Sleep disturbance and insomnia are common in patients with Alzheimer’s disease (AD) but evidence for the efficacy of sleep medications in this population is limited. Suvorexant, a first-in-class orexin receptor antagonist that enables sleep to occur via competitive antagonism of wake-promoting orexins, is approved for treating insomnia in elderly and non-elderly adults. We conducted a clinical trial to evaluate its efficacy and safety for treating insomnia in patients with AD using sleep laboratory polysomnography (PSG) assessments. This randomized, placebo-controlled trial consisted of a 3-week screening period followed by a double-blind 4-week treatment period (ClinicalTrials.gov: NCT02750306). Patients met diagnostic criteria for both AD and insomnia and had a qualified trial partner/caregiver. Participants were randomized to an initial dose of suvorexant 10mg, that could be increased to 20mg based on clinical response, or matching placebo. Assessments included overnight sleep laboratory PSG visits, a 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 objective was to test the hypothesis that suvorexant would be superior to placebo in improving PSG-derived total sleep time (TST) at Week-4. A total of 285 participants (suvorexant N=142, placebo N=143) were randomized from 35 sites in 8 countries worldwide. Of these, 277 (97%) completed the study (suvorexant N=136, placebo N=141). One patient in each group discontinued study treatment due to an adverse event. Mean (SD) TST at baseline was 278 (77) minutes for suvorexant and 274 (84) minutes for placebo. At Week-4, the model-based least squares mean changes-from-baseline were 73 minutes for suvorexant and 45 minutes for placebo (difference = 28 minutes [95% CI:11,45], p<0.005). Regarding safety, 22.5% of suvorexant-treated patients and 16.1% of placebo-treated patients experienced ≥1 adverse events. Somnolence was reported in 4.2% of suvorexant-treated patients and 1.4% of placebo-treated patients. Suvorexant was effective and generally well-tolerated for treating insomnia in patients with AD. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA
Plasminogen activator inhibitor-1 (PAI-1) accumulates within thrombi and forming whole blood clots. To explore this phenomenon at the molecular level, PAI-1 binding to fibrin was examined. The experiments were performed by adding 125I-PAI-1, which retains its complete tissue-type plasminogen (t-PA) inhibitory activity, to fibrin matrices formed in 2-cm2 tissue culture wells. Guanidine HCl-activated PAI-1 binding was reversible and was inhibited in the presence of excess, unlabeled PAI-1. Activated 125I-PAI-1 recognized 2 sites on fibrin: a very small number of high affinity sites (Kd less than 1 nM) and principally a large number of low affinity sites with an approximate Kd of 3.8 microM. Latent PAI-1 bound to fibrin at a site indistinguishable from the lower affinity site recognized by activated PAI-1. Fibrin, pretreated with activated PAI-1, was protected from t-PA-mediated plasmin degradation in a PAI-1 dose-responsive manner (IC50 = 12.3 nM). Clot protection correlated with partial occupancy of the low affinity PAI-1 binding site on fibrin and was due to the formation of sodium dodecyl sulfate-stable, PAI-1.t-PA complexes. Latent PAI-1 (27 nM) did not protect the fibrin from dissolution. The localization of PAI-1 to a thrombus by virtue of its fibrin binding potential could result in significant protection of the thrombus from the degradative effects of the fibrinolytic system.
Recent research has identified important bidirectional relationships between sleep and Alzheimer's disease (AD). Sleep disturbance and insomnia are common in patients with AD but evidence for the efficacy of sleep medications in this population is limited. Furthermore, potential worsening of cognitive impairment/next-day function is a concern. Suvorexant is an orexin receptor antagonist that enables sleep to occur via competitive antagonism of wake-promoting orexins. We conducted a trial to evaluate its profile for treating insomnia in patients with AD. This randomized, placebo-controlled trial consisted of a 3-week screening period followed by a double-blind 4-week treatment period (ClinicalTrials.gov NCT02750306). Participants were required to meet diagnostic criteria for both AD and insomnia and have a qualified trial partner/caregiver. Eligible participants were randomized to an initial dose of suvorexant 10mg, that could be increased to 20mg based on clinical response, or matching placebo. Sleep was assessed by polysomnography (PSG) during overnight sleep laboratory visits. The primary objective was to test the hypothesis that suvorexant would be superior to placebo in improving PSG-derived total sleep time (TST) at Week-4. PSG-derived wake after sleep onset (WASO) was assessed as a secondary endpoint. A total of 285 participants (suvorexant N=142, placebo N=143) were randomized. Of these, 277 (97%) completed the study (suvorexant N=136, placebo N=141). The percentage of participants who had their dose titrated up was 77% for suvorexant and 73% for placebo. The model-based least squares mean increase from baseline in TST at Week-4 was 73 minutes for suvorexant and 45 minutes for placebo; the increase for suvorexant relative to placebo was 28 minutes [95% CI: 11,45], p<0.005. The model-based least squares mean reduction from baseline in WASO at Week-4 was -45 minutes for suvorexant and -29 minutes for placebo; the reduction for suvorexant relative to placebo was -16 minutes [95% CI: -28,-3], p<0.05. Regarding tolerability, 22.5% and 16.1% of participants experienced one or more adverse events when treated with suvorexant or placebo, respectively. Somnolence was reported in 4.2% of suvorexant-treated participants and 1.4% of those administered placebo. Suvorexant was effective and generally well-tolerated for treating insomnia in patients with AD.
We evaluated the orexin receptor antagonist filorexant (MK-6096) for treatment augmentation in patients with major depressive disorder. We conducted a 6-week, double-blind, placebo-controlled, parallel-group, Phase II, proof-of-concept study. Patients with major depressive disorder (partial responders to ongoing antidepressant therapy) were randomized 1:1 to once-daily oral filorexant 10 mg or matching placebo. Due to enrollment challenges, the study was terminated early, resulting in insufficient statistical power to detect a prespecified treatment difference; of 326 patients planned, 129 (40%) were randomized and 128 took treatment. There was no statistically significant difference in the primary endpoint of change from baseline to week 6 in Montgomery Asberg Depression Rating Scale total score; the estimated treatment difference for filorexant-placebo was -0.7 (with negative values favoring filorexant) (P=.679). The most common adverse events were somnolence and suicidal ideation. The interpretation of the results is limited by the enrollment, which was less than originally planned, but the available data do not suggest efficacy of orexin receptor antagonism with filorexant for the treatment of depression. (Clinical Trial Registry: clinicaltrials.gov: NCT01554176)
To compare the efficacy and tolerability of dorzolamide to acetazolamide.Following a timolol and acetazolamide run-in, 105 patients with elevated intraocular pressure (IOP) were randomized to dorzolamide or acetazolamide, in addition to timolol, for 12 weeks.More patients receiving acetazolamide discontinued due to clinical adverse experiences than patients receiving dorzolamide; 13 (25%) vs. 1 (2%); p<0.001. The prevalence of systemic adverse experiences for the dorzolamide group dropped by 50% by Week 12, but remained unchanged for the acetazolamide group, as compared to baseline; p<0.001. Ocular burning/stinging was more common in the dorzolamide group (21% vs. 0%; p<0.001). The mean trough IOP at Day 1 and Week 12 were 20.5 mmHg and 21.8 mmHg for the dorzolamide group, and 20.4 mmHg and 20.5 mmHg for the acetazolamide group. The mean peak IOP at Dayl and Week 12 were 18.9 mmHg and 20.0 mmHg for the dorzolamide group, and 18.7 mmHg and 18.6 mmHg for the acetazolamide group.Mean IOP was slightly lower (by approximately 1 mmHg) with acetazolamide, while dorzolamide demonstrated much better tolerability.
Suvorexant is an orexin receptor antagonist approved for treating insomnia at a maximum dose of 20 mg. Phase-3 trials evaluated two age-adjusted (non-elderly/elderly) dose-regimes of 40/30 mg and 20/15 mg with the primary focus on 40/30 mg. We report here results from pooled analyses of the 20/15 mg dose-regime, which was evaluated as a secondary objective in the trials.Prespecified analysis of pooled data from two identical randomized, double-blind, placebo-controlled, parallel-group, 3-month trials in non-elderly (18-64 years) and elderly (≥ 65 years) patients with insomnia. Patients were randomized to suvorexant 20/15 mg (non-elderly/elderly), suvorexant 40/30 mg (non-elderly/elderly), or placebo; by design, fewer patients were randomized to 20/15 mg. Efficacy was assessed by self-reported and polysomnography (PSG; subset of patients) sleep maintenance and onset endpoints.Suvorexant 20/15 mg (N = 493 treated) was effective compared to placebo (N = 767 treated) on patient-reported and PSG sleep maintenance and onset endpoints at Night-1 (PSG endpoints) / Week-1 (subjective endpoints), Month-1 and Month-3, except for effects on PSG sleep onset at Month-3. Suvorexant 20/15 mg was generally well tolerated, with 3% of patients discontinuing due to adverse events over 3 months vs. 5.2% on placebo. Somnolence was the most common adverse event (6.7% vs. 3.3% for placebo). There was no systematic evidence of rebound or withdrawal signs or symptoms when suvorexant was discontinued after 3 months of nightly use.Suvorexant 20/15 mg improved sleep onset and maintenance over 3 months of nightly treatment and was generally safe and well tolerated.ClinicalTrials.gov trial registration numbers: NCT01097616, NCT01097629.
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.
Objective: To evaluate suvorexant for treating insomnia in patients with Alzheimer’s disease (AD) using gold-standard sleep laboratory polysomnography (PSG) assessments. Background: Sleep disturbance and insomnia are common in patients with 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, is approved for treating insomnia in elderly and non-elderly adults. Its clinical profile may help to address an important unmet medical need in patients with AD who have insomnia. Design/Methods: This randomized, placebo-controlled trial consisted of a screening period followed by a double-blind 4-week treatment period (clinicalTrials.govNCT02750306). Participants were required to meet diagnostic criteria for both AD and insomnia and have a qualified trial partner. Eligible participants were randomized to suvorexant 10 mg (could be increased to 20 mg) or placebo. Assessments included overnight sleep laboratory 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. Results: Enrollment of the trial started in May 2016 and completed in September 2018. A total of 285 participants were randomized from 35 sites in 8 countries worldwide. Results will be available in 2019 and will be presented at the meeting. Conclusions: This is the largest randomized controlled trial of the effects of a sleep medication on PSG sleep measures undertaken in an AD population. Results from the trial will help inform on the efficacy and safety of suvorexant for treating insomnia in AD. Disclosure: Dr. Herring has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Merck & Co., Inc.. Dr. Herring holds stock and/or stock options in Merck & Co., Inc. which sponsored research in which Dr. Herring was involved as an investigator. Dr. Herring holds stock and/or stock options in Merck & Co., Inc. Dr. Ceesay has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Merck & Co, Inc. Dr. Ceesay holds stock and/or stock options in Merck & Co, Inc. Dr. Snyder has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Merck & Co., Inc. Dr. Snyder holds stock and/or stock options in Merck & Co., Inc. Dr. Biwise has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Merck & Co., Inc., Ferring, Jazz, Eisai, Respicardia. Dr. Biwise has received research support from Merck & Co., Inc., Ferring, Jazz, Eisai, Respicardia. Dr. Budd has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Merck & Co., Inc.. Dr. Budd holds stock and/or stock options in Merck & Co., Inc.. Dr. Hutzelmann has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Merck & Co., Inc. Dr. Hutzelmann holds stock and/or stock options in Merck & Co., Inc. Dr. Stevens has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Merck & Co., Inc.. Dr. Stevens has received compensation for serving on the Board of Directors of Merck &Co., Inc. Dr. Stevens holds stock and/or stock options in Merck & Co., Inc. which sponsored research in which Dr. Stevens was involved as an investigator. . Dr. Michelson has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Merck & Co., Inc. Dr. Michelson holds stock and/or stock options in Merck & Co., Inc. which sponsored research in which Dr. Michelson was involved as an investigator. Dr. Michelson holds stock and/or stock options in Merck & Co., Inc.
