To compare the tolerability and efficacy of a fixed combination solution of dorzolamide/timolol (Cosopt), administered twice daily with the concomitant administration of its components, dorzolamide (Trusopt) twice daily and timolol (Timoptic) twice daily.
METHODS
After a 2 week timolol run in, patients with open angle glaucoma or ocular hypertension were randomised (1:1) to receive treatment with either the dorzolamide/timolol combination solution twice daily (combination) or the dorzolamide solution twice daily plus timolol maleate solution twice daily (concomitant) for 3 months.
RESULTS
299 patients were entered and 290 patients completed the study. Compared with the timolol baseline, additional IOP lowering of 16% was observed at trough (hour 0) and 22% at peak (hour 2) at month 3 in both the concomitant and combination groups. The IOP lowering effects of the two treatment groups were clinically and statistically equivalent as demonstrated by the extremely small point differences (concomitant − combination) observed in this study−0.01 mm Hg at trough and 0.08 mm Hg at peak. The safety variables of the concomitant and combination groups were very similar. Both combination and concomitant therapy were well tolerated and few patients discontinued due to adverse effects.
CONCLUSIONS
The dorzolamide/timolol combination solution administered twice daily is equivalent in efficacy and has a similar safety profile to the concomitant administration of the components administered twice daily.
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.
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 vívosmart ® 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.
To assess the utility of orexin receptor antagonism as a novel approach to treating insomnia.We evaluated suvorexant, an orexin receptor antagonist, for treating patients with primary insomnia in a randomized, double-blind, placebo-controlled, 2-period (4 weeks per period) crossover polysomnography study. Patients received suvorexant (10 mg [n = 62], 20 mg [n = 61], 40 mg [n = 59], or 80 mg [n = 61]) in one period and placebo (n = 249) in the other. Polysomnography was performed on night 1 and at the end of week 4 of each period. The coprimary efficacy end points were sleep efficiency on night 1 and end of week 4. Secondary end points were wake after sleep onset and latency to persistent sleep.Suvorexant showed significant (p values <0.01) dose-related improvements vs placebo on the coprimary end points of sleep efficiency at night 1 and end of week 4. Dose-related effects were also observed for sleep induction (latency to persistent sleep) and maintenance (wake after sleep onset). Suvorexant was generally well tolerated.The data suggest that orexin receptor antagonism offers a novel approach to treating insomnia.This study provides Class I evidence that suvorexant improves sleep efficiency over 4 weeks in nonelderly adult patients with primary insomnia.
Plasminogen activator inhibitor-1 (PAI-1), the specific, fast-acting inhibitor of tissue-type plasminogen activator (t-PA), binds to fibrin and has been found in high concentrations within arterial thrombi. These findings suggest that the localization of PAI-1 to a thrombus protects that same thrombus from fibrinolysis. In this study, clot-bound PAI-1 was assessed for its ability to suppress clot lysis in vivo.Autologous, canine whole blood clots were formed in the presence of increasing amounts of activated PAI-1 (0-30 micrograms/ml). Approximately 6-8% of the PAI-1 bound to the clots under the experimental conditions. Control and PAI-1-enriched clots containing iodine-125-labeled fibrin (ogen) were homogenized, washed to remove nonbound elements, and delivered to the lungs of anesthetized dogs where the homogenates subsequently underwent lysis by the endogeneous fibrinolytic system. 125I-labeled fibrin degradation products appeared in the blood of control animals within 10 minutes and were maximal by 90 minutes. PAI-1 reduced fibrin degradation product release in a dose-responsive manner at all times between 30 minutes and 5 hours (greater than or equal to 76% inhibition at 30 minutes, PAI-1 greater than or equal to 6 micrograms/ml). PAI-1 also suppressed D-dimer release from clots containing small amounts of human fibrin (ogen). t-PA administration attenuated the effects of PAI-1, whereas latent PAI-1 (20 micrograms/ml) had no effect on clot lysis. Blood levels of PA and PAI activity remained unaltered during these experiments.The results indicate that PAI-1 markedly inhibits endogenous fibrinolysis in vivo and, moreover, suggest that the localization of PAI-1 to a forming thrombus is an important physiological mechanism for subsequent thrombus stabilization.
Abstract Introduction Suvorexant, an orexin receptor antagonist, improved total sleep time (TST) in a sleep laboratory polysomnography (PSG) study of patients with Alzheimer’s disease (AD) and insomnia. The study included a pilot evaluation of an actigraphy watch for continuously recording patient’s sleep and daytime activity. We report on the utility of the watch for assessing sleep in relation to gold-standard PSG. Methods This was a randomized, double-blind, 4-week trial (ClinicalTrials.gov NCT02750306). Participants who met diagnostic criteria for both probable AD dementia and insomnia were randomized to suvorexant 10-20mg or placebo. Overnight sleep laboratory PSG was performed on 3 nights: screening, baseline, and Night-29 (last dose). An actigraphy watch (Garmin vívosmart® HR) was worn continuously by the patient. Separate analyses were performed for PSG and watch. We compared treatment effects on change-from-baseline in PSG-TST at Night-29 and WATCH-TST at Week-4 (average TST per night over Week-4). We also analyzed Night-29 data only with watch data restricted to the PSG recording time. Results A total of 274 participants were included in the Night-29 PSG analysis (suvorexant=135, placebo=139) and 223 in the Week-4 watch analysis (suvorexant=113, placebo=110). Suvorexant improved Night-29 PSG-TST by 28 minutes versus placebo (p=0.001) and Week-4 WATCH-TST by 17 minutes versus placebo (p=0.144). In the subgroup who had usable data for both assessments at Night-29 (suvorexant=57, placebo=50), the watch overestimated TST compared to PSG (e.g. placebo baseline scores = 412 minutes for WATCH-TST and 265 minutes for PSG-TST) and underestimated change-from-baseline treatment effects: the suvorexant versus placebo difference was 35 minutes for PSG-TST (p=0.057) and 20 minutes for WATCH-TST (p=0.405). Conclusion The watch was less sensitive than PSG for evaluating treatment effects on TST. However, results obtained with the watch were directionally similar to PSG in indicating a benefit of suvorexant versus placebo for improving TST in AD patients with insomnia. Support Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA
