On-the-road driving performance the morning after bedtime use of suvorexant 15 and 30 mg in healthy elderly

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. The objective of this study was to evaluate next-morning driving performance in older adults after single and repeated doses of suvorexant. Double-blind, randomized, placebo-controlled, 4-period crossover study in 24 healthy volunteers (10 females), aged 65-80 years. Subjects were treated with suvorexant (15 and 30 mg) for eight consecutive nights, zopiclone 7.5 mg nightly on days 1 and 8, and placebo. Driving performance was assessed on days 2 and 9 (9 h after dosing) using a 1-h standardized highway driving test in normal traffic, measuring standard deviation of lateral position (SDLP). Drug-placebo differences in SDLP > 2.4 cm were considered to reflect clinically meaningful driving impairment. Driving performance as measured by SDLP was not impaired following suvorexant. Mean drug-placebo differences in SDLP following suvorexant 15 and 30 mg on day 2 and 9 were 0.6 cm or less. Their 90 % CIs were all below the threshold of 2.4 cm for clinical relevance and included zero, indicating effects were not clinically meaningful or statistically significant. Symmetry analysis showed no significant differences between the number of participants who had SDLP differences > 2.4 cm and those who had SDLP differences There was no clinically meaningful residual effect of suvorexant 15 and 30 mg on next-morning driving (9 h after bedtime dosing) in healthy older adults, as assessed by mean changes in SDLP and by the number of participants on drug versus placebo that exceeded a predetermined threshold for clinically meaningful impairment

On-the-Road Driving Performance the Morning after Bedtime Use of Suvorexant 20 and 40 mg: A Study in Non-Elderly Healthy Volunteers

Study Objective: To evaluate next-morning driving performance in adults younger than 65 years, after single and repeated doses of suvorexant 20 and 40 mg. Design: Double-blind, placebo-controlled, 4-period crossover study. Setting: Maastricht University, The Netherlands. Participants: 28 healthy volunteers (15 females), aged 23 to 64 years. Interventions: Suvorexant (20 and 40 mg) for 8 consecutive nights; zopiclone 7.5 mg nightly on day 1 and 8; placebo. Measurements: Performance on day 2 and 9 (9 h after dosing) using a one-hour standardized highway driving test in normal traffic, measuring standard deviation of lateral position (SDLP). Drug-placebo changes in SDLP > 2.4 cm were considered to reflect meaningful driving impairment. Results: Mean drug-placebo changes in SDLP following suvorexant 20 and 40 mg were 1.01 and 1.66 cm on day 2, and 0.48 and 1.31 cm on Day 9, respectively. The 90% CIs of these changes were all below 2.4 cm. Symmetry analysis showed that more subjects had SDLP changes > 2.4 cm than < -2.4 cm following suvorexant 20 and 40 mg on day 2, and following suvorexant 40 mg on day 9. Four female subjects requested that a total of 5 driving tests-all following suvorexant-stop prematurely due to self-reported somnolence. Conclusions: As assessed by mean changes in standard deviation of lateral position (SDLP), there was no clinically meaningful residual effect of suvorexant in doses of 20 and 40 mg on next-morning driving (9 h after bedtime dosing) in healthy subjects < 65 years old. There may be some individuals who experience next-day effects, as suggested by individual changes in SDLP and prematurely stopped tests

Rhinovirus-16 induced temporal interferon responses in nasal epithelium links with viral clearance and symptoms

Background: The temporal in vivo response of epithelial cells to a viral challenge and its association with viral clearance and clinical outcomes has been largely unexplored in asthma. Objective: To determine gene expression profiles over time in nasal epithelial cells (NECs) challenged in vivo with rhinovirus-16 (RV16) and compare to nasal symptoms and viral clearance. Methods: Patients with stable mild to moderate asthma (n = 20) were challenged intranasally with RV16. Nasal brush samples for RNA sequencing were taken 7 days prior to infection and 3, 6 and 14 days post-infection, and blood samples 4 days prior to infection and day 6 post-infection. Viral load was measured in nasal lavage fluid at day 3, 6 and 14. Results: Top differentially (>2.5-fold increase) expressed gene sets in NECs post-RV16 at days 3 and 6, compared with baseline, were interferon alpha and gamma response genes. Patients clearing the virus within 6 days (early resolvers) had a significantly increased interferon response at day 6, whereas those having cleared the virus by day 14 (late resolvers) had significantly increased responses at day 3, 6 and 14. Interestingly, patients not having cleared the virus by day 14 (non-resolvers) had no enhanced interferon responses at any of these days. The daily Cold Symptom Scores (CSS) peaked at days 3 to 5 and correlated positively with interferon response genes at day 3 (R = 0.48), but not at other time-points. Interferon response genes were also enhanced in blood at day 6 after RV16 challenge. Conclusion and Clinical Relevance: This study shows that viral load and clearance varies markedly over time in mild to moderate asthma patients exposed to a fixed RV16 dose. The host's nasal interferon response to RV16 at day 3 is associated with upper respiratory tract symptoms. The temporal interferon response in nasal epithelium associates with viral clearance in the nasal compartment

Validated and longitudinally stable asthma phenotypes based on cluster analysis of the ADEPT study

BACKGROUND: Asthma is a disease of varying severity and differing disease mechanisms. To date, studies aimed at stratifying asthma into clinically useful phenotypes have produced a number of phenotypes that have yet to be assessed for stability and to be validated in independent cohorts. The aim of this study was to define and validate, for the first time ever, clinically driven asthma phenotypes using two independent, severe asthma cohorts: ADEPT and U-BIOPRED. METHODS: Fuzzy partition-around-medoid clustering was performed on pre-specified data from the ADEPT participants (n = 156) and independently on data from a subset of U-BIOPRED asthma participants (n = 82) for whom the same variables were available. Models for cluster classification probabilities were derived and applied to the 12-month longitudinal ADEPT data and to a larger subset of the U-BIOPRED asthma dataset (n = 397). High and low type-2 inflammation phenotypes were defined as high or low Th2 activity, indicated by endobronchial biopsies gene expression changes downstream of IL-4 or IL-13. RESULTS: Four phenotypes were identified in the ADEPT (training) cohort, with distinct clinical and biomarker profiles. Phenotype 1 was "mild, good lung function, early onset", with a low-inflammatory, predominantly Type-2, phenotype. Phenotype 2 had a "moderate, hyper-responsive, eosinophilic" phenotype, with moderate asthma control, mild airflow obstruction and predominant Type-2 inflammation. Phenotype 3 had a "mixed severity, predominantly fixed obstructive, non-eosinophilic and neutrophilic" phenotype, with moderate asthma control and low Type-2 inflammation. Phenotype 4 had a "severe uncontrolled, severe reversible obstruction, mixed granulocytic" phenotype, with moderate Type-2 inflammation. These phenotypes had good longitudinal stability in the ADEPT cohort. They were reproduced and demonstrated high classification probability in two subsets of the U-BIOPRED asthma cohort. CONCLUSIONS: Focusing on the biology of the four clinical independently-validated easy-to-assess ADEPT asthma phenotypes will help understanding the unmet need and will aid in developing tailored therapies. TRIAL REGISTRATION: NCT01274507 (ADEPT), registered October 28, 2010 and NCT01982162 (U-BIOPRED), registered October 30, 2013