bluuebunny/crossref_metadata_2025_split huggingface dataset:
0481 Impact of Lemborexant on Fatigue Severity in Subjects with Clinically Significant Levels of Fatigue at Baseline
Authors: Rosenberg R , Kumar D , Pinner K , Perdomo C , Moline M 
Published: May 2020

Abstract

Introduction
In Phase 3 SUNRISE-1 (NCT02783729; E2006-G000-304) and SUNRISE-2 (NCT02952820; E2006-G000-303), lemborexant (LEM) provided significant benefit versus placebo on sleep diary-based sleep onset/maintenance outcomes over 1mo and 6mo, respectively, in subjects with insomnia disorder. The impact of LEM on patient-reported fatigue, assessed using the Fatigue Severity Scale (FSS), in subjects with clinically significant fatigue (CSF) at baseline was examined for each study.

Methods
SUNRISE-1 was a 1mo, randomized, double-blind, placebo- and active-controlled, parallel-group study in female (≥55y) and male (≥65y) subjects (n=1006); subjects received placebo, LEM 5mg (LEM5), LEM 10mg (LEM10) or zolpidem tartrate extended-release (not reported here). SUNRISE-2 was a 12mo, randomized, double-blind study in subjects age ≥18y (n=949). Subjects received placebo, LEM5, or LEM10 for 6mo. Placebo subjects were rerandomized to LEM5 or LEM10 for another 6mo; LEM subjects continued assigned treatment. CSF was defined as FSS total score (FSSts) ≥36.

Results
In subjects with baseline CSF, in SUNRISE-1, baseline FSSts was 46.8, 46.5, and 46.6 in placebo (n=117), LEM5 (n=157), and LEM10 (n=153) groups, respectively, and, in SUNRISE-2, was 45.7, 46.4, and 45.8 in placebo (n=169), LEM5 (n=181), and LEM10 (n=173) groups, respectively. At 1mo, mean changes from baseline in FSSts were not significantly different vs placebo for LEM5 in both studies, and for LEM10 in SUNRISE-1. In SUNRISE-2, LEM10 significantly decreased mean [SD] FSSts from baseline vs placebo at 1mo (LEM10, −11.2[13.9] vs placebo, −8.7[10.5]; P=0.03). By 6mo in SUNRISE-2, both LEM5 and LEM10 significantly decreased mean [SD] FSSts from baseline versus placebo (LEM5, −15.4[13.8]; LEM10, −15.0[14.2] vs placebo, −11.2[11.6]; both P&lt;0.05). At 12mo, mean [SD] FSSts improvements were sustained for LEM5 (−20.4[12.8]) and LEM10 (−18.1[14.7]).

Conclusion
In subjects with CSF, longer treatments (&gt;1mo) may be needed to observe significant FSSts improvements, which were evident at 6mo and sustained at 12mo with continuous LEM treatment.

Support
Eisai Inc.
0502 Safety, Tolerability, and Efficacy of a Novel, Highly Potent and Selective Partial Agonist for Nociceptin/Orphanin-FQ Peptide (NOP) Receptors in Patients with Insomnia Disorder
Authors: Zhou M , Harris S , Kapil R , Cipriano A , He E , Shet M , Fukumura K , Matsuo Y , Uehira M , Zammit G 
Published: May 2020

Abstract

Introduction
V117957 is a recently described investigational oral, potent, and selective nociceptin/orphanin-FQ peptide (NOP) receptor partial agonist which was previously evaluated in ~200 healthy subjects. Its satisfactory safety/tolerability profile has been established with the top doses at 30mg following a single oral administration and 10mg once daily for 2 weeks. V117957 demonstrated favorable drug-like properties for insomnia treatment, including oral bioavailability, fast absorption, and rapid elimination.

Methods
A total of 52 patients with insomnia disorder have been evaluated in two separate randomized, double-blind, crossover, placebo-controlled sleep studies. Insomnia disorder was confirmed by screening polysomnography (PSG). All subjects received orally, for two consecutive nights, either V117957 10mg or placebo in Study #1 or 0.5, 1, 3, 6mg or placebo in Study #2. Efficacy was measured via PSG for the primary endpoint of sleep efficiency (SE) and secondary endpoints of sleep onset (latency to persistent sleep [LPS]) and maintenance (wakefulness after sleep onset [WASO]). Efficacy also was measured by patient diary (subjective sleep latency [sSL], subjective total sleep time [sTST], sWASO). Pharmacodynamics (PD) on next-day residual effects were also measured, including cognitive, psychomotor and mood effects.

Results
V117957 showed statistically significant greater sleep efficiency and less WASO in a dose-dependent manner (0.5-10 mg) and a statistically significant reduction in LPS at 10mg, as compared to placebo. V117957 at 0.5mg and 1mg exhibited next-day residual effects similar to placebo. At doses of 3mg or higher, V117957 showed dose-dependent next-day residual effects. V117957 was safe and well-tolerated across all doses tested with no serious adverse events, with somnolence being the most frequent treatment-emergent adverse event. No concerning laboratory findings and no clinically significant findings on vital signs and electrocardiograms have been attributed to V117957 in these subjects.

Conclusion
V117957 was safe and well-tolerated in patients with insomnia disorder. These results demonstrated that NOP receptors represent a novel mechanistic treatment for insomnia disorder and support continued evaluation of V117957.

Support
Funded by Shionogi and Imbrium Therapeutics, a subsidiary of Purdue Pharma L.P.
0511 Patterns of Concomitant Over-the-Counter, Natural Product and Prescription Sleep Aid Use: A Population-Based Study
Authors: Cheung J M , Jarrin D C , Beaulieu-Bonneau S , Ivers H , Morin G , Morin C M 
Published: May 2020

Abstract

Introduction
Despite limited evidence, over-the-counter medications (OTC) and natural products (NP) are increasingly combined with prescribed medications (Rx) to manage insomnia symptoms. Self-medication patterns are expected to be heterogenous and may predispose individuals to inappropriate medication-taking behaviors, but little is known about the usage trajectories of sleep aids. This study investigates patterns of concomitant NP, OTC and Rx use in a Canadian population-based sample.

Methods
Data were derived from a longitudinal study on the natural history of insomnia. Participants were 3416 adults (62% female, Mage = 49.7, MInsomnia Severity Index= 8.4). Self-reported data for OTC, NP and Rx use in the last year (yes/no) was extracted at 0-, 6- and 12-month follow-up. A Latent Class Growth Curve Analysis was conducted to identify patterns of concomitant sleep aid use. Participants also completed a battery of clinical measures including the Ford Insomnia Response to Stress Test, Dysfunctional Beliefs and Attitudes about Sleep scale (16-item), Beck Depression Inventory, Insomnia Severity Index and the Pittsburgh Sleep Quality Index. Preliminary associations between class membership and baseline covariates were evaluated using the χ 2 test or a one-way ANOVA. Sampling weights were applied to all analyses, adjusting for partial non-response.

Results
Analyses revealed a 6-class solution; each class reflected a preferential agent(s) choice, which remained stable over 12-months: Minimal Use (74.5%), Rx-Dominant (11.3%), NP-Dominant (6.3%), OTC-Dominant (4.3%), Rx-NP-Dominant (2.4%), and Rx-OTC-Dominant (1.1%). Classes with prominent prescribed agent use were older [F(5, 207.6) =27.2, p&lt;0.001], more likely to seek help [χ 2(5, n=2977) =653.1, p&lt; 0.001] and consume alcohol [χ 2(5, n=2968) =49.2, p&lt; 0.001]. Clinically, these individuals reported greater stress reactivity [F(5, 2966) =48.4, p&lt; 0.001], depressive symptoms [F(5,197.4) =32.0, p&lt;0.001], dysfunctional sleep beliefs [F(5, 2987) =54.3, p&lt; 0.001], insomnia severity [F(5, 2983) =88.4, p&lt; 0.001] and poorer sleep quality [F(5, 203.8) =124.2, p&lt; 0.001].

Conclusion
A majority of adults used agents minimally. Stability of medication-taking patterns suggests that individuals adopt less sporadic approaches when combining sleep aids than previously assumed. Clinical profiles and sleep aid choice could pre-empt vulnerabilities to inappropriate self-medication.

Support
Research supported by a grant from the Canadian Institutes of Health Research (MOP#115103)
0512 Impact of a Patient Decision-Aid When Selecting Insomnia Treatments and Factors Associated with Decisional Conflict: Preliminary Findings from an Ongoing Pragmatic Clinical Trial
Authors: Cheung J M , Ji X , Ivers H , Morin C M 
Published: May 2020

Abstract

Introduction
Preferences play an important role in determining insomnia treatment outcomes, but the validity of patient choice is rarely assessed. Uninformed preferences can lead to decisional conflict, which can negatively impact on treatment initiation, adherence, and subsequent outcomes. The current study aims to evaluate the impact of integrating a patient decision-aid as part of a pragmatic clinical trial and to identify baseline covariates associated with clinically significant decisional conflict (CSDC).

Methods
Secondary analysis of an ongoing pragmatic clinical trial for a two-stage cognitive behavioral therapy for insomnia (CBT-I) intervention was undertaken. Participants were referred from primary care clinics in Quebec City, Canada. Upon enrolment, participants were guided by a decision-aid, outlining the risks and benefits of prospective treatment options, when selecting their preferred arm of treatment in Phase 1. Options included SHUTi, SHUTi combined with an existing medication or continuing usual treatment with medication alone. Participants also completed a battery of sleep and mental health measures at baseline. Prior to treatment initiation, the 4-item SURE (Sure of myself; Understand information; Risk-Benefit ratio; Encouragement) scale was administered to screen for CSDC. Relationships between CSDC and baseline covariates were explored using Pearson correlations.

Results
Of the 55 participants initially enrolled, 94.5% (n=52) of participants preferentially selected SHUTi, either as sole treatment (n=24) or in combination with an existing medication (n=28), over usual treatment with medication alone (n=3). Overall, CSDC was only reported by 5.5% (n=3) of the sample population, with no group differences observed, suggesting effective clarification of treatment options through the decision-aid. Interestingly, higher SURE scores (i.e. less decisional conflict) were negatively correlated with depressive symptoms (r= -0.295, n= 55, p= 0.029) and anxiety symptoms (r= -0.301, n= 55, p= 0.026). Correlations with age, insomnia symptoms, duration of insomnia and fatigue were not statistically significant.

Conclusion
The patient decision-aid appeared to resolve decisional conflict for 94.5% (n=52) of participants. Findings allude to the potential influence of emotional status on information processing pathways in an insomnia context, warranting further research.

Support
Research supported by a grant from the Canadian Institutes of Health Research (CIHR-IRSC:0441002152).
0516 Chinese Patients with Insomnia Recruited from Traditional Chinese Medicine (TCM) Hospital Successfully Treated With Telehealth Group CBT-I in Mandarin
Authors: Xu Y , Barwick F , Li C 
Published: May 2020

Abstract

Introduction
Cognitive Behavioral Therapy for Insomnia (CBTI) is the recommended treatment for insomnia in the United States, Europe and China. Individual, group and online formats are effective, with moderate to large effect sizes in treatment outcomes. Although the prevalence of insomnia is 15% in China, most individuals do not seek CBTI and often prefer TCM. This study investigated whether CBTI delivered to Chinese in Mandarin via group telehealth showed similar outcomes compared to other countries.

Methods
Chinese patients &gt; 18 years with insomnia &gt; 7 on the ISI were recruited from a sleep clinic in collaboration with Chongqing TCM Hospital in China. CBTI was delivered via 4-session telehealth group. Components included sleep education, sleep restriction, stimulus control, cognitive reframing, and relaxation. TCM use was extracted from medical records. Scores on self-report questionnaires assessing insomnia symptoms, sleep effort, sleep beliefs, and depression were compared pre- and post-treatment using paired sample t-tests with correction for multiple comparisons.

Results
All patients (N=34) completed pre-post measures. Mean age was 44 years, sample was 82% female, and 91% had a bachelor or advanced degree. Average insomnia duration was 4.1 years, and 80% of sample used TCM during CBTI. Post-treatment outcomes showed significant decreases in insomnia symptoms (ISI Mdiff=4.0, SDdiff=6.4, p=.001, ES=.63), sleep effort (GSES Mdiff=2.3, SDdiff=3.2, p=.000, ES=.72), and unhelpful sleep beliefs (DBAS Mdiff=5.4, SDdiff=5.4, p=.000, ES=1.0), along with significantly lower depression symptoms (PHQ9 Mdiff =2.6, SD=3.8, p=.000, ES=.68) and improvement in daytime functioning (PSQI Mdiff.=0.6 SDdiff =1.2, p=.008, SE=.50). Medication use also decreased significantly (PSQI Mdiff=1.5 SDdiff =1.6, p=.000).

Conclusion
Chinese patients with insomnia can be recruited successfully and treated effectively using CBTI via telehealth. Outcomes and effect sizes are similar to those seen with CBTI in other countries. Future comparison of CBTI with and without concurrent TCM could provide clinically relevant information.

Support
None
0521 Daridorexant (ACT-541468), A Dual Orexin Receptor Antagonist for the Treatment of Insomnia Disorder: Double Blind, Randomized, Phase 3 Studies for Efficacy and Safety in Adult and Elderly Patients
Authors: Zammit G , Seboek Kinter D , Bassetti C , Leger D , Hermann V , Pain S , Roth T 
Published: May 2020

Abstract

Introduction
Daridorexant, a potent and selective orally administered dual orexin receptor antagonist (DORA), has shown dose-dependent efficacy and is well tolerated with minimal residual next-morning effects in two phase 2 studies in adult and elderly subjects with insomnia disorder. Following the favorable phase 2 results, clinical development was pursued with two pivotal phase 3 multi-center, double-blind, randomized, placebo-controlled studies to further assess efficacy and safety in adult and elderly subjects with insomnia disorder. Long-term safety and tolerability are being further evaluated in a double-blind placebo-controlled extension study.

Methods
Each of the pivotal studies include ~900 patients (~40% ≥65y), randomized 1:1:1 to one of two daridorexant arms or placebo. The studies differ in dose only (10 or 25 mg [NCT03545191], 25 or 50 mg [NCT03575104]). Both report objective primary outcomes at 1 and 3 months based on PSG (WASO and LSP). Secondary endpoints include self-reported nighttime benefit with Total Sleep Time (sTST), and daytime benefit using the validated Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ). The patients undergo screening (7-13 d) and run-in (7-18 d) periods establishing eligibility and baseline, a 3-month double-blind treatment period, followed by a placebo run-out (7 d) to evaluate rebound insomnia and withdrawal effects and a 30-day safety follow-up. Additionally, subjects completing treatment could enroll in the 40-week double-blinded placebo-controlled extension trial [NCT03679884] to assess long-term safety.

Results
Enrollment in NCT03575104 (25/50 mg) was successfully completed and involves 76 sites across 10 countries; expected completion March 2020. Recruitment to study NCT03545191 (10/25 mg) is advanced; completion expected June 2020.

Conclusion
The comprehensive daridorexant phase 3 program includes 3 dose levels and replication of objective and subjective measurements at 1 and 3 months, while assessing self-reported nighttime benefit, and benefit during the day with a validated PRO instrument, as well as safety in insomnia disorder.

Support
Medical writing Randall Watson, (Idorsia). These studies were sponsored by Idorsia Pharmaceuticals Ltd.
0522 Subtypes of Insomniacs Treated by Cognitive-Behavioral Therapy
Authors: Sforza M , Castronovo V , Galbiati A , Zucconi M , Oldani A , Casoni F , Ferini-Strambi L 
Published: May 2020

Abstract

Introduction
Insomnia disorder (ID) is characterized by high degree of heterogeneity. Aim of our study was to identify ID patients subtypes in terms of sleep and non-sleep clinical baseline (BL) features and CBT-I efficacy.

Methods
294 chronic insomnia patients (61.6% female, mean age 40.7 ± 12.3 yrs) underwent 7-sessions group CBT-I. By use of latent class analysis (LCA) we identified ID subtypes according to BL score of Glasgow Sleep Effort Scale (GSES); Epworth Sleepiness Scale (ESS); Dysfunctional Beliefs and Attitudes about Sleep (DBAS -16); Morningness-Eveningness Questionnaire Self-Assessment (MEQ-SA); Perceived Stress Scale (PSS); Profile of Mood States (POMS); Beck Depression Inventory (BDI-II); Stay-Trait Anxiety Inventory (STAI-Y); Treatment effectiveness (Delta score of Insomnia Severity Index ISI between BL and end-of-treatment).

Results
We chose 3 latent classes as most parsimonious model. According to questionnaires’ cut-off, we labeled three classes: Class 1 (insomnia+anxiety+depression+stress) (n=62), Class 2 (insomnia+anxiety+depression) (n=153), Class 3 (only insomnia) (n=79). The variables that best differentiate the 3 classes were POMS (.772), STAY (.660), PSS (.545), BDI (.406) and ISI (.228) at BL. In particular, for ISI, the best item predicting groups differentiation was item 3 on the impact of insomnia on daytime functioning (.224). Moreover, we found a significant interaction between CBT-I treatment effect and the 3 classes at the ISI score (p=.001), GSES score (p=.002), DBAS score (p&lt;.05), PSS score (p&lt;.001), POMS score (p&lt;.001), BDI score (p&lt;.001) and STAI-Y score (p&lt;.001).

Conclusion
Our data driven analysis results suggest that the heterogeneity of ID patients can be best represented by non-sleep scores, in particular those regarding depression, anxiety, stress and daytime functioning. These information can be useful in predicting the outcome of CBT-I.

Support
No
0529 Behavioral Therapy Components for Insomnia and Fatigue in COPD
Authors: Kapella M , Steffen A , Laghi F , Prasad B , Vispute S , Teixeira C , Kemner G , Peters T , Carley D 
Published: May 2020

Abstract

Introduction
Insomnia contributes to fatigue, a common symptom in COPD. Our study aims were: (1) to determine the efficacy of a) cognitive behavioral therapy for insomnia (CBT-I) and b) COPD education (COPD-ED) on insomnia and fatigue, and (2) to define potential mechanistic contributors to pre/post intervention change in insomnia and fatigue in patients with COPD and insomnia.

Methods
A randomized 2x2 factorial design was used with factors representing CBT-I (yes/no) and COPD-ED (yes/no). Attention control (health videos) were used in the absence of CBT-I or COPD-ED. All patients received 6, 75-minute weekly sessions. Dependent variables included insomnia severity (Sleep Impairment Index (SII), range 0-28) and fatigue (Chronic Respiratory Disease Questionnaire (CRQ) range 1-7) measured at baseline, just post-intervention, and at 3-months post-intervention.

Results
One hundred nine patients (FEV1% predicted 67 ± 24% (mean ± SD), age 65 ± 8 years, SII 15.9 ± 8, CRQ 3.7 ± 1.1) participated in the study. After 6 sessions, insomnia decreased more in patients who received CBT-I (-5.8) than those who did not (-2.2; p=0.0002). This effect was sustained at the 3-month follow-up (p=0.0003). Fatigue showed no significant differences for CBT-I at 6-weeks (p=.27) but at 3-months patients receiving CBT-I showed marginally better improvement (.75, a clinically important difference) compared to those who did not receive CBT-I (.43; p=.09). COPD-ED showed no effect on insomnia or fatigue. Two main effects suggest mechanisms for the pre-post efficacy of CBT-I: improved sleep beliefs (p=0.0257) and self-efficacy for sleep (p=0.0619) after 6 sessions which were sustained at 3 months (p=0.0184 and p=0.0431 respectively).

Conclusion
CBT-I produced sustained decreases in insomnia in patients with COPD. Results suggest that changes in beliefs about sleep and improved self-efficacy for managing sleep may mediate CBT-I associated decreases in insomnia.

Support
This research was supported by the National Institute of Nursing Research of the National Institutes of Health R01NR013937.
0534 Cognitive Behavioral Therapy for Perinatal Insomnia: Effects on Postpartum Depressive Symptoms
Authors: Manber R , Bei B , Simpson N , Rangel E 
Published: May 2020

Abstract

Introduction
Poor sleep during pregnancy is a risk for postpartum depression. Using data from an RCT of CBT-I for insomnia disorder during pregnancy, we examined whether improvement in insomnia reduced postpartum depression symptom severity. We hypothesized that better response to treatment during pregnancy would result in lower depressive symptom severity during the postpartum.

Methods
Pregnant women (N=179; gestation age 18-30 weeks) with insomnia disorder were randomized to CBT-I or an active control (CTRL) therapy (5 sessions during pregnancy, one at 6 weeks postpartum). Women with depressive disorders and those using prescription medications that impact sleep were excluded. The Insomnia Severity Index (ISI) and the Edinburgh Postpartum Depression Scale (EPDS) were administered at baseline, during pregnancy, and at 8, 18, and 30 weeks postpartum. The Perinatal Risk Questionnaire (PRQ) was administered at baseline. Included in the analyses were women who provided data for at least one of three postpartum assessments (62 in CBT-I; 55 in CTRL).

Results
Mixed effects models revealed that lower ISI following the pregnancy treatment phase (p &lt; .001) and greater reduction in ISI during pregnancy (p = .053) predicted overall lower EPDS scores during postpartum; but these effects did not differ significantly between treatment arms. Average postpartum EPDS scores, which were low overall, were higher in women with ISI score at or above the median of 9 (6.6±3.9), compared to those below the median (3.5±3.3). Compared to CTRL, participants in the CBT-I condition were nearly twice likely to have ISI scores below the median following the pregnancy treatment phase (29.1% versus 56.5%). Although higher PRQ scores were associated with overall higher postpartum EPDS (p=.0026), PRQ did not moderate postpartum EPDS trajectories.

Conclusion
We have previously shown that CBT-I is effective for antenatal insomnia, which is a risk for postpartum depression. Our current findings suggest that improving insomnia in pregnancy may reduce the risk for postpartum depression. Limitations include a small sample and missing data during the postpartum follow-up. A larger study among women specifically at risk for postpartum depression could help identify patient related factors that predict therapeutic benefits of CBT-I on postpartum depression.

Support
NR013662