Paulette Ceesay’s research while affiliated with Merck & Co. and other places

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.

Introduction Full montage polysomnography (PSG) is the gold standard for the objective evaluation of sleep but is time consuming and inaccessible to most clinicians. A Clinician’s Global Impression of Severity (CGI-S) scale can be used in clinical practice to provide a subjective assessment of patients’ insomnia severity. However, the utility of a CGI-S scale for assessing insomnia in patients with Alzheimer’s disease (AD)-dementia is not well understood. In a recent Phase III randomized, placebo-controlled clinical trial (NCT02750306), patients on suvorexant with AD-dementia and insomnia showed improvements in both PSG total sleep time (TST) and CGI-S scores. We conducted additional analyses to examine the association between CGI-S and PSG-TST to inform on the possible use of a CGI-S scale to assess insomnia severity in patients with AD-dementia in real-world settings. Methods Patients (N=285) met clinical diagnostic criteria for both probable mild-to-moderate AD-dementia and insomnia. The primary endpoint was change-from-baseline in overnight PSG-TST at Week-4. A single-item CGI-S rating of insomnia with responses of 1 (normal, not ill at all) to 7 (among the most extremely ill patients) was completed by a trained rater at baseline and after 2 and 4 weeks. CGI-S was an exploratory endpoint. Post-hoc correlational analyses and analyses of distribution of change-from-baseline to Week-4 in CGI-S response categories were performed. Results Pearson correlation indicated a significant association at baseline between PSG-TST and CGI-S (r=-0.18, nominal p=0.004). A correlation of change-from-baseline to Week-4 also indicated an association between PSG-TST and CGI-S (r=-0.24, nominal p<.0001). The distribution of change in CGI-S response category results at Week-4 showed that, compared to placebo, numerically less patients on suvorexant remained stable or worsened by >1 response category (21.8% vs. 29.4%, respectively) and numerically more improved by ≥1 response category (73.3% vs. 67.9%, respectively). Conclusion Our findings suggest that a CGI-S scale may be a useful tool for assessing insomnia severity in mild-to-moderate AD-dementia patients. Future studies with these patients are needed to determine the utility of a CGI-S scale in real-world settings. Support (if any) This study was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA

Introduction Suvorexant, an orexin receptor antagonist that enables sleep to occur via competitive antagonism of wake-promoting orexins, improved total sleep time (TST) in a sleep laboratory polysomnography (PSG) study of patients with AD and insomnia. Here we report on the effects of suvorexant on sleep architecture in the study. Methods This was a randomized, double-blind, 4-week trial (ClinicalTrials.gov NCT02750306). Participants who met diagnostic criteria for both probable AD dementia (of mild to moderate severity) and insomnia were randomized to suvorexant 10mg (could be increased to 20mg based on clinical response) or matching placebo. Overnight sleep laboratory PSG was performed on 3 nights: screening, baseline, and Night-29 (last night of dosing). Suvorexant differences from placebo in changes-from-baseline at Night-29 for sleep architecture were analyzed as exploratory endpoints. Results A total of 274 participants were included in the analysis (suvorexant N=135, placebo N=139). At Night-29, suvorexant improved TST by 28 minutes versus placebo (p=0.001). There were no significant differences between suvorexant and placebo in the % of TST spent in REM (1.3%, 95% CI: -0.5, 3.0), N1 (0.6%, 95% CI: -1.2, 2.5), N2 (-1.0%, 95% CI: -3.2, 1.2), or N3 (-0.6%, 95% CI: -1.8, 0.6). There was no significant difference between suvorexant and placebo in latency to REM (-5.4 minutes, 95% CI: -23.4, 12.7). Conclusion Suvorexant improves TST without altering the underlying sleep architecture in AD patients with insomnia. Support Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA

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

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.

Introduction 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. Methods 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. Results 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. Conclusion Suvorexant was effective and generally well-tolerated for treating insomnia in patients with AD. Support (If Any) Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA

Benefit-risk (BR) assessment is essential to ensure the best decisions are made for a medical product in the clinical development process, regulatory marketing authorization, post-market surveillance, and coverage and reimbursement decisions. One challenge of BR assessment in practice is that the benefit and risk profile may keep evolving while new evidence is accumulating. Regulators and the International Conference on Harmonization (ICH) recommend performing periodic benefit-risk evaluation report (PBRER) through the product's lifecycle. In this paper, we propose a general statistical framework for periodic benefit-risk assessment, in which Bayesian meta-analysis and stochastic multi-criteria acceptability analysis (SMAA) will be combined to synthesize the accumulating evidence. The proposed approach allows us to compare the acceptability of different drugs dynamically and effectively and accounts for the uncertainty of clinical measurements and imprecise or incomplete preference information of decision makers. We apply our approaches to two real examples in a post-hoc way for illustration purpose. The proposed method may easily be modified for other pre and post market settings, and thus be an important complement to the current structured benefit-risk assessment (sBRA) framework to improve the transparent and consistency of the decision-making process.