357 Daridorexant Does Not Impair Respiratory Function in Patients with Mild/Moderate Obstructive Sleep Apnea Irrespective of Severity

SLEEP ◽  
2021 ◽  
Vol 44 (Supplement_2) ◽  
pp. A142-A143
Author(s):  
Marie-Laure Boof ◽  
Ingo Fietze ◽  
Katharina Lederer ◽  
Anne-Sophie Guern ◽  
Vincent Lemoine ◽  
...  

Abstract Introduction Daridorexant is a dual orexin receptor antagonist developed for the treatment of insomnia. The effect of the highest phase-3 dose of 50 mg daridorexant on nighttime respiratory function was evaluated in patients with mild/moderate obstructive sleep apnea (OSA). This study showed that repeated doses of daridorexant had no clinically meaningful effect on nighttime respiration (i.e., apnea-hypopnea index [AHI] and peripheral oxygen saturation [SpO2]). In the same study, other relevant respiratory endpoints were evaluated. Methods In this randomized, double-blind, placebo-controlled, two-period, crossover study, daridorexant or placebo was administered in each period once daily for 5 consecutive nights to 28 patients. Treatment differences (daridorexant – placebo) for total number and mean/longest duration of apneas and hypopneas as well as mean and lowest SpO2 during apnea/hypopnea events in Night 5 were explored using linear mixed-effects modeling. Treatment differences for the above-mentioned endpoints versus AHI during TST at baseline (i.e., OSA severity) was analyzed by linear regression using least square approach. Results Of 28 patients enrolled, 25 completed the study and were included in the analysis (n=15/10 with mild/moderate OSA; mean [standard deviation, SD] AHI: 16.3 events/h [8.2]). Compared to placebo, daridorexant increased mean duration of TST and accordingly to a not statistically significant extent the mean number of apneas + hypopneas by 16.4 events (n=103 versus 86.2; 90% confidence interval [CI]: -0.4–33.2]) without difference in mean [SD] AHI between daridorexant (15.1 events/h [7.9] and placebo (14.2 [7.7]). No treatment difference was detected for mean (0.0 sec [-2.6–2.7]) or longest (0.8 sec [-8.9–10.5]) duration of apneas nor for mean (0.2 sec [-2.2–2.5]) or longest (8.3 sec [6.4–23.1]) duration of hypopneas. No treatment difference was observed for mean (0.3% [-0.2–2.1]) and lowest (0.9% [0.3–2.1]) SpO2 during apnea/hypopnea events. Treatment differences for any of the evaluated endpoints did not significantly correlate with AHI at baseline as a marker of OSA severity (r2 ≤ 0.09). Conclusion Daridorexant can safely be administered to patients with mild/moderate OSA as treatment differences for respiratory-related endpoints were not of statistical significance and independent of disease severity in the studied population. Support (if any) Funded by Idorsia Pharmaceuticals Ltd.

SLEEP ◽  
2020 ◽  
Author(s):  
Marie-Laure Boof ◽  
Jasper Dingemanse ◽  
Katharina Lederer ◽  
Ingo Fietze ◽  
Mike Ufer

Abstract In this randomized, double-blind, placebo-controlled, two-period crossover study, the effect of the dual orexin receptor antagonist daridorexant was evaluated on nighttime respiratory function and sleep in 28 patients with mild and moderate obstructive sleep apnea (OSA). In each period, 50 mg daridorexant or placebo was administered every evening for 5 days. The primary endpoint was apnea/hypopnea index (AHI) during total sleep time (TST) after the last dosing. Other endpoints included peripheral oxygen saturation (SpO2), sleep duration, latency to persistent sleep (LPS), wake after sleep onset (WASO), and sleep efficiency index (SEI). Pharmacokinetics, safety, and tolerability were also assessed. The mean treatment difference for AHI during TST (i.e. daridorexant − placebo) after the last dosing was 0.74 events/hour (90% confidence interval [CI]: –1.43, 2.92). The corresponding treatment difference for SpO2 during TST was 0.16% [90% CI: –0.21, 0.53]. Overall, there was no clinically relevant effect of daridorexant on AHI or SpO2-related data after single and repeated dosing irrespective of sleep phase (i.e. rapid eye movement [REM] vs non-REM). Moreover, after single and repeated dosing, daridorexant prolonged TST by 39.6 minutes (90% CI: 16.9, 62.3) and 38.8 minutes (19.7, 57.9), respectively, compared with placebo and favorably modulated other sleep-related endpoints (i.e. increased SEI, decreased WASO, and shortened LPS). It attained expected plasma concentrations and was well tolerated in patients with mild and moderate OSA. These results indicate that single and repeated doses of 50 mg daridorexant do not impair nighttime respiratory function and improve sleep in patients with mild and moderate OSA. Clinical Trial Registration ClinicalTrials.gov NCT03765294. A study to investigate the effects of ACT-541468 on nighttime respiratory function in patients with mild to moderate obstructive sleep apnea. https://clinicaltrials.gov/ct2/show/ NCT03765294.


2021 ◽  
pp. 135245852110103
Author(s):  
Sulaiman Khadadah ◽  
R John Kimoff ◽  
Pierre Duquette ◽  
Vincent Jobin ◽  
Yves Lapierre ◽  
...  

Objective: The aim of this study was to evaluate the effect of continuous positive airway pressure (CPAP) treatment on the Fatigue Severity Scale (FSS, preplanned primary outcome), another fatigue measure, sleep quality, somnolence, pain, disability, and quality of life in multiple sclerosis (MS) patients with obstructive sleep apnea-hypopnea (OSAH). Methods: In a randomized, double-blind trial (NCT01746342), MS patients with fatigue, poor subjective sleep quality, and OSAH (apnea-hypopnea index of ⩾ 15 events per hour/sleep), but without severe OSAH (apnea-hypopnea index > 30, and 4% oxygen desaturation index > 15 events/hour or severe somnolence), were randomized to fixed CPAP or sham CPAP for 6 months. Outcome assessments were performed at 3 and 6 months. Results: Of 49 randomized patients, 34 completed the protocol. Among completers, FSS did not improve with CPAP compared to sham at 6 months. FSS tended to improve ( p = 0.09), and sleepiness (Epworth Sleepiness Scale) improved significantly ( p = 0.03) at 3 months with CPAP compared to sham, but there were no other improvements with CPAP at either study evaluation. Conclusion: In non-severe OSAH patients, CPAP did not significantly improve the primary outcome of FSS change at 6 months. In secondary analyses, we found a trend to improved FSS, and a significant reduction in somnolence with CPAP at 3 months.


Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Krishan Patel ◽  
Hussain Basrawala ◽  
Pavan Reddy ◽  
Edwin Valladares ◽  
Vincent Grbach ◽  
...  

Introduction: Obstructive sleep apnea (OSA) is associated with increased rates of atrial fibrillation (AF). Recent randomized data suggest that traditional scoring of OSA needs to evolve to improve cardiovascular outcomes. Traditional scoring of OSA does not fully reflect pathophysiological links between OSA and AF, particularly regarding OSA-induced prolongation of p-wave duration (PWD), which is the most powerful predictor of AF occurrence. Hypothesis: We hypothesized that OSA episodes that closely follow each other (serially stacked apneas, ssOSA) exert greater effect on PWD compared to isolated OSA (iOSA) episodes. Methods: Sleeping patients (adults with mild-moderate OSA and presence of both iOSA and ssOSA, but without other cardiovascular comorbidities) undergoing diagnostic polysomnography were recorded by continuous 8-lead ECG. iOSA was defined as OSA episodes with no other episode within 30 seconds. ssOSA consisted of ≥3 consecutive apneas with inter-OSA intervals <30 seconds. PWD was defined from onset of p-wave in any ECG lead to termination in any lead (measured by digital calipers, averaged over 3 beats from first half of OSA and 3 beats from second half of OSA). Wilcoxon rank-sum test was used. Results: We analyzed 208 OSA episodes (51.0% iOSA, 49.0% ssOSA) which occurred in 12 patients (7 women; age 63.1±11.5 years; apnea hypopnea index 16.8±5.4). PWD was longer during ssOSA compared to iOSA (median 117.7ms vs 109.6ms; p<0.0001). The following variables did not differ between ssOSA and iOSA: PR interval (p=0.3139), RR interval (p=0.7531), peripheral oxygen saturation (p=0.7776). Conclusions: The impact of OSA on atrial conduction delay is exacerbated by the phenomenon of OSA stacking, which seems independent of oxygen desaturation and heart rate. Stacking of OSA episodes may be an underused and cost-efficient variable in evaluating the severity of OSA and the effectiveness of OSA treatments with the ultimate goal of reducing occurrence of AF.


SLEEP ◽  
2021 ◽  
Vol 44 (Supplement_2) ◽  
pp. A143-A143
Author(s):  
Marie-Laure Boof ◽  
Ingo Fietze ◽  
Katharina Lederer ◽  
Anne-Sophie Guern ◽  
Vincent Lemoine ◽  
...  

Abstract Introduction Daridorexant is a dual orexin receptor antagonist developed for the treatment of insomnia. The effect of the highest phase-3 dose of 50 mg daridorexant on nighttime respiratory function was evaluated in patients with mild/moderate obstructive sleep apnea (OSA). This study showed that repeated doses of daridorexant had no clinically meaningful effect on the apnea-hypopnea index (AHI) or on peripheral oxygen saturation. In the same study, the effect on objective sleep parameters was also explored by polysomnography (PSG). Methods In this randomized, double-blind, placebo-controlled, two-period, crossover study, daridorexant or placebo was administered in each period once daily for 5 consecutive nights to 28 patients. Treatment difference (daridorexant – placebo) for total sleep time (TST), latency to persistent sleep (LPS), and wake after sleep onset (WASO) was analyzed for Night 5 using linear mixed-effects modeling. In addition, sleep was further explored based on sleep duration during each hour of PSG recording, duration of the different sleep phases (rapid eye movement [REM], non-REM [including N1 to N3 sleep stages]), as well as number and mean/longest duration of awakenings. Results Of 28 patients enrolled, 25 completed the study and were included in the analysis (n=15/10 with mild/moderate OSA; mean [standard deviation] AHI: 16.3 [8.2] events/h). One patient had mild insomnia symptoms at baseline. Compared to placebo, daridorexant prolonged mean TST by 38.8 min (90% confidence interval: 19.7–57.9), shortened mean LPS by 17.2 min (-35.5–1.02), and reduced mean WASO by 31.0 min (-47.3 to 14.7). Sleep architecture was maintained as no treatment differences in the duration of the evaluated sleep stages were observed when normalized to TST. Sleep duration was prolonged in the second part of the night. mean and longest duration of awakenings were decreased by a mean (90% CI) of 2.0 min (-3.1 to 0.9) and 16.3 min (-24.1 to -8.6), respectively, without treatment difference for the total number of awakenings. Conclusion Daridorexant improved objective sleep parameters in patients with mild to moderate OSA without modifying sleep architecture. Support (if any) Funded by Idorsia Pharmaceuticals Ltd.


2021 ◽  
Author(s):  
Chong Pei ◽  
Shuyu Gui

Abstract Background To evaluate the effect of arterial bicarbonate (HCO3−) concentration on the accuracy of STOP-Bang questionnaire (SBQ) screening for obstructive sleep apnea (OSA). Methods A total of 144 patients with suspected OSA were included. Polysomnograms (PSG) and blood gas analysis were performed, and the Epworth Sleepiness Scale (ESS), STOP-Bang questionnaire, and Berlin questionnaire were completed. The correlation between the arterial HCO3− concentration, apnea hypopnea index (AHI), and other related indicators was analyzed. The scoring results of the ESS, SBQ, and Berlin questionnaire were compared with the PSG results, and the sensitivity and specificity were calculated in the form of a four-cell table. The changes in the sensitivity and specificity of OSA screening after SBQ alone and combined with HCO3− concentration were compared, and ROC curves were drawn. Results Arterial HCO3− concentration was positively correlated with AHI (r = 0.537, P < 0.001). The ratio of HCO3− concentration ≥ 24.6 mmol/L in the non-OSA group was significantly lower than that in the OSA group (25.0% VS 80.8%, P < 0.001). The sensitivity of the SBQ was higher than that of the ESS (97.5% VS 81.7%, P < 0.001) and the Berlin questionnaire (97.5% VS 79.2%, P < 0.001). There was no statistical significance in the specificity of the three scales (25%, 37.5%, 37.5%). A combined SBQ score ≥ 3 and HCO3− concentration ≥ 24.6 mmol/L showed increased specificity and decreased sensitivity compared with an SBQ score ≥ 3 alone, with a corresponding AUC of 0.771 (P < 0.01) and 0.613 (P > 0.05), respectively. Conclusion The sensitivity of the SBQ was better than that of the Berlin questionnaire and ESS. After combining arterial blood HCO3− concentration, the SBQ questionnaire increased the specificity of OSA prediction and decreased the sensitivity, which improved the accuracy of screening.


SLEEP ◽  
2020 ◽  
Vol 43 (Supplement_1) ◽  
pp. A263-A264
Author(s):  
J L Yu ◽  
B T Keenan ◽  
S T Kuna ◽  
M Younes

Abstract Introduction Upper airway stimulation (UAS) is a surgical method of treating obstructive sleep apnea (OSA). UAS involves an implantable neuro-stimulator that stimulates the hypoglossal nerve to protrude the tongue during sleep. OSA fails to improve in 22% of patients who receive UAS as defined by a &gt; 50% reduction in Apnea-Hypopnea Index (AHI) and an AHI &lt;20 events/hour. Light sleep may predict UAS failure in that it may limit the stimulus strength that can be applied. The odds ratio product (ORP) is a novel polysomnographic (PSG) metric of sleep depth. We hypothesized that ORP values prior to surgery will be higher (lighter sleep) in non-responders. Having markers that predict surgical success can help reduce unnecessary surgeries. Methods This is a retrospective cohort study of 126 patients (83 responders vs. 43 non-responders) who received UAS implantation for the treatment of OSA. PSG data was obtained from the Stimulation for Apnea Reduction (STAR) trial. Raw baseline PSG data were analyzed and ORP values calculated using Michele Sleep Scoring Software (Cerebra Medical, Winnipeg, CA). In addition, 13 PSG metrics that were considered possibly relevant to surgical outcome were calculated as an exploratory analysis. The measurements included: spindle density, spindle power, spindle frequency, alpha intrusion, Right/Left sleep depth correlation coefficient, respiratory duty cycle, respiratory flow limitation, and arousal intensity. Statistical Analysis: Comparisons between responders and non-responders used parametric t-tests for continuous data and chi-squared or Fisher’s exact tests for categorical data. Statistical significance was based on a Bonferroni-corrected p&lt;0.00357. Results Differences in ORP values and other PSG metrics between responders and non-responders were not statistically significant. Of all PSG metrics only differences in spindle density approached statistical significance (Responders = 2.33 spindles/minute vs Non-Responders = 1.39 spindles/minute, p=0.00360). Conclusion The findings suggest that differences in sleep depth and several other sleep characteristics do not play a significant role in determining response to UAS therapy. Support This project was supported by a Sleep Research Society Career Development Award #023-JP-19


2018 ◽  
Vol 42 (6) ◽  
pp. 475-477 ◽  
Author(s):  
Luca Levrini ◽  
Giussepa Sara Salone ◽  
German O Ramirez-Yanez

Objective: The purpose of this study was to determine the efficacy of the Myobrace/MyOSA myofunctional appliance for the treatment of mild to moderate Obstructive Sleep Apnea (OSA) in children, by means of the Apnea/Hypopnea Index (AHI). Study design: Nine children with a diagnosis of mild to moderate OSA were included in the study. The subjects wore the Myobrace/MyOSA myofunctional appliance for a period of 90 days. The initial AHI, determined by means of a sleep test, was used as baseline (To), and a second AHI, computed at the end of the experimental period, was used as final data (T1). The differences between the AHIs at To and T1 were calculated (diff AHI) and used for statistical purposes. The level of Oxygen Saturation (SaO2) was also recorded before and after treatment, and their differences calculated as diff SaO2. Statistical analysis was performed with a paired-t- test and statistical significance was established at 95 per cent level of confidence. Results: A statistical significant reduction in the AHI of the studied subjects was computed at the end of the experimental period (p = 0.0425). Although there was an improvement in the SaO2, it did not reach a statistically significant difference. Conclusions: The present results suggest that the Myobrace/MyOSA myofunctional appliance can be an alternative to treat mild to moderate OSA in children. However further studies are necessary to determine the stability of the results after treatment.


2021 ◽  
Vol 2 (Supplement_1) ◽  
pp. A1-A1
Author(s):  
T Altree ◽  
A Aishah ◽  
K Loffler ◽  
R Grunstein ◽  
D Eckert

Abstract Introduction Noradrenergic and muscarinic processes are crucial for pharyngeal muscle control during sleep. Selective norepinephrine reuptake inhibitors (SNRIs) such as reboxetine combined with an antimuscarinic reduce obstructive sleep apnea (OSA) severity. The effects of reboxetine alone on OSA severity are unknown. Methods Double-blind, placebo-controlled, three-way crossover trial in 16 people with OSA. Each participant completed three overnight polysomnograms (~1-week washout). Single doses of reboxetine 4mg, placebo, or reboxetine+oxybutynin 5mg were administered before sleep (randomized order). The primary outcome was apnea-hypopnea index (AHI). Secondary outcomes included other polysomnography parameters, next day sleepiness and alertness. Endotyping analysis was performed to determine the medications’ effects on OSA pathophysiological mechanisms. Results Reboxetine reduced the AHI by 5.4 [95% CI -10.4 to -0.3] events/h, P=0.03 (men: -24±27%; women: -0.7±32%). The addition of oxybutynin did not further reduce AHI. Reboxetine alone and reboxetine+oxybutynin reduced overnight hypoxemia versus placebo (e.g. 4% oxygen desaturation index 10.4±12.8 vs. 10.6±12.8 vs. 15.7±14.7 events/h, P=0.02). Mechanistically, reboxetine and reboxetine+oxybutynin improved pharyngeal collapsibility and respiratory control stability. Men had higher baseline loop gain. Larger reductions in AHI with reboxetine occurred in those with high loop gain. Neither drug intervention changed next day sleepiness or alertness. Discussion A single 4mg dose of reboxetine modestly reduces OSA severity without further improvement with the addition of an antimuscarinic. Reboxetine increases breathing stability via improvements in pharyngeal collapsibility and respiratory control. These findings provide new insight into the role of SNRIs on upper airway stability during sleep and have important implications for pharmacotherapy development for OSA.


2009 ◽  
Vol 67 (1) ◽  
pp. 35-39 ◽  
Author(s):  
Michele Dominici ◽  
Marleide da Mota Gomes

BACKGROUND: The relationship between obstructive sleep apnea (OSA) and depressive symptoms is ambiguous in the literature. PURPOSE: To investigate if there is a correlation between depressive symptoms and the severity of OSA. METHOD: A retrospective, cross-sectional study of data from 123 consecutive adults patients with neither mental illness nor psychotropic drugs intake, referred to a sleep laboratory for an evaluation of OSA. For the statistical analysis (uni- and multivariate), we used the following variables: gender and age, as well as scores based on several scales and indexes such as Beck Depressive Inventory (BDI), Epworth Sleepiness Scale (ESS), Body Mass Index (BMI) and Apnea-Hypopnea Index (AHI). RESULTS: Univariate analysis found a weak but statistically significant negative correlation between BDI and AHI. However, with the multivariate logistic regression analysis model, the inverse relation between AHI and BDI no longer has statistical significance. CONCLUSION: There is no causal relationship between OSA and depressive symptoms in the population studied.


2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Chong Pei ◽  
Shuyu Gui

Abstract Background To evaluate the effect of arterial bicarbonate (HCO3−) concentration on the accuracy of STOP-Bang questionnaire (SBQ) screening for obstructive sleep apnea (OSA). Methods A total of 144 patients with suspected OSA were included. Polysomnograms (PSG) and blood gas analysis were performed, and the Epworth Sleepiness Scale (ESS), STOP-Bang questionnaire, and Berlin questionnaire were completed. The correlation between the arterial HCO3− concentration, apnea hypopnea index (AHI), and other related indicators was analyzed. The scoring results of the ESS, SBQ, and Berlin questionnaire were compared with the PSG results, and the sensitivity and specificity were calculated in the form of a four-cell table. The changes in the sensitivity and specificity of OSA screening after SBQ alone and combined with HCO3− concentration were compared, and ROC curves were drawn. Results Arterial HCO3− concentration was positively correlated with AHI (r = 0.537, P < 0.001). The ratio of HCO3− concentration ≥ 24.6 mmol/L in the non-OSA group was significantly lower than that in the OSA group (25.0% VS 80.8%, P < 0.001). The sensitivity of the SBQ was higher than that of the ESS (97.5% VS 81.7%, P < 0.001) and the Berlin questionnaire (97.5% VS 79.2%, P < 0.001). There was no statistical significance in the specificity of the three scales (25%, 37.5%, 37.5%). A combined SBQ score ≥ 3 and HCO3− concentration ≥ 24.6 mmol/L showed increased specificity and decreased sensitivity compared with an SBQ score ≥ 3 alone, with a corresponding AUC of 0.771 (P < 0.01) and 0.613 (P > 0.05), respectively. Conclusion The sensitivity of the SBQ was better than that of the Berlin questionnaire and ESS. After combining arterial blood HCO3− concentration, the SBQ questionnaire increased the specificity of OSA prediction and decreased the sensitivity, which improved the accuracy of screening.


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