Abstract
Introduction
Idiopathic hypersomnia (IH) is a rare central hypersomnolence disorder. In a randomized, controlled study of lower-sodium oxybate (LXB; Xywav™) in adults with IH (NCT03533114), ...significant differences for LXB compared with placebo were observed in Epworth Sleepiness Scale (ESS; primary efficacy endpoint), self-reported Patient Global Impression of Change (PGIc), and IH Severity Scale (IHSS; key secondary endpoints). In this clinical study, investigators were permitted to initiate LXB dosing on a once-nightly or twice-nightly regimen.
Methods
Eligible participants aged 18–75 years began LXB treatment, administered once or twice nightly during an open-label treatment/titration and optimization period (OLTTOP; 10–14 weeks); dose amount/regimen could be adjusted during this period. Participants next entered a 2-week, open-label, stable-dose period (SDP), then were randomized to placebo or to continue LXB treatment during a 2-week, double-blind, randomized withdrawal period (DBRWP). P values are nominal for this exploratory analysis.
Results
Of 154 enrolled participants, 40 (26%) initiated LXB treatment on a once-nightly regimen. In the efficacy population (n=115), 27 participants were on a once-nightly regimen during SDP (48.1% of whom initiated treatment once nightly during OLTTOP) and 88 participants were on a twice-nightly regimen during SDP (86.4% of whom initiated treatment twice nightly during OLTTOP). During SDP, median (min, max) LXB total dose was 4.5 (2.5, 6) g/night (once-nightly group) and 7.5 (4.5, 9) g/night (twice-nightly group). ESS scores worsened in participants randomized to placebo vs those continuing LXB in the once-nightly group (n=11 and n=15, respectively; LS mean difference 95% CI: −4.93 −7.41, −2.46; P=0.0004) and twice-nightly group (n=47 and n=41, respectively; LS mean difference 95% CI: −7.44 −9.15, −5.72; P<0.0001). Worsening was also observed in PGIc (once-nightly: 81.8% placebo vs 26.7% LXB; P=0.0077; twice-nightly: 89.4% placebo vs 19.5% LXB; P<0.0001) and IHSS score (estimated median difference 95% CI, once-nightly: −9.00 −16.0, −3.0; P=0.0028; twice-nightly: −12.00 −15.0, −8.0; P<0.0001). Common adverse events included nausea (21.4%), headache (16.2%), anxiety (14.9%), dizziness (11.7%), insomnia (11.7%), and vomiting (10.4%).
Conclusion
The efficacy and safety of LXB in IH were demonstrated for both once-nightly and twice-nightly regimens. The majority of participants initiated and remained on a twice-nightly regimen.
Support (if any)
Jazz Pharmaceuticals
Abstract
Introduction
histamine H3 receptor (H3R) antagonists/ inverse agonists increase histaminergic neurotransmission and offer a therapeutic option for the treatment of narcolepsy. Samelisant ...(SUVN-G3031) is a potent and selective H3R inverse agonist exhibited selectivity over 70 other targets. Samelisant showed wake-promoting and anticataplectic effects in orexin knockout mice suggesting its potential therapeutic utility in the treatment of EDS and cataplexy associated with narcolepsy. Safety and tolerability studies in animals and healthy humans suggested a favorable risk/benefit profile.
Methods
The current study is a 2 week treatment, multicenter, double-blind, placebo controlled, parallel-group study in patients with Narcolepsy with or without Cataplexy. Eligibility criteria include age between 18 to 50 years old, an ESS score of ≥ 12; and mean MWT time of < 12 minutes and a confirm diagnosis of narcolepsy as per ICSD-3. Further, the randomization will be stratified according to type of narcolepsy (Type-1 or Type-2). Each subject will receive either placebo or study drug once daily for 2 weeks in a fixed ratio of 1:1:1. The primary efficacy endpoint is change in maintenance of wakefulness test (MWT) score from baseline to week 2. Key secondary endpoints include change from baseline to week 2 in ESS and an improvement in CGI-S scores. Safety will be monitored by medical monitor and by an independent data safety monitoring committee. Baseline clinical and demographic data for the currently enrolled study is summarized descriptively. Since the study is blinded, a breakdown of baseline characteristics by treatment group will not be available until after completion.
Results
As of data cutoff date of Dec 20, 2020, a total of 54 subjects were completed in the study. The median age of subjects was 30 years (range: 18 - 50 years) with mean BMI of 28.6 (range: 18.3 - 43.1 kg/m2). Overall, 74% of subjects were female and 83% were Caucasian. Mean (SD) baseline values of MWT and ESS are 5.65 (3.5) and 16.7 (2.5), respectively.
Conclusion
Baseline characteristics are consistent with the general narcolepsy population. The study is currently enrolling the subjects with Narcolepsy with or without Cataplexy, and the Data readout is expected in the second half of 2021.
Support (if any):
Human circadian variations Gentry, Nicholas W; Ashbrook, Liza H; Fu, Ying-Hui ...
The Journal of clinical investigation,
08/2021, Letnik:
131, Številka:
16
Journal Article
Recenzirano
Odprti dostop
Circadian rhythms, present in most phyla across life, are biological oscillations occurring on a daily cycle. Since the discovery of their molecular foundations in model organisms, many inputs that ...modify this tightly controlled system in humans have been identified. Polygenic variations and environmental factors influence each person's circadian rhythm, contributing to the trait known as chronotype, which manifests as the degree of morning or evening preference in an individual. Despite normal variation in chronotype, much of society operates on a "one size fits all" schedule that can be difficult to adjust to, especially for certain individuals whose endogenous circadian phase is extremely advanced or delayed. This is a public health concern, as phase misalignment in humans is associated with a number of adverse health outcomes. Additionally, modern technology (such as electric lights and computer, tablet, and phone screens that emit blue light) and lifestyles (such as shift or irregular work schedules) are disrupting circadian consistency in an increasing number of people. Though medical and lifestyle interventions can alleviate some of these issues, growing research on endogenous circadian variability and sensitivity suggests that broader social changes may be necessary to minimize the impact of circadian misalignment on health.
Abstract
Introduction
Evaluation of hypersomnia includes polysomnography followed by mean sleep latency testing (MSLT). As consistent with guidelines as applied in most centers, the overnight portion ...of the study will be terminated to begin sleep latency testing. For patients with prolonged sleep duration, this interruption could result in REM sleep on nap testing that reflects continuation of their biological night, rather than abnormalities in REM sleep pressure/regulation.
Methods
We reviewed 42 consecutive extended (unrestricted) sleep studies for patients with a total sleep time greater than 600 minutes. For studies with sleep onset before midnight, we evaluated for REM period onset after 6AM, the number of REM periods after 6AM and 8AM, and the time of the final REM period onset.
Results
42 hypnograms were reviewed for patients undergoing evaluation of hypersomnia, median age 32 years (range 19-92) with a median total sleep time of 663 minutes (range 602-832), of these 28/42 (67%) had sleep onset before midnight (12 AM) and were included in the analysis. 27/28 (96%) of hypnograms reviewed had REM sleep after 6 AM, 24/28 (86%) had REM sleep after 8 AM, with the onset of the final REM period ranging from 4:46 AM-12:30 PM for patients with sleep onset time before midnight (12 AM).
Conclusion
These data suggest that termination of overnight polysomnography to complete mean sleep latency testing, as is standard in most sleep labs, may influence the presence of REM sleep on MSLT for patients with prolonged total sleep duration. These results may have implications for the interpretation of MSLT for patients with long sleep duration, and may explain why a given individual may test as type II narcolepsy or idiopathic hypersomnia unpredictably on repeat testing.
Support
Sleep Medicine Fellowship at BIDMC
1227 A CASE OF A FEARFUL SLUMBER Asis, Aristotle; Wilson, Annise Georgette; Alapat, Philip Mani
Sleep (New York, N.Y.),
05/2020, Letnik:
43, Številka:
Supplement_1
Journal Article
Recenzirano
Odprti dostop
Abstract
Introduction
Isolated sleep paralysis (ISP) occurs when rapid eye movement (REM)-based atonia intrudes into wakefulness, outside the context of narcolepsy, substance abuse, mental disorder ...or other medical conditions. No “gold standard” assessment and diagnostic instrument currently exists.
Report of Case
A 63-year old female with hypersomnia and positive airway pressure (PAP)-controlled obstructive sleep apnea was referred for recurrent episodes of paralysis during sleep-wake transitions, lasting 15-20 seconds, occurring every 2-3 years since the age of 15, and associated with fear and anxiety. Episodes were more frequent in the last 2 years after significant sleep deprivation and starting a weight loss supplement, BIO-X4, which contains green tea and probiotics. No cataplexy, or history of traumatic brain injury and stroke were identified. Epworth Sleepiness Scale score was 14 on armodafinil. Reported sleep amounts were regularly scheduled 6-7-hour periods, with no suggestion of circadian dysfunction. In 2016, polysomnogram showed Apnea-Hypopnea index of 2.6/hour, Respiratory Disturbance Index of 13.8/hour with oxygen nadir of 92% in the setting of hypersomnia. Continuous PAP of 11 cmH20 was initiated after a successful titration with controlled residual AHI during follow-ups. Multiple Sleep Latency Test during the same time revealed mean sleep latency of 5.5 minutes and no sleep-onset REM with 5 naps. Brain imaging and electroencephalogram were both normal as well as drug panel, blood counts, metabolic profile and thyroid function. Decreased episodes and severity of recurrent ISP were reported after discontinuation of the supplement. Apart from anxiety related to the episodes, the patient denied any interference with daytime function.
Conclusion
Isolated sleep paralysis is an important sleep disorder that requires proper evaluation to rule out competing diagnoses and consideration of therapeutic interventions. Likely associated with a lack of understanding and available literature, the prevalence in the general population is likely higher than what is currently perceived.
Abstract
Introduction
Patients with narcolepsy have an increased risk of automobile accidents. Solriamfetol, a dopamine/norepinephrine reuptake inhibitor, is approved in the US (Sunosi®) for adults ...with excessive daytime sleepiness (EDS) associated with narcolepsy (75-150 mg/day). This study evaluated the effects of solriamfetol on on-road driving performance in participants with narcolepsy.
Methods
In each period of this randomized, double-blind, placebo-controlled, crossover study (NCT 02806908; EudraCT 2015-003931-36), driving performance during an on-road driving test (a 1-hour drive on a public highway) was assessed at
2 hours and 6 hours postdose following 7 days of treatment with solriamfetol (150 mg/day × 3, then 300 mg/day × 4) or placebo. For assessment of driving performance, the primary endpoint was standard deviation of lateral position (SDLP), a measure of “weaving,” at 2 hours postdose. Comparisons (solriamfetol vs placebo) used a Wilcoxon signed-rank test.
Results
The study included 24 participants (54% male; mean age, 40 years); 22 were included in the analyses of SDLP data. At 2 hours postdose, SDLP for solriamfetol (median, 19.08 cm) was statistically significantly lower than that for placebo (median, 20.46 cm; P=0.0022; incomplete driving tests: solriamfetol, n=4; placebo, n=7), indicating a better performance with solriamfetol. At 6 hours postdose, SDLP for solriamfetol (median, 19.59 cm) was not statistically significantly different from that for placebo (median, 19.78 cm; P=0.1245; incomplete driving tests: solriamfetol, n=3; placebo, n=10). Common adverse events (≥5%) were headache, decreased appetite, somnolence, sleep disorder, agitation, nausea, and palpitations.
Conclusion
Solriamfetol (300 mg/day) improved SDLP, an important measure of driving performance, at 2 hours after administration in participants with narcolepsy.
Support
Jazz Pharmaceuticals
Abstract
Introduction
Functional imaging of narcolepsy type 1 (NT1) has shown disparate results, with evidence for both regional hyper- and hypo-metabolism. A FDG-PET study of idiopathic hypersomnia ...(IH) demonstrated regional hypermetabolism within the salience network.
Methods
Patients with NT1 (n=14) or IH (n=16) were recruited, with age-matched, non-sleepy controls (HC, n=8). Patients discontinued treatment for ≥5 half-lives. Participants underwent injection of 18F-fludeoxyglucose (FDG) in a dimly-lit room and were asked to remain awake, seated quietly. Simultaneous 6-channel EEG, EOG, and EMG were collected. Participants were alerted by a loud noise if sleep onset was observed. Thirty minutes after injection, patients underwent 36-minute PET scan. Images were spatially normalized to MPRAGE images and analyzed for group differences using SPM8.
Results
Groups were similar in age (NT1: 30.0 (+/-SD 8.3), IH: 36.3 (+/-12.4), HC: 33.2 (+/-16.2), p=0.29) and gender (%women, NT1: 71%, IH: 87.5%, HC: 62.5%, p=0.37). Patients were sleepier than controls by Epworth (NT1: 18.2 (+/-3.5), IH: 15.8 (+/-3.2), HC: 5.0 (+/-2.7), p<0.0001) and MSLT mean latency (NT1: 2.0 (+/-1.4), IH: 5.1 (+/-1.7), HC: 14.6 (+/-2.6), p<0.0001). Despite attempts to remain awake, NT1 patients had difficulty maintaining wakefulness during uptake, obtaining 6.2 (+/-5.9) minutes sleep versus <1 minute for the other groups. Compared to controls, NT1 patients demonstrated increased activation in bilateral precentral gyri, left postcentral gyrus, left middle frontal gyrus, right insula, right inferior and superior temporal gyri, right fusiform gyrus, and bilateral inferior frontal gyri. Compared to controls, IH patients demonstrated increased activation in bilateral precuneus, bilateral inferior and middle frontal gyri, left middle and superior temporal gyri, left inferior parietal lobule, and left anterior cingulate.
Conclusion
Different patterns of metabolic activity are seen in two hypersomnia disorders, implying disease-specific activity rather than non-specific sleepiness. Inadvertent sleep during uptake is more common in NT1.
Support
K23 NS083748
Abstract
Introduction
Narcolepsy is a hypersomnolence that is characterized by sleep fragmentation, sleep paralysis, hypnagogic hallucinations and cataplexy that is characterized by atonia induced by ...strong emotions. The amygdala is the trigger for cataplexy through GABAergic mechanisms. Taiep is a myelin mutant with TUBB4A tubulopathy which showed spontaneous episodes of atonia or induced by manipulations from the tail or the thorax. EEG recordings during immobility episodes (IE′s) had a cerebral cortex desynchronized associated to theta rhythm in the hippocampus. The aim of this sturdy was to analyze the effects of bicuculine administration on IE′s and sleep-wake pattern on adult male taiep rats.
Methods
We used 6 taiep male rats at 9 months of age. The subjects (Ss) lived in individual acrylic cages with water and food pellets available ad libitum, under a 12:12 light-dark cycle (lights on at 0700), with controlled temperature and humidity recording room. All Ss were implanted to record EEG, EMG and EOG to characterize EI′s. We evaluated a basal 24 h EEG recording and then after bicuculine i.p. administration of 0.5, 1 y 1.5 mg/Kg every 48h. We measured the number, mean duration and latency to the first IE′s.
Results
The duration of IE′s increased 527% with 1 mg/Kg and reach 700% with 1.5 mg/Kg of bicuculine (P<0.01) with respect to saline-treated control group. Importantly, the frequency of IEs did not differ among the groups and did not affect the number of awake, slow wave or rapid eye movements sleep phases.
Conclusion
Bicuculine, a specific GABA antagonist, modify the duration of IES but not their frequency supporting a role of GABAergic mechanism on IE′s. It is relevant because sodium oxybate, an indirect GABA agonist, reduced cataplexy and improved sleep quality on narcoleptic patients.
Support
CONACYT grants 243333 and 243247 to CC and JRE, respectively and from VIEP-BUAP 2019 to CA in Neuroendocrinología BUAP-CA-288.
Abstract
Introduction
This analysis evaluated the efficacy of pitolisant over time in three 7- to 8-week, randomized, placebo-controlled studies of adults with narcolepsy.
Methods
Patients in all 3 ...studies (HARMONY-1, HARMONY-1bis, HARMONY-CTP) experienced excessive daytime sleepiness (EDS) at study baseline; patients in HARMONY-CTP also experienced ≥3 cataplexy attacks/week. Pitolisant was titrated to a maximum dose of 35.6 mg/day (HARMONY-1, HARMONY-CTP) or 17.8 mg/day (HARMONY-1bis). Change from baseline in mean Epworth Sleepiness Scale (ESS) score (3 studies) and mean weekly rate of cataplexy (WRC; 1 study) was compared for pitolisant versus placebo.
Results
In the higher-dose HARMONY-1 (pitolisant, n=31; placebo, n=30) and HARMONY-CTP (pitolisant, n=54; placebo, n=51) studies, ESS score improvement was significantly greater with pitolisant versus placebo beginning at Week 2 (LS mean difference, -2.8; P=0.015) and Week 3 (LS mean difference, -2.0; P=0.005), respectively. In the lower-dose HARMONY-1bis study (pitolisant, n=66; placebo, n=32), significant separation from placebo was first observed at Week 7 (LS mean difference, -2.3; P=0.044). At end-of-treatment, LS mean difference in ESS score change from baseline was -3.1 (P=0.022) in HARMONY-1, -3.4 (P<0.001) in HARMONY-CTP, and -2.2 (P=0.030) in HARMONY-1bis. In HARMONY-CTP, LS mean WRC with pitolisant was 11.7 at baseline, 4.6 at end-of-treatment, and 5.1 after a 1-week, placebo-washout period. Improvement in WRC was significantly greater with pitolisant versus placebo beginning at Week 2 (LS mean difference, -5.3; P=0.004) and continued through end-of-treatment (LS mean difference, -6.2; P<0.001); there was no evidence of rebound cataplexy after placebo-washout (LS mean difference, -4.9; P=0.027).
Conclusion
During pitolisant treatment, improvement in EDS occurred sooner (within first few weeks) and was more robust in studies that permitted titration to the maximum recommended dose (35.6 mg/day). The rate of cataplexy attacks decreased early during treatment, with no evidence of rebound when pitolisant was withdrawn.
Support
Bioprojet Pharma and Harmony Biosciences, LLC.
Abstract
Introduction
Fitness-based wearables and other emerging sensor technologies have the potential to track sleep across large populations longitudinally in at-home environments. To understand ...how these devices can inform research studies, limitations of available trackers need to be compared to traditional polysomnography (PSG). Here we assessed discrepancies in sleep staging in activity trackers vs. PSG in subjects with various sleep disorders.
Methods
Twelve subjects (age 41-78, 7f, 5m) wore a Fitbit Charge 3 while undergoing a scheduled sleep study. Six subjects had been previously diagnosed with a sleep disorder (5 OSA, 1 CSA). 4 subjects used CPAP throughout the night, 2 had a split night (CPAP 2nd half of the night), and 6 had a PSG only. Activity tracker staging was compared to 2 RPSGTs staging.
Results
Of the 12 subjects, eight subjects’ sleep was detected in the activity tracker, and compared across sleep stages to the PSG (7 female, 1 male, ages 41-78, AHI 0.3-87, RDI 0.5-94.4, sleep efficiency 74%+/-18, 4 PSG, 1 split, 3 CPAP). The activity tracker matched either tech 52% (+/- 13). The average difference in score tech and activity tracker staging for sleep onset (SO) was 16 +/- 15 minutes and wake after sleep onset was 43.5 +/- 44 minutes. Sensitivity, specificity, and balanced accuracy were found for each sleep stage. Respectively, Wake: 0.45+/-0.27, 0.97+/-0.03, 0.71+/-0.12, REM: 0.41+/-0.30, 0.90+/-0.06, 0.60+/-0.28, Light: 0.71+/-0.09, 0.58+/-0.19, 0.65+/-0.10, Deep: 0.63+/-0.52, 0.88+/-0.05, 0.59+/-0.49.
Conclusion
From this study of 12 subjects seen at a sleep clinic for suspected sleep disorders, activity trackers performed best in wake, REM and deep sleep specificity (>=88%), while they lacked sensitivity to REM and wake (<=45%) stages. The tracker did not detect sleep in 4 subjects who had elevated AHI or low sleep efficiency. Further analysis can identify whether discrepancies between the Fitbit and PSG can be predicted by distinct patterns in sleep staging and/or identify subject exclusion criteria for activity tracking studies.
Support
This project in on-going with the support of Academy Diagnostics Sleep and EEG Center and staff.
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