese subjects. Additionally, effect of race on LEM exposure was independently examined as part of a population PK analysis incorporating LEM data from 9 Phase 1 studies (n=407), and Studies 201 (NCT01995838; n=235), 303 (NCT02952820; n=726) and 304 (NCT02783729; n=524) (Lalovic et al., 2020). Plasma concentrations of LEM were quantified from plasma by validated liquid chromatography with tandem mass spectrometry. Adverse events (AE) were recorded.

Results
Exposure of LEM increased in an approximately dose-proportional manner across the dose range (2.5 mg to 25 mg) in studies 003 and 014. There were no significant exposure differences between Japanese and White subjects following single LEM10 administration on Day 1 in Study 003 (maximum concentration [Cmax] mean[SD], ng/mL: Japanese, 46.5[25.8]; White, 47.3[28.1]; area under the curve from time zero to 24h [AUC0-24] mean[SD], ng·h/mL: Japanese, 231[40.2]; White, 208[83.4]) or when comparing PK data from Chinese subjects in Study 014 following single dose administration on Day 1 (Cmax mean[SD], ng/mL: LEM5, 29.8[12.8]; LEM10, 56.2[16.9]; LEM25, 116[46.8]; AUC0-24 mean[SD], ng·h/mL: LEM5, 106[29.9]; LEM10, 205[35.6]; LEM25, 549[116]) to Japanese and White subjects in Study 003. These results are supported by the cross-study, population PK model-based analysis, indicating no significant clinical or statistical differences in LEM PK attributable to the intrinsic factor race.

Conclusion
LEM exposure is not significantly affected by race. Therefore, dosing of LEM can be consistent across patient populations from different racial groups.

Support (If Any)
Eisai Inc.
0454 Response to Lemborexant in Older Subjects with Insomnia Disorder and Comorbid Pain at Baseline
Authors: Kaplan Alan , Cheng Jocelyn , Suzuki Masahiro , Kumar Dinesh , Malhotra Manoj , Moline Margaret , Pappadopulos Elizabeth 
Published: May 2022

Abstract

Introduction
The reciprocal relationship between pain and poor sleep has been well established. Pain interferes with sleep, and insomnia increases pain sensitivity, thus reducing quality of life. Therefore, it is of clinical importance to evaluate whether a sleep-promoting drug such as the dual orexin receptor antagonist, lemborexant (LEM; approved in multiple countries to treat adults with insomnia) can improve sleep in older patients, in whom both sleep and ongoing pain are prevalent.

Methods
Study 304 (NCT02783729), was a 1-month, double-blind, PBO- and active-controlled study in subjects age ≥55y with insomnia (full analysis set [FAS]=1006). Those who also endorsed some/severe pain at baseline on the pain/discomfort dimension of the EuroQual-5 Dimension-3 Level scale (EQ-5D-3L; no problems/some problems/extreme problems) at baseline were eligible for these post-hoc analyses. Medical history of pain conditions and/or ongoing therapy were not required for eligibility and were not evaluated. Subjects were randomized to bedtime doses of placebo, LEM 5mg (LEM5),10mg (LEM10) or zolpidem tartrate extended release (not reported here). Changes from baseline (CFB) in objective sleep parameters assessed by polysomnography (latency to persistent sleep [LPS]; wake after sleep onset [WASO]) were analyzed by mixed-effect repeated measures analyses adjusted for relevant factors.

Results
Approximately 18% of the FAS reported some or extreme pain at baseline (PBO=55; LEM5=78; LEM10=50). For LPS, baseline median values (minutes) were 31.0, 29.4 and 42.1 for PBO, LEM5 and LEM10, respectively. Median CFB for LPS were larger and statistically significantly different for both LEM doses compared with PBO at the beginning of treatment (mean of Nights 1/2: +2.5; -8.4, -15.8; P&lt;0.005); and were (mean of Nights 29/30: -7.1,-9.9, -9.0) at the end of treatment LEM5 (P=0.031), LEM10 (P=0.054). For WASO, baseline median values (minutes) were 101.0, 103.6 and 111.1 for PBO, LEM5 and LEM10, respectively. Median CFB for WASO were larger and statistically significantly different (P&lt;0.001) for both LEM doses compared with PBO at the beginning (Nights 1/2; -1.5; -41.5, -64.4) and end of treatment (Nights 29/30; -1.1, -37.9, -52.5).

Conclusion
These data suggest that lemborexant can effectively treat insomnia in older adults with concomitant painful conditions.

Support (If Any)
Eisai Inc.
0456 Comparative Safety and Efficacy of Hypnotics: A Quantitative Risk-Benefit Analysis
Authors: Cheung Janet , Scott Hannah , Muench Alexandria , Morales Knashawn , Grunstein Ronald , Krystal Andrew , Riemann Dieter , Perlis Michael 
Published: May 2022

Abstract

Introduction
Hypnotics continue to be preferentially used in practice for the treatment of chronic insomnia, yet the comparative safety and efficacy of medication options are unclear. While several position statements and network meta-analyses have provided some guidance, none have provided a quantitative assessment of risk-benefit. In the present analysis, each therapeutic class commonly used for chronic insomnia is quantitatively ranked with respect to safety, efficacy, and risk-benefit.

Methods
Safety data for FDA-approved hypnotics were extracted from the package insert adverse event tables and standardized to form a placebo-adjusted adverse event rate per 1000 (AEr). Efficacy data were extracted from randomized controlled trials identified in professional society position statements and published systematic reviews. The efficacy metric was computed from placebo adjusted pre-post change scores for self-reported sleep continuity (i.e., sleep latency [SL], wake after sleep onset [WASO], and total sleep time [TST]) and represented as a summed composite effect size score (SWT). Risk-benefit (R/B) was represented as a ratio between AEr and SWT. Comparative safety, efficacy, and risk-benefit metrics were calculated for five therapeutic classes: Benzodiazepines (BZs), non-benzodiazepine benzodiazepine receptor agonists (BZRAs), dual orexin receptor antagonists (DORAs), melatonin receptor agonists (MELAs), and sedating antidepressants (SADs).

Results
With respect to safety, MELAs had the lowest adverse event rate (AEr=43.1) and BZRAs had the highest rate (AEr=255.0). With respect to efficacy, BZs were the most efficacious (SWT=1.94, Mean ES=0.59) and MELAs were least efficacious (SWT=0.11, Mean ES=0.02). Overall, with respect to risk-benefit, SADs had the most favorable profile (R/B=69.5), while MELAs had the least favorable profile (R/B=395.7).

Conclusion
The optimal selection of hypnotics requires consideration of both risk and benefit. Findings suggest that SADs can be considered the first-line pharmacotherapeutic option due to the superior risk-benefit profile. If treatment responses are inadequate or if SADs are contraindicated, risk-benefit rankings may serve as a decision tree as part of a medical algorithm protocol to guide treatment selection for patients with chronic insomnia.

Support (If Any)
Sleep Research Society Mentor-Mentee Award (Cheung); K24AG055602 & R01AG054521 (Perlis)
0464 Patient perspectives on facilitators and barriers to engagement with digital CBT-I
Authors: Melikyan Diana , Santarossa Sara , Sagong Chaewon , Sultan Zain , Drake Christopher , Cheng Philip 
Published: May 2022

Abstract

Introduction
Digital Cognitive Behavioral Therapy for Insomnia (dCBT-I) is a highly effective self-guided mHealth treatment for insomnia; however, completion and adherence rates are poor, especially among marginalized individuals. The present study explored facilitators and barriers to engagement with dCBT-I.

Methods
Thematic analysis was conducted on qualitative data collected in those who engaged with dCBT-I. A total of 151 written feedback, 34 individual interviews, and 1 focus group of six racial minorities with low socioeconomic status (SES) was used. A combined inductive and deductive approach was utilized, where an initial codebook was developed but emergent codes were also included in the coding process. Consensus between four independent coders were achieved prior to thematic analysis.

Results
Thematic analysis revealed five themes: digital person to person component, type and extent of information, users’ sense of autonomy, app functionality, and importance of tailored content. Overall, users felt that the dCBT-I content was engaging (e.g., “easily understandable”, “well-paced”), and valued the accessibility of a digital treatment (e.g., “I greatly enjoyed the weekly sessions in the privacy of my own home”). Participants across demographic groups felt that the virtual therapist (i.e., “The Prof”) increased engagement (e.g., “The Prof was entertaining”, “The Prof has a great voice…educated and soothing without condescension”).Barriers to engagement, particularly in those with lower SES, included eHealth literacy (e.g., “I had issues filling out my sleep diary”) and a desire for more human contact (e.g., “I maybe would have liked more communication throughout, maybe just checking in once to see if things were okay”). There was strong consensus among non-completers that additional support would have prevented treatment dropout (e.g., “HELP button or someone you could’ve asked questions”). Others expressed concerns about the lack of tailoring to their specific circumstances (e.g., “this system does not take into consideration ‘physical’ causes of my sleep problems”).

Conclusion
Although dCBT-I has high accessibility and scalability, those with lower health literacy may experience lower self-efficacy and negative outcome expectancy as barriers to treatment engagement and completion. There is support that enhancing dCBT-I with personalized support and tailored content may improve treatment adherence and completion.

Support (If Any)
K23HL136188; R01HL159180
0466 Living Alone as a Predictor of Symptom Change During Cognitive Behavioral Therapy for Insomnia
Authors: Tutek Joshua , Gumport Nicole , Dietch Jessee , Tully Isabelle , Simpson Norah , Manber Rachel 
Published: May 2022

Abstract

Introduction
Interpersonal factors have implications for sleep quality. Research has begun to explore how such factors may play a role in cognitive behavioral therapy for insomnia (CBTI). This study investigated whether living alone predicts reductions in insomnia severity and sleep-related daytime impairment across the first two months of treatment in a trial of CBTI.

Methods
Participants were 224 middle-to-older-aged adults with insomnia (166 women, M age = 63.16) enrolled in the ongoing Randomized Controlled Study on Effectiveness of Stepped-Care Sleep Therapy (RESTING). All study participants received CBTI, delivered either via a therapist or a validated software program. At baseline, participants indicated whether they lived alone or with at least one other person. The Insomnia Severity Index (ISI) and PROMIS Sleep-Related Impairment (SRI) short form were administered at baseline and two months after starting treatment. Mixed effects models assessed whether living alone predicted reduction in symptoms across the first two months of CBTI.

Results
Across the total sample, ISI scores decreased from baseline to two months (β=-3.52, SE=0.35, p&lt;.001, 95% CI=-4.20, -2.84). Living alone was not associated with baseline ISI scores nor change in ISI score. A reduction in PROMIS SRI score was also observed in the total sample from baseline to two months (β=-4.18, SE=0.50, p&lt;.001, 95% CI=-5.15, -3.21). Living alone was not associated with baseline SRI score, but it did predict reduction in SRI score (β=-3.23, SE=0.88, p=.001, 95% CI=1.31, 5.15). Participants living alone displayed less reduction in SRI compared to those living with at least one other person.

Conclusion
Participants undergoing CBTI who live alone experienced reduction in insomnia severity over the course of treatment, but they displayed less improvement in daytime sequalae of poor sleep compared to those living with others. Future studies should further explore how living status contributes to insomnia treatment response across both nighttime and daytime sleep symptomology. Regular engagement with others living in the home may be important for insomnia treatment to translate into perceived functional improvements during the day.

Support (If Any)
1R01AG057500
0469 The Apnea and Insomnia Research (AIR) Trial: An Interim Report
Authors: Edinger Jack , Manber Rachel , Simmons Bryan , Johnson Rachel , Horberg Roxane , Depew Ann , Abraibesh Aysha , Simpson Norah , Eldridge-Smith E Devon , Strand Matthew , Espie Colin , Kushida Clete , Tsai Sheila 
Published: May 2022

Abstract

Introduction
Many sleep apnea patients suffer from comorbid insomnia disorder. Although cognitive behavioral insomnia therapy (CBTI) has proven effective for insomnia among such patients, access to trained CBTI providers remains limited. The current study is testing a digital CBTI (dCBTI) among PAP-prescribed sleep apnea patients with comorbid insomnia.

Methods
Patients enrolled in this trial complete baseline measures and are randomized to dCBTI or sleep hygiene (CTRL). After 8 weeks, all patients are reassessed. Patients in the dCBTI arm who reach remission by this time point are offered no additional insomnia treatment, whereas those who do not achieve insomnia remission are randomly assigned either another 8 weeks of dCBTI or a therapist delivered CBTI (TCBTI). All groups are reassessed at the end of this second 8-week treatment phase and then again at 3- and 6-month follow-ups. This report considers changes in scores on the Insomnia Severity Index (ISI) from baseline to the end of the second 8-week treatment, as well as insomnia remission (ISI &lt; 8) and responder rates (&gt; 8 point decline on the ISI) of dCBTI and TCBTI relative to the CTRL. The sample for this report included the first 305 participants (mean age = 56.5±12.5 yrs.; 57.1% females).

Results
Both dCBTI and TCBTI recipients showed greater (p = .0001) and comparable reductions in ISI scores from baseline to the end of the second 8-week treatment phase than did those in the CTRL group. Average ISI score improvements moved dCBTI and TCBTI recipients from moderately severe to mild insomnia symptoms. Significant group differences were noted for both the responder (X2 (2) =19.29, p &lt; 0.0001) and remission rates (X2 (2) =13.89, p = 0.001). Responder rates for those participants switched to TCBTI (50%) were noteably higher than those continued with dCBTI (30.5%) and those in the CTRL group (19.2%); but remission rates were comparable (30.5% vs. 29.2%) and sigificantly higher than the rates shown by the CTRL group (19.2%).

Conclusion
The dCBTI tested compares well with TCBTI for reducing insomnia symptoms and achieving insomnia remission in those with insomnia and sleep apnea, but insomnia responder rates may be improved by switching patients to TCBTI.

Support (If Any)
Funding support from the National Heart, Lung and Blood Institute, Grant # 1R01HL130559-01A1.
0476 A Mobile App-Based Behavioral Intervention for Insomnia Among College Students
Authors: Floyd Veronica , Vargas Ivan 
Published: May 2022

Abstract

Introduction
Nearly 60% of college students suffer from poor sleep quality and 7.7% of students meet criteria for a sleep disorder (Schlarb et al., 2017). The most common of these sleep disorders is insomnia. Cognitive Behavioral Therapy for Insomnia (CBT-I) is the frontline treatment for insomnia. The time and cost of CBT-I, however, has limited overall treatment uptake, especially among individuals with less severe symptom profiles or who are otherwise relatively healthy (e.g., college students). The goal of this study is to pilot-test a mobile application version of CBT-I (i.e., CBT-I Coach) to evaluate its effectiveness in treating insomnia symptoms among college students. The testing will also demonstrate the feasibility of using a CBT-I app for insomnia symptom treatment.

Methods
The study uses a between- and within-subjects design to assess biweekly variations in insomnia symptom severity among college students over a period of 8 weeks. Participants are randomized into the intervention group or a wait-list control group (where they were asked to initiate the intervention after a four-week delay). Participants in both groups are asked to use the CBT-I Coach app daily for 4 weeks. Every two weeks, online surveys are completed to assess sleepiness (via the Epworth Sleepiness Scale) and the insomnia symptom severity (via the Insomnia Severity Index).

Results
While data collection is ongoing, to-date we have collected data from 17 participants. The mean baseline ISI score was 15.3. Of the 17 participants that completed the baseline, 65% (n=11) filled out the 4-week online survey. The mean ISI score at the 4-week follow-up was 12.7. Ten participants (or 59% of those that completed the baseline) completed the eight-week follow-up survey. Data collection is scheduled to be completed in April 2022, and a full summary of the results will be presented at the APSS conference in Charlotte.

Conclusion
An effective app-based version of CBT-I has the potential to increase the accessibility of behavioral interventions for sleep to populations that are often missed by healthcare providers. Making CBT-I more available to college students and young adults may also decrease the onset of more chronic forms of insomnia.

Support (If Any)
N/A
0477 Comparison of a Non-Contact Sleep Monitoring Device with Wrist Actigraphy in a Sample of Individuals with Chronic Insomnia
Authors: Teeter Naomi , Skeiky Lillian , Gottlieb Elie , Raymann Roy , Buchwald Dedra , Watson Nathaniel , Van Dongen Hans , Hansen Devon , Finlay Myles , Peterson Mary 
Published: May 2022

Abstract

Introduction
Non-contact devices (NCDs) have been developed to measure sleep longitudinally and unobtrusively in the naturalistic home setting. We compared longitudinal measurements from a wrist actigraph (Actiwatch-2, Philips Respironics) and from a NCD (SleepScore Max, SleepScore Labs) in a sample of adults with insomnia

Methods
N=71 adults (ages 39.0±13.0y; 50 women) who met ICSD-3 criteria for chronic insomnia and were otherwise healthy participated in an at-home sleep monitoring study. Participants continuously wore the actigraph for one week, then used the NCD to record only nightly sleep periods for the next 8 weeks. Week-by-week within-subject averages and standard deviations (SDs) over days were assessed for five major sleep parameters: total sleep time (TST), sleep onset latency (SOL), wake after sleep onset (WASO), time in bed (TIB), and sleep efficiency (SE). These sleep parameters were analyzed with mixed-effects ANOVA comparing week one (actigraphy) to the next 8 weeks (NCD), and correlations between the first week (actigraphy) and second week (NCD) were calculated.

Results
Significant differences for actigraphy versus NCD were found for the weekly averages of SOL and WASO (F&gt;25.8, p&lt;0.001). The NCD measured longer average SOL (M±SEM=25.0±1.5min) than actigraphy (12.6±2.0min) and less average WASO (40.5±2.7min) than actigraphy (51.1±3.2min). Further, significant differences were found for the weekly within-subject SDs of TST and WASO (F&gt;7.52, p&lt;0.01). The NCD measured greater SD for TST (71.6±2.8min) than actigraphy (60.0±4.7min) and greater SD for WASO (25.0±1.4min) than actigraphy (19.2±2.2min). Actigraphy and NCD weekly averages were positively correlated for TST, WASO, TIB, and SE (p&lt;0.001), but not SOL (r=0.03, p=0.80). Similarly, weekly within-subject SDs were positively correlated for TST, WASO, TIB, and SE (p≤0.05), but not SOL (r=–0.03, p=0.81).

Conclusion
Actigraphy and NCD were not used simultaneously, precluding a direct comparison between these measurement modalities. Nonetheless, in this ecologically valid context, significant differences were only found for the weekly averages of SOL and WASO and for the weekly within-subject variability of SOL and TST, with significant correlations between the devices for all variables except SOL. Although actigraphy tends to underestimate SOL, NCD validation against polysomnography in chronic insomnia is warranted.

Support (If Any)
NIH grant KL2TR002317; research devices provided by SleepScore Labs.
0481 Effectiveness of a digital therapeutic compared to medications and cognitive behavioral therapy for treating chronic insomnia in adults
Authors: Forma Felicia , Pratiwadi Ramya , El-Moustaid Fadoua , Smith Nathaniel , Velez Fulton 
Published: May 2022

Abstract

Introduction
Limitations on the availability of guideline-recommended cognitive behavioral therapy for insomnia (CBT-I) constrain its use and create an unmet need for innovative ways to expand access. Digital therapeutics offer a potential solution. This study compared a digital intervention, traditional face-to-face CBT-I, and prescription medications for insomnia.

Methods
Of 184 articles identified in a systematic literature review, 13 studies reported ISI mean change from baseline data: 1 using the digital therapeutic (DT) SHUTi (now known as the prescription digital therapeutic Somryst), 1 on the medication eszopiclone, and 11 on traditional CBT. A Bayesian network meta-analysis (NMA) was performed on the mean change from baseline and the proportion of remitters using the insomnia severity index (ISI) endpoint with follow-up timepoints between 6-12 weeks. Mean change in ISI score from baseline was analyzed as a continuous endpoint while comparisons of the proportion of remitters was performed using odds ratios. The analysis used a random-effects model for the base case analysis. A surface under the cumulative ranking curve (SUCRA) analysis was performed to rank the treatments on each endpoint.

Results
Only the DT and CBT-I were significantly different than placebo. The DT had the greatest mean change from baseline in ISI from placebo (-5.77 points, 95% Credible Interval (CrI) [-8.53, -3.07]), followed by CBT-I (-4.3 points, 95% CrI [-6.32, -2.39]). In the SUCRA analysis, the DT had the highest probability (56%) of being the most effective treatment based on ISI mean change from baseline. 8 studies reported the proportion of ISI remitters. Only the DT showed a statistically significant difference in remission vs. placebo, and the DT had the highest odds ratio for remission vs. placebo (OR 12.33; 95%CrI [2.28, 155.91]). The DT had the highest probability (64%), of being the most effective treatment for inducing remission using ISI definitions.

Conclusion
The DT in this study was projected to be the most effective therapy on both mean change in ISI and ISI remission within 6-12 weeks of treatment start vs. either traditional CBT-I or medications.

Support (If Any)
This analysis was funded by Pear Therapeutics, Inc.