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David Michelson - One of the best experts on this subject based on the ideXlab platform.

  • polysomnographic assessment of Suvorexant in patients with probable alzheimer s disease dementia and insomnia a randomized trial
    Alzheimers & Dementia, 2020
    Co-Authors: Joseph W Herring, Kerry Budd, Jill Hutzelmann, Joanne Stevens, Ellen Snyder, Christopher Lines, Donald L. Bliwise, Paulette Ceesay, David Michelson
    Abstract:

    INTRODUCTION We evaluated the clinical profile of the orexin receptor antagonist Suvorexant for treating insomnia in patients with mild-to-moderate probable Alzheimer's disease (AD) dementia. METHODS Randomized, double-blind, 4-week trial of Suvorexant 10 mg (could be increased to 20 mg based on clinical response) or placebo in patients who met clinical diagnostic criteria for both probable AD dementia and insomnia. Sleep was assessed by overnight polysomnography in a sleep laboratory. The primary endpoint was change-from-baseline in polysomnography-derived total sleep time (TST) at week 4. RESULTS Of 285 participants randomized (Suvorexant, N = 142; placebo, N = 143), 277 (97%) completed the trial (Suvorexant, N = 136; placebo, N = 141). At week 4, the model-based least squares mean improvement-from-baseline in TST was 73 minutes for Suvorexant and 45 minutes for placebo; (difference = 28 minutes [95% confidence interval 11-45], p < 0.01). Somnolence was reported in 4.2% of Suvorexant-treated patients and 1.4% of placebo-treated patients. DISCUSSION Suvorexant improved TST in patients with probable AD dementia and insomnia.

  • orexin receptor antagonists for the treatment of insomnia and potential treatment of other neuropsychiatric indications
    Journal of Sleep Research, 2019
    Co-Authors: Joseph W Herring, Andrew D Krystal, Thomas Roth, David Michelson
    Abstract:

    In this review, we outline the role of orexin receptor antagonists in disorders of sleep/wake and other potential neuropsychiatric conditions, with a focus on Suvorexant, which is currently the only approved agent in this class. The efficacy of Suvorexant was established in Phase 2-3 trials with treatment durations ranging from 1 to 12 months in patients with insomnia. Suvorexant is effective at improving sleep assessed by patient self-report and by polysomnography, with generally little effect on underlying sleep architecture. The main side-effect is next day somnolence. With the growing realization of the important connections between sleep and other disorders, studies are ongoing to explore this novel mechanism in other disorders such as Alzheimer's disease and depression.

  • effects of Suvorexant on the insomnia severity index in patients with insomnia analysis of pooled phase 3 data
    Sleep Medicine, 2017
    Co-Authors: Joseph W Herring, Charles M Morin, Ellen Snyder, Duane B. Snavely, Kathryn M Connor, Christopher Lines, David Michelson
    Abstract:

    Abstract Objective Suvorexant is an orexin receptor antagonist that is approved in the US, Japan and Australia for the treatment of insomnia. Using outcomes from the Insomnia Severity Index (ISI) in the core registration studies, we explored Suvorexant effects on sleep problems and their impact on daytime function. Methods Data were pooled from two similar Phase 3, randomized, double-blind, placebo-controlled, parallel-group, three-month trials in elderly (≥65 years) and non-elderly (18–64 years old) insomnia patients. Age-adjusted (non-elderly/elderly) dose-regimes of 40/30 mg and 20/15 mg were evaluated. The ISI, a 7-item self-rated questionnaire with each item rated on 0–4 scale (higher score corresponds to increasing severity), was administered to patients as an exploratory assessment in both studies at baseline and one and three months after randomization. Results The analysis included 1824 patients. Suvorexant improved change-from-baseline ISI total scores to a greater extent than placebo (Month three: 20/15 mg = −6.2, 40/30 mg = −6.7, placebo = −4.9, p-values for both active arms vs. placebo Conclusions Suvorexant 20/15 mg and 40/30 mg improved sleep to a greater extent than placebo as assessed by the ISI in patients with insomnia. Improvement in sleep onset/maintenance as well as a reduction of the impact of sleep problems on daytime function contributed to the overall improvement observed in ISI total score. ClinicalTrials.gov identifier NCT01097616, NCT01097629.

  • Clinical Trial Design for Assessment of the Orexin Receptor Antagonist Suvorexant in the Treatment of Insomnia in Patients with Alzheimer’s Disease (P3.066)
    Neurology, 2017
    Co-Authors: W.j. Herring, Kerry Budd, Jill Hutzelmann, Ellen Snyder, Donald L. Bliwise, Sonia Ancoli-israel, Tien Dam, David Michelson
    Abstract:

    Objective: To evaluate Suvorexant for the treatment of insomnia in Alzheimer’s disease (AD) patients. Background: Sleep disturbance and insomnia are common in AD but evidence for the efficacy of sleep medications in this population is limited, with few randomized controlled trials. Furthermore, potential worsening of cognitive impairment/next-day function is a concern. Suvorexant, a first-in-class orexin receptor antagonist that enables sleep to occur via competitive antagonism of wake-promoting orexins, was recently approved for treating elderly and non-elderly adults with insomnia. Its unique profile may help to address an important unmet medical need in AD patients with insomnia. Design/Methods: This randomized, placebo-controlled trial consists of a screening period followed by a double-blind 4-week treatment period (clinicalTrials.gov NCT02750306). Patients are required to meet diagnostic criteria for both AD and insomnia and have a qualified trial partner. Eligible patients are randomized to Suvorexant 10mg (may be increased to 20mg) or placebo. Assessments include overnight polysomnography (PSG) visits, an electronic sleep diary (completed by the trial partner), an activity/sleep watch (worn by the patient), and exploratory measures of cognition and neuropsychiatric behavior. The primary hypothesis is that Suvorexant is superior to placebo in improving PSG-derived total sleep time (TST) at Week-4. The planned sample size of 260 randomized subjects/117 evaluable subjects per treatment group has approximately 80% power to detect a 25-minute difference in change-from-baseline in TST between treatment groups (effect size of 0.4). Results: Enrollment of the trial started in May 2016. Results are anticipated in late 2017. Conclusions: This is the largest randomized controlled trial of a sleep medication undertaken in an AD population to date. Results from the trial will help establish the utility of Suvorexant for treating insomnia in AD patients. Study Supported by: Merck & Co. Inc., Kenilworth, NJ, USA Disclosure: Dr. Herring has received personal compensation for activities with Merck as an employee. Dr. Herring holds stock and/or stock options in Merck. Dr. Snyder has received personal compensation for activities with Merck as an employee. Dr. Snyder holds stock and/or stock options in Merck. Dr. Bliwise has received personal compensation for activities with Ferring, Merck, Georgia Institute of Technology, New England Research Institute, Vantia Therapeutics, and Morehouse School of Medicine as a consultant. Dr. Ancoli-Israel has received personal compensation from Merck and Pernix as a speaker and/or advisor. Dr. Budd has received personal compensation for activities with Merck as an employee. Dr. Hutzelmann has received personal compensation for activities with Merck as an employee. Dr. Hutzelmann holds stock and/or stock options in Merck. Dr. Dam has received personal compensation for activities with Merck as an employee. Dr. Dam holds stock and/or stock options in Merck, Dr. Michelson has received personal compensation for activities with Merck & Co., Inc. as an employee. Dr. Michelson hold stock and/or stock options in Merck.

  • effects of Suvorexant on the insomnia severity index in patients with insomnia analysis of pooled phase 3 data p4 292
    Neurology, 2016
    Co-Authors: W.j. Herring, Ellen Snyder, Duane B. Snavely, Christopher Lines, David Michelson
    Abstract:

    Objective: To evaluate the effects of Suvorexant on the Insomnia Severity Index (ISI) which assesses sleep problems and their impact on daytime function. Background: Previously-reported Phase-3 results showed that the orexin receptor antagonist Suvorexant improves sleep maintenance and onset. Methods: The analysis included pooled-data from two similar randomized, double-blind, placebo-controlled, parallel-group, 3-month trials in elderly (≥65y) and non-elderly (18-64y) insomnia patients. Age-adjusted (non-elderly/elderly) dose-regimes of 40/30mg and 20/15mg were evaluated. Fewer patients were assigned to 20/15mg than 40/30mg or placebo. The ISI, a 7-item patient questionnaire, was administered as an exploratory assessment at Months 1 and 3. Results: 1824 patients were included in the analysis. Compared to placebo, Suvorexant improved change-from-baseline in total score at both timepoints (Month 3: 20/15mg = -6.2, 40/30mg = -6.7, placebo = -4.9, p-values <0.001) and the percentage of responders (≥6-point improvement from baseline) at both timepoints (Month 3: 20/15mg = 55.5[percnt], 40/30mg = 54.9[percnt], placebo = 42.2[percnt], p-values <0.001). Scores for individual items of the ISI showed numerical improvement for both Suvorexant dose regimes versus placebo at both timepoints; the “impact of insomnia” component (last 3 items) which assesses the impact of insomnia on daytime function/quality-of-life was also improved by both dose regimes. Conclusions: Suvorexant 20/15mg and 40/30 mg improve sleep as assessed by the ISI in patients with insomnia. Improvement in sleep onset/maintenance as well as a reduction of the impact of sleep problems on daytime function contribute to the overall improvement observed in ISI total score. Given that the maximum approved dose is 20mg, the 20/15mg data are the most clinically relevant. Study Support: Merck & Co. Inc., Kenilworth, NJ, USA Disclosure: Dr. Herring has received personal compensation for activities with Merck & Co. Inc., as an employee. Dr. Snyder has received personal compensation for activities for Merck. Dr. Snavely has received personal compensation for activities with Merck & Co., Inc. as an employee. Dr. Lines has received personal compensation for activities with Merck as an employee. Dr. Michelson has received personal compensation for activities with Merck & Co., Inc. as an employee.

Christopher Lines - One of the best experts on this subject based on the ideXlab platform.

  • pilot evaluation of a consumer wearable device to assess sleep in a clinical polysomnography trial of Suvorexant for treating insomnia in patients with alzheimer s disease
    Journal of Sleep Research, 2021
    Co-Authors: Vladimir Svetnik, Kerry Budd, Jill Hutzelmann, Joanne Stevens, Ellen Snyder, Donald L. Bliwise, Paulette Ceesay, T Wang, Omar Ceren, Christopher Lines
    Abstract:

    The orexin receptor antagonist Suvorexant was previously reported to significantly improve total sleep time (TST), by 28 min per night versus placebo after 4 weeks, in a sleep laboratory polysomnography (PSG) study of patients with Alzheimer's disease and insomnia. The study included an exploratory evaluation of a consumer-grade wearable "watch" device for assessing sleep that we report on here. Participants who met diagnostic criteria for both probable Alzheimer's disease dementia and insomnia were randomized to Suvorexant 10-20 mg (N = 142) or placebo (N = 143) in a double-blind, 4-week trial. Patients were provided with a consumer-grade wearable watch device (Garmin vivosmart® HR) to be worn continuously. Overnight sleep laboratory PSG was performed on three nights: screening, baseline and Night 29 (last dose). Watch treatment effects were assessed by change-from-baseline in watch TST at Week 4 (average TST per night). We also analysed Night 29 data only, with watch data restricted to the PSG recording time. In the 193 participants included in the Week 4 watch analysis (Suvorexant = 97, placebo = 96), the Suvorexant-placebo difference in watch TST was 4 min (p = .622). In patients with usable data for both assessments at the baseline and Night 29 PSG (Suvorexant = 57, placebo = 50), the watch overestimated TST compared to PSG (e.g., placebo baseline = 412 min for watch and 265 min for PSG) and underestimated change-from-baseline treatment effects: the Suvorexant-placebo difference was 20 min for watch TST (p = .405) and 35 min for PSG TST (p = .057). These findings show that the watch was less sensitive than PSG for evaluating treatment effects on TST.

  • effects of bedtime dosing with Suvorexant and zolpidem on balance and psychomotor performance in healthy elderly participants during the night and in the morning
    Journal of Clinical Psychopharmacology, 2021
    Co-Authors: Hubert Bland, Eric Mangin, Joseph W Herring, Christopher Lines, Ka Lai Yee, Gillian Gillespie
    Abstract:

    PURPOSE/BACKGROUND This study was designed as an early assessment of the safety of the orexin receptor antagonist Suvorexant, but also included exploratory assessments of balance and psychomotor performance that are the focus of this report. METHODS/PROCEDURES This was a double-blind, randomized, 3-period, crossover, phase 1 study. Balance and psychomotor performance were evaluated during the night in 12 healthy elderly participants after bedtime administration of Suvorexant 30 mg (a supratherapeutic dose), the GABAergic agonist zolpidem 5 mg (the recommended dose in the elderly), or placebo. Balance (body sway measured by platform stability) and psychomotor performance (measured by choice reaction time) were assessed predose and at 1.5, 4, and 8 hours postdose in each period. Memory (measured by word recall) was assessed predose and at 4 hours postdose. FINDINGS/RESULTS At 1.5 hours after nighttime administration of each drug (the approximate time of their anticipated maximal plasma concentrations), both zolpidem and Suvorexant increased body sway versus placebo, with a greater increase for zolpidem than Suvorexant. Suvorexant increased choice reaction time compared with placebo or zolpidem at 1.5 hours. There were no treatment differences on body sway or choice reaction time at 4 or 8 hours, or on word recall at 4 hours. IMPLICATIONS/CONCLUSIONS These exploratory data suggest that a 30-mg dose of Suvorexant (supratherapeutic) and a 5-mg dose of zolpidem (recommended dose in the elderly) impaired balance at 1.5 hours in healthy elderly people, with potentially less impairment for Suvorexant relative to zolpidem, but no treatment differences on body sway or psychomotor performance at 4 and 8 hours. Because of their exploratory nature, these findings and their clinical relevance, if any, require confirmation in a prospective study.

  • polysomnographic assessment of Suvorexant in patients with probable alzheimer s disease dementia and insomnia a randomized trial
    Alzheimers & Dementia, 2020
    Co-Authors: Joseph W Herring, Kerry Budd, Jill Hutzelmann, Joanne Stevens, Ellen Snyder, Christopher Lines, Donald L. Bliwise, Paulette Ceesay, David Michelson
    Abstract:

    INTRODUCTION We evaluated the clinical profile of the orexin receptor antagonist Suvorexant for treating insomnia in patients with mild-to-moderate probable Alzheimer's disease (AD) dementia. METHODS Randomized, double-blind, 4-week trial of Suvorexant 10 mg (could be increased to 20 mg based on clinical response) or placebo in patients who met clinical diagnostic criteria for both probable AD dementia and insomnia. Sleep was assessed by overnight polysomnography in a sleep laboratory. The primary endpoint was change-from-baseline in polysomnography-derived total sleep time (TST) at week 4. RESULTS Of 285 participants randomized (Suvorexant, N = 142; placebo, N = 143), 277 (97%) completed the trial (Suvorexant, N = 136; placebo, N = 141). At week 4, the model-based least squares mean improvement-from-baseline in TST was 73 minutes for Suvorexant and 45 minutes for placebo; (difference = 28 minutes [95% confidence interval 11-45], p < 0.01). Somnolence was reported in 4.2% of Suvorexant-treated patients and 1.4% of placebo-treated patients. DISCUSSION Suvorexant improved TST in patients with probable AD dementia and insomnia.

  • insight into reduction of wakefulness by Suvorexant in patients with insomnia analysis of wake bouts
    Sleep, 2018
    Co-Authors: Vladimir Svetnik, Ellen Snyder, Thomas Roth, Christopher Lines, Peining Tao, Thomas E Scammell, Joseph W Herring
    Abstract:

    Study objectives To examine the duration and frequency of wake bouts underlying the wakefulness-after-sleep-onset (WASO) reduction with Suvorexant. Methods We analyzed polysomnogram recordings from clinical trials involving 1518 insomnia patients receiving Suvorexant (40/30, 20/15 mg) or placebo to determine the following: (1) the number of, and time spent in, long or short wake bouts and (2) the association between sleep quality and bout characteristics. We also compared wake and sleep bout characteristics of Suvorexant in insomnia patients versus zolpidem in healthy subjects undergoing experimentally induced transient insomnia. Results Relative to placebo, Suvorexant decreased the number and time spent in long wake bouts (>2 minutes) and increased the number and time spent in short wake bouts (≤2 minutes). The time spent in long wake bouts during Night-1 decreased by 32-54 minutes, whereas the time spent in short wake bouts increased by 2-6 minutes. On average, a patient returned to sleep from his or her longest awakening more than twice as fast on Suvorexant than placebo. The reduced time spent in long wake bouts resulted in odds ratios of self-reported good or excellent sleep quality ranging from 1.59 to 2.19 versus placebo. The small increase in time spent in short wake bouts had no effect on odds ratios. Findings were more pronounced for the higher (40/30 mg) doses of Suvorexant. The wake and sleep bout characteristics of Suvorexant differed from zolpidem which equally decreased the number of wake and sleep bouts of all durations during the early part of the night. Conclusion Suvorexant reduces WASO by reducing long wake bouts. This reduction has a positive effect on sleep quality. Clinical trials Trial registration at www.clinicaltrials.gov NCT01097616; NCT01097629.

  • effects of Suvorexant on the insomnia severity index in patients with insomnia analysis of pooled phase 3 data
    Sleep Medicine, 2017
    Co-Authors: Joseph W Herring, Charles M Morin, Ellen Snyder, Duane B. Snavely, Kathryn M Connor, Christopher Lines, David Michelson
    Abstract:

    Abstract Objective Suvorexant is an orexin receptor antagonist that is approved in the US, Japan and Australia for the treatment of insomnia. Using outcomes from the Insomnia Severity Index (ISI) in the core registration studies, we explored Suvorexant effects on sleep problems and their impact on daytime function. Methods Data were pooled from two similar Phase 3, randomized, double-blind, placebo-controlled, parallel-group, three-month trials in elderly (≥65 years) and non-elderly (18–64 years old) insomnia patients. Age-adjusted (non-elderly/elderly) dose-regimes of 40/30 mg and 20/15 mg were evaluated. The ISI, a 7-item self-rated questionnaire with each item rated on 0–4 scale (higher score corresponds to increasing severity), was administered to patients as an exploratory assessment in both studies at baseline and one and three months after randomization. Results The analysis included 1824 patients. Suvorexant improved change-from-baseline ISI total scores to a greater extent than placebo (Month three: 20/15 mg = −6.2, 40/30 mg = −6.7, placebo = −4.9, p-values for both active arms vs. placebo Conclusions Suvorexant 20/15 mg and 40/30 mg improved sleep to a greater extent than placebo as assessed by the ISI in patients with insomnia. Improvement in sleep onset/maintenance as well as a reduction of the impact of sleep problems on daytime function contributed to the overall improvement observed in ISI total score. ClinicalTrials.gov identifier NCT01097616, NCT01097629.

Ellen Snyder - One of the best experts on this subject based on the ideXlab platform.

  • pilot evaluation of a consumer wearable device to assess sleep in a clinical polysomnography trial of Suvorexant for treating insomnia in patients with alzheimer s disease
    Journal of Sleep Research, 2021
    Co-Authors: Vladimir Svetnik, Kerry Budd, Jill Hutzelmann, Joanne Stevens, Ellen Snyder, Donald L. Bliwise, Paulette Ceesay, T Wang, Omar Ceren, Christopher Lines
    Abstract:

    The orexin receptor antagonist Suvorexant was previously reported to significantly improve total sleep time (TST), by 28 min per night versus placebo after 4 weeks, in a sleep laboratory polysomnography (PSG) study of patients with Alzheimer's disease and insomnia. The study included an exploratory evaluation of a consumer-grade wearable "watch" device for assessing sleep that we report on here. Participants who met diagnostic criteria for both probable Alzheimer's disease dementia and insomnia were randomized to Suvorexant 10-20 mg (N = 142) or placebo (N = 143) in a double-blind, 4-week trial. Patients were provided with a consumer-grade wearable watch device (Garmin vivosmart® HR) to be worn continuously. Overnight sleep laboratory PSG was performed on three nights: screening, baseline and Night 29 (last dose). Watch treatment effects were assessed by change-from-baseline in watch TST at Week 4 (average TST per night). We also analysed Night 29 data only, with watch data restricted to the PSG recording time. In the 193 participants included in the Week 4 watch analysis (Suvorexant = 97, placebo = 96), the Suvorexant-placebo difference in watch TST was 4 min (p = .622). In patients with usable data for both assessments at the baseline and Night 29 PSG (Suvorexant = 57, placebo = 50), the watch overestimated TST compared to PSG (e.g., placebo baseline = 412 min for watch and 265 min for PSG) and underestimated change-from-baseline treatment effects: the Suvorexant-placebo difference was 20 min for watch TST (p = .405) and 35 min for PSG TST (p = .057). These findings show that the watch was less sensitive than PSG for evaluating treatment effects on TST.

  • polysomnographic assessment of Suvorexant in patients with probable alzheimer s disease dementia and insomnia a randomized trial
    Alzheimers & Dementia, 2020
    Co-Authors: Joseph W Herring, Kerry Budd, Jill Hutzelmann, Joanne Stevens, Ellen Snyder, Christopher Lines, Donald L. Bliwise, Paulette Ceesay, David Michelson
    Abstract:

    INTRODUCTION We evaluated the clinical profile of the orexin receptor antagonist Suvorexant for treating insomnia in patients with mild-to-moderate probable Alzheimer's disease (AD) dementia. METHODS Randomized, double-blind, 4-week trial of Suvorexant 10 mg (could be increased to 20 mg based on clinical response) or placebo in patients who met clinical diagnostic criteria for both probable AD dementia and insomnia. Sleep was assessed by overnight polysomnography in a sleep laboratory. The primary endpoint was change-from-baseline in polysomnography-derived total sleep time (TST) at week 4. RESULTS Of 285 participants randomized (Suvorexant, N = 142; placebo, N = 143), 277 (97%) completed the trial (Suvorexant, N = 136; placebo, N = 141). At week 4, the model-based least squares mean improvement-from-baseline in TST was 73 minutes for Suvorexant and 45 minutes for placebo; (difference = 28 minutes [95% confidence interval 11-45], p < 0.01). Somnolence was reported in 4.2% of Suvorexant-treated patients and 1.4% of placebo-treated patients. DISCUSSION Suvorexant improved TST in patients with probable AD dementia and insomnia.

  • insight into reduction of wakefulness by Suvorexant in patients with insomnia analysis of wake bouts
    Sleep, 2018
    Co-Authors: Vladimir Svetnik, Ellen Snyder, Thomas Roth, Christopher Lines, Peining Tao, Thomas E Scammell, Joseph W Herring
    Abstract:

    Study objectives To examine the duration and frequency of wake bouts underlying the wakefulness-after-sleep-onset (WASO) reduction with Suvorexant. Methods We analyzed polysomnogram recordings from clinical trials involving 1518 insomnia patients receiving Suvorexant (40/30, 20/15 mg) or placebo to determine the following: (1) the number of, and time spent in, long or short wake bouts and (2) the association between sleep quality and bout characteristics. We also compared wake and sleep bout characteristics of Suvorexant in insomnia patients versus zolpidem in healthy subjects undergoing experimentally induced transient insomnia. Results Relative to placebo, Suvorexant decreased the number and time spent in long wake bouts (>2 minutes) and increased the number and time spent in short wake bouts (≤2 minutes). The time spent in long wake bouts during Night-1 decreased by 32-54 minutes, whereas the time spent in short wake bouts increased by 2-6 minutes. On average, a patient returned to sleep from his or her longest awakening more than twice as fast on Suvorexant than placebo. The reduced time spent in long wake bouts resulted in odds ratios of self-reported good or excellent sleep quality ranging from 1.59 to 2.19 versus placebo. The small increase in time spent in short wake bouts had no effect on odds ratios. Findings were more pronounced for the higher (40/30 mg) doses of Suvorexant. The wake and sleep bout characteristics of Suvorexant differed from zolpidem which equally decreased the number of wake and sleep bouts of all durations during the early part of the night. Conclusion Suvorexant reduces WASO by reducing long wake bouts. This reduction has a positive effect on sleep quality. Clinical trials Trial registration at www.clinicaltrials.gov NCT01097616; NCT01097629.

  • effects of Suvorexant on the insomnia severity index in patients with insomnia analysis of pooled phase 3 data
    Sleep Medicine, 2017
    Co-Authors: Joseph W Herring, Charles M Morin, Ellen Snyder, Duane B. Snavely, Kathryn M Connor, Christopher Lines, David Michelson
    Abstract:

    Abstract Objective Suvorexant is an orexin receptor antagonist that is approved in the US, Japan and Australia for the treatment of insomnia. Using outcomes from the Insomnia Severity Index (ISI) in the core registration studies, we explored Suvorexant effects on sleep problems and their impact on daytime function. Methods Data were pooled from two similar Phase 3, randomized, double-blind, placebo-controlled, parallel-group, three-month trials in elderly (≥65 years) and non-elderly (18–64 years old) insomnia patients. Age-adjusted (non-elderly/elderly) dose-regimes of 40/30 mg and 20/15 mg were evaluated. The ISI, a 7-item self-rated questionnaire with each item rated on 0–4 scale (higher score corresponds to increasing severity), was administered to patients as an exploratory assessment in both studies at baseline and one and three months after randomization. Results The analysis included 1824 patients. Suvorexant improved change-from-baseline ISI total scores to a greater extent than placebo (Month three: 20/15 mg = −6.2, 40/30 mg = −6.7, placebo = −4.9, p-values for both active arms vs. placebo Conclusions Suvorexant 20/15 mg and 40/30 mg improved sleep to a greater extent than placebo as assessed by the ISI in patients with insomnia. Improvement in sleep onset/maintenance as well as a reduction of the impact of sleep problems on daytime function contributed to the overall improvement observed in ISI total score. ClinicalTrials.gov identifier NCT01097616, NCT01097629.

  • Clinical Trial Design for Assessment of the Orexin Receptor Antagonist Suvorexant in the Treatment of Insomnia in Patients with Alzheimer’s Disease (P3.066)
    Neurology, 2017
    Co-Authors: W.j. Herring, Kerry Budd, Jill Hutzelmann, Ellen Snyder, Donald L. Bliwise, Sonia Ancoli-israel, Tien Dam, David Michelson
    Abstract:

    Objective: To evaluate Suvorexant for the treatment of insomnia in Alzheimer’s disease (AD) patients. Background: Sleep disturbance and insomnia are common in AD but evidence for the efficacy of sleep medications in this population is limited, with few randomized controlled trials. Furthermore, potential worsening of cognitive impairment/next-day function is a concern. Suvorexant, a first-in-class orexin receptor antagonist that enables sleep to occur via competitive antagonism of wake-promoting orexins, was recently approved for treating elderly and non-elderly adults with insomnia. Its unique profile may help to address an important unmet medical need in AD patients with insomnia. Design/Methods: This randomized, placebo-controlled trial consists of a screening period followed by a double-blind 4-week treatment period (clinicalTrials.gov NCT02750306). Patients are required to meet diagnostic criteria for both AD and insomnia and have a qualified trial partner. Eligible patients are randomized to Suvorexant 10mg (may be increased to 20mg) or placebo. Assessments include overnight polysomnography (PSG) visits, an electronic sleep diary (completed by the trial partner), an activity/sleep watch (worn by the patient), and exploratory measures of cognition and neuropsychiatric behavior. The primary hypothesis is that Suvorexant is superior to placebo in improving PSG-derived total sleep time (TST) at Week-4. The planned sample size of 260 randomized subjects/117 evaluable subjects per treatment group has approximately 80% power to detect a 25-minute difference in change-from-baseline in TST between treatment groups (effect size of 0.4). Results: Enrollment of the trial started in May 2016. Results are anticipated in late 2017. Conclusions: This is the largest randomized controlled trial of a sleep medication undertaken in an AD population to date. Results from the trial will help establish the utility of Suvorexant for treating insomnia in AD patients. Study Supported by: Merck & Co. Inc., Kenilworth, NJ, USA Disclosure: Dr. Herring has received personal compensation for activities with Merck as an employee. Dr. Herring holds stock and/or stock options in Merck. Dr. Snyder has received personal compensation for activities with Merck as an employee. Dr. Snyder holds stock and/or stock options in Merck. Dr. Bliwise has received personal compensation for activities with Ferring, Merck, Georgia Institute of Technology, New England Research Institute, Vantia Therapeutics, and Morehouse School of Medicine as a consultant. Dr. Ancoli-Israel has received personal compensation from Merck and Pernix as a speaker and/or advisor. Dr. Budd has received personal compensation for activities with Merck as an employee. Dr. Hutzelmann has received personal compensation for activities with Merck as an employee. Dr. Hutzelmann holds stock and/or stock options in Merck. Dr. Dam has received personal compensation for activities with Merck as an employee. Dr. Dam holds stock and/or stock options in Merck, Dr. Michelson has received personal compensation for activities with Merck & Co., Inc. as an employee. Dr. Michelson hold stock and/or stock options in Merck.

Joseph W Herring - One of the best experts on this subject based on the ideXlab platform.

  • effects of bedtime dosing with Suvorexant and zolpidem on balance and psychomotor performance in healthy elderly participants during the night and in the morning
    Journal of Clinical Psychopharmacology, 2021
    Co-Authors: Hubert Bland, Eric Mangin, Joseph W Herring, Christopher Lines, Ka Lai Yee, Gillian Gillespie
    Abstract:

    PURPOSE/BACKGROUND This study was designed as an early assessment of the safety of the orexin receptor antagonist Suvorexant, but also included exploratory assessments of balance and psychomotor performance that are the focus of this report. METHODS/PROCEDURES This was a double-blind, randomized, 3-period, crossover, phase 1 study. Balance and psychomotor performance were evaluated during the night in 12 healthy elderly participants after bedtime administration of Suvorexant 30 mg (a supratherapeutic dose), the GABAergic agonist zolpidem 5 mg (the recommended dose in the elderly), or placebo. Balance (body sway measured by platform stability) and psychomotor performance (measured by choice reaction time) were assessed predose and at 1.5, 4, and 8 hours postdose in each period. Memory (measured by word recall) was assessed predose and at 4 hours postdose. FINDINGS/RESULTS At 1.5 hours after nighttime administration of each drug (the approximate time of their anticipated maximal plasma concentrations), both zolpidem and Suvorexant increased body sway versus placebo, with a greater increase for zolpidem than Suvorexant. Suvorexant increased choice reaction time compared with placebo or zolpidem at 1.5 hours. There were no treatment differences on body sway or choice reaction time at 4 or 8 hours, or on word recall at 4 hours. IMPLICATIONS/CONCLUSIONS These exploratory data suggest that a 30-mg dose of Suvorexant (supratherapeutic) and a 5-mg dose of zolpidem (recommended dose in the elderly) impaired balance at 1.5 hours in healthy elderly people, with potentially less impairment for Suvorexant relative to zolpidem, but no treatment differences on body sway or psychomotor performance at 4 and 8 hours. Because of their exploratory nature, these findings and their clinical relevance, if any, require confirmation in a prospective study.

  • polysomnographic assessment of Suvorexant in patients with probable alzheimer s disease dementia and insomnia a randomized trial
    Alzheimers & Dementia, 2020
    Co-Authors: Joseph W Herring, Kerry Budd, Jill Hutzelmann, Joanne Stevens, Ellen Snyder, Christopher Lines, Donald L. Bliwise, Paulette Ceesay, David Michelson
    Abstract:

    INTRODUCTION We evaluated the clinical profile of the orexin receptor antagonist Suvorexant for treating insomnia in patients with mild-to-moderate probable Alzheimer's disease (AD) dementia. METHODS Randomized, double-blind, 4-week trial of Suvorexant 10 mg (could be increased to 20 mg based on clinical response) or placebo in patients who met clinical diagnostic criteria for both probable AD dementia and insomnia. Sleep was assessed by overnight polysomnography in a sleep laboratory. The primary endpoint was change-from-baseline in polysomnography-derived total sleep time (TST) at week 4. RESULTS Of 285 participants randomized (Suvorexant, N = 142; placebo, N = 143), 277 (97%) completed the trial (Suvorexant, N = 136; placebo, N = 141). At week 4, the model-based least squares mean improvement-from-baseline in TST was 73 minutes for Suvorexant and 45 minutes for placebo; (difference = 28 minutes [95% confidence interval 11-45], p < 0.01). Somnolence was reported in 4.2% of Suvorexant-treated patients and 1.4% of placebo-treated patients. DISCUSSION Suvorexant improved TST in patients with probable AD dementia and insomnia.

  • orexin receptor antagonists for the treatment of insomnia and potential treatment of other neuropsychiatric indications
    Journal of Sleep Research, 2019
    Co-Authors: Joseph W Herring, Andrew D Krystal, Thomas Roth, David Michelson
    Abstract:

    In this review, we outline the role of orexin receptor antagonists in disorders of sleep/wake and other potential neuropsychiatric conditions, with a focus on Suvorexant, which is currently the only approved agent in this class. The efficacy of Suvorexant was established in Phase 2-3 trials with treatment durations ranging from 1 to 12 months in patients with insomnia. Suvorexant is effective at improving sleep assessed by patient self-report and by polysomnography, with generally little effect on underlying sleep architecture. The main side-effect is next day somnolence. With the growing realization of the important connections between sleep and other disorders, studies are ongoing to explore this novel mechanism in other disorders such as Alzheimer's disease and depression.

  • insight into reduction of wakefulness by Suvorexant in patients with insomnia analysis of wake bouts
    Sleep, 2018
    Co-Authors: Vladimir Svetnik, Ellen Snyder, Thomas Roth, Christopher Lines, Peining Tao, Thomas E Scammell, Joseph W Herring
    Abstract:

    Study objectives To examine the duration and frequency of wake bouts underlying the wakefulness-after-sleep-onset (WASO) reduction with Suvorexant. Methods We analyzed polysomnogram recordings from clinical trials involving 1518 insomnia patients receiving Suvorexant (40/30, 20/15 mg) or placebo to determine the following: (1) the number of, and time spent in, long or short wake bouts and (2) the association between sleep quality and bout characteristics. We also compared wake and sleep bout characteristics of Suvorexant in insomnia patients versus zolpidem in healthy subjects undergoing experimentally induced transient insomnia. Results Relative to placebo, Suvorexant decreased the number and time spent in long wake bouts (>2 minutes) and increased the number and time spent in short wake bouts (≤2 minutes). The time spent in long wake bouts during Night-1 decreased by 32-54 minutes, whereas the time spent in short wake bouts increased by 2-6 minutes. On average, a patient returned to sleep from his or her longest awakening more than twice as fast on Suvorexant than placebo. The reduced time spent in long wake bouts resulted in odds ratios of self-reported good or excellent sleep quality ranging from 1.59 to 2.19 versus placebo. The small increase in time spent in short wake bouts had no effect on odds ratios. Findings were more pronounced for the higher (40/30 mg) doses of Suvorexant. The wake and sleep bout characteristics of Suvorexant differed from zolpidem which equally decreased the number of wake and sleep bouts of all durations during the early part of the night. Conclusion Suvorexant reduces WASO by reducing long wake bouts. This reduction has a positive effect on sleep quality. Clinical trials Trial registration at www.clinicaltrials.gov NCT01097616; NCT01097629.

  • effects of Suvorexant on the insomnia severity index in patients with insomnia analysis of pooled phase 3 data
    Sleep Medicine, 2017
    Co-Authors: Joseph W Herring, Charles M Morin, Ellen Snyder, Duane B. Snavely, Kathryn M Connor, Christopher Lines, David Michelson
    Abstract:

    Abstract Objective Suvorexant is an orexin receptor antagonist that is approved in the US, Japan and Australia for the treatment of insomnia. Using outcomes from the Insomnia Severity Index (ISI) in the core registration studies, we explored Suvorexant effects on sleep problems and their impact on daytime function. Methods Data were pooled from two similar Phase 3, randomized, double-blind, placebo-controlled, parallel-group, three-month trials in elderly (≥65 years) and non-elderly (18–64 years old) insomnia patients. Age-adjusted (non-elderly/elderly) dose-regimes of 40/30 mg and 20/15 mg were evaluated. The ISI, a 7-item self-rated questionnaire with each item rated on 0–4 scale (higher score corresponds to increasing severity), was administered to patients as an exploratory assessment in both studies at baseline and one and three months after randomization. Results The analysis included 1824 patients. Suvorexant improved change-from-baseline ISI total scores to a greater extent than placebo (Month three: 20/15 mg = −6.2, 40/30 mg = −6.7, placebo = −4.9, p-values for both active arms vs. placebo Conclusions Suvorexant 20/15 mg and 40/30 mg improved sleep to a greater extent than placebo as assessed by the ISI in patients with insomnia. Improvement in sleep onset/maintenance as well as a reduction of the impact of sleep problems on daytime function contributed to the overall improvement observed in ISI total score. ClinicalTrials.gov identifier NCT01097616, NCT01097629.

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  • on the road driving performance the morning after bedtime use of Suvorexant 15 and 30 mg in healthy elderly
    Psychopharmacology, 2016
    Co-Authors: A Vermeeren, John Palcza, E F P M Vuurman, Stefan Jongen, Anita C M Van Oers, T Laethem, Ingeborg Heirman, An Bautmans, Eva Vets, Matthew D. Troyer
    Abstract:

    Rationale Suvorexant is a first-in-class orexin receptor antagonist for treating insomnia. There is a general concern that hypnotics may impair next-morning driving ability.

  • Effects of Suvorexant, an Orexin Receptor Antagonist, on Respiration during Sleep In Patients with Obstructive Sleep Apnea.
    Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine, 2016
    Co-Authors: John Palcza, Adrianna Gipson, Russell Rosenberg, Meir H Kryger, John A Wagner, Deborah Card, Christopher Lines, Matthew D. Troyer
    Abstract:

    Study Objectives:To investigate the respiratory effects of Suvorexant, an orexin receptor antagonist for treating insomnia, in patients with obstructive sleep apnea (OSA).Methods:This was a randomi...

  • psychomotor effects pharmacokinetics and safety of the orexin receptor antagonist Suvorexant administered in combination with alcohol in healthy subjects
    Journal of Psychopharmacology, 2015
    Co-Authors: Hong Sun, Eric Mangin, John A Wagner, Ka Lai Yee, Sean Gill, Wen Liu, Deborah Panebianco, Dennis Morrison, Jacqueline B. Mccrea, Matthew D. Troyer
    Abstract:

    A double-blind crossover study investigated psychomotor effects, pharmacokinetics, and safety of the orexin receptor antagonist Suvorexant with and without alcohol. Healthy adults (n=31) were randomized to receive placebo or Suvorexant (40 mg) plus placebo solution or alcohol (0.7 g/kg) in each of four treatments (single doses; morning administration). The US Food and Drug Administration approved Suvorexant dose is 10 mg (up to 20 mg) daily. Pharmacodynamic effects were assessed using tests of digit vigilance (DVT; primary endpoint), choice reaction time, digit symbol substitution, numeric working memory, immediate/delayed word recall, body sway and subjective alertness. Suvorexant alone did not significantly affect DVT reaction time, but did impact some pharmacodynamic tests. Suvorexant with alcohol increased reaction time versus either alone (mean difference at 2 h: 44 ms versus Suvorexant, p<0.001; 24 ms, versus alcohol, p<0.05) and had additive negative effects on tests of vigilance, working/episodic memory, postural stability and alertness. No effects of Suvorexant alone or with alcohol were observed by 9 h. No important changes in pharmacokinetic parameters were observed upon co-administration. All treatments were generally well tolerated without serious adverse events. In conclusion, co-administration of 40 mg Suvorexant and 0.7 g/kg alcohol had additive negative psychomotor effects. Patients are advised not to consume alcohol with Suvorexant.

  • Effects of the orexin receptor antagonist Suvorexant on respiration during sleep in healthy subjects
    The Journal of Clinical Pharmacology, 2015
    Co-Authors: Naoto Uemura, Christopher Lines, Gary Zammit, Hong Sun, Jacqueline B. Mccrea, Mardik Donikyan, Rong Liu, Bonnie Louridas, Sabrina Marsilio, Matthew D. Troyer
    Abstract:

    Abstract Suvorexant is an orexin receptor antagonist for treating insomnia. The maximum approved dose in the United States and Japan is 20 mg. We evaluated Suvorexant effects on respiration during sleep in a randomized, double-blind, 3-period crossover study of healthy adult men (n = 8) and women (n = 4) ≤ 50 years old who received single-dose Suvorexant 40 mg, 150 mg, and placebo. Respiration during sleep was measured by oxygen saturation (SpO2 , primary end point) and the Apnea Hypopnea Index (AHI). The study was powered to detect a reduction greater than 5% in SpO2 . There was no effect of Suvorexant on mean SpO2 during sleep. The mean (90%CI) treatment differences versus placebo were -0.3 (-1.2-0.6) for 40 mg and 0.0 (-0.9-0.9) for 150 mg. There were no dose-related trends in individual SpO2 values. Mean SpO2 was >96% for all treatments during total sleep time and during both non-REM and REM sleep. There was no effect of either Suvorexant dose on AHI. The mean (90%CI) treatment differences versus placebo were 0.8 (-0.7-2.3) for 40 mg and -0.2 (-1.7-1.3) for 150 mg. Suvorexant was generally well tolerated; there were no serious adverse experiences or discontinuations. These data from healthy subjects suggest that Suvorexant lacks clinically important respiratory effects during sleep at doses greater than the maximum recommended dose for treating insomnia.

  • effects of Suvorexant an orexin receptor antagonist on breathing during sleep in patients with chronic obstructive pulmonary disease
    Respiratory Medicine, 2015
    Co-Authors: John Palcza, Russell Rosenberg, Tara Siringhaus, Janice Rowe, Meir H Kryger, John A Wagner, Christopher Lines, Matthew D. Troyer
    Abstract:

    Summary Objectives There is a general concern that hypnotic medications in patients with respiratory disorders have the potential to decrease respiratory effort and blunt the arousal response to hypoxemia which may lead to sleep breathing disorders. We investigated whether Suvorexant, an orexin receptor antagonist approved for treatment of insomnia at a maximum daily dose of 20 mg in the US, causes sleep breathing disorders in patients with chronic obstructive pulmonary disease (COPD). Design This was a randomized, double-blind, placebo-controlled, 2-period, cross-over, study performed in 9 sleep laboratories/clinical research units in the United States. The participants were 25 COPD patients aged 39–72 y with mild-to-moderate airflow limitation based on GOLD spirometry criteria. In each period, patients received Suvorexant (40 mg in 2 , primary endpoint) and Apnea Hypopnea Index (AHI, secondary endpoint). The study was powered to rule out a difference between treatments of −2 percentage points in SpO 2 on Day 4. Results There was no treatment effect following single and multiple doses of Suvorexant on mean SpO 2 during total sleep time (Day 1: Suvorexant = 93.14%, placebo = 93.24%, difference = −0.10 [90% CI: −0.50, 0.31]; Day 4: Suvorexant = 93.38%, placebo = 92.99%, difference = 0.39 [90% CI: −0.12, 0.91]). There was no clinically meaningful increase in mean AHI by Suvorexant compared with placebo on Day 1 (difference = 0.72 [90% CI: −0.60, 2.04]) or Day 4 (difference = 2.05 [90% CI: 0.33, 3.77]). Conclusions These data do not suggest an overt respiratory depressant effect with 30–40 mg daily doses of Suvorexant, up to twice the maximum recommended dose for treating insomnia in the US, in patients with mild-to-moderate COPD. Trial registration Clinicaltrials.gov identifier: NCT01293006.

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