Randomized, controlled, proof-of-concept trial of gefapixant for endometriosis-related pain.

Objective: To evaluate the P2X3 receptor antagonist, gefapixant, for treating moderate-to-severe endometriosis-related pain.

Design: Randomized, double-blind, phase 2, and proof-of-concept trial.

Setting: Outpatients at hospitals, medical centers or clinical research sites.

Progression from Prodromal Alzheimer's Disease to Mild Alzheimer's Disease Dementia in the Verubecestat APECS Study: Adjudicating Diagnostic Transitions.

Background: Delay of progression from prodromal Alzheimer's disease (AD) to dementia is an important outcome in AD trials. Centralized adjudication is intended to improve the consistency of dementia diagnosis but has not been scrutinized.

Objective: To evaluate centralized adjudication for determining progression to dementia compared with Site Investigator opinion or change in Clinical Dementia Rating (CDR).

Comparison of polysomnography in people with Alzheimer's disease and insomnia versus non-demented elderly people with insomnia.

Background: We used baseline polysomnography (PSG) data obtained during the clinical program development for suvorexant to compare the PSG profiles of people with Alzheimer's disease and insomnia (ADI) versus age-matched elderly individuals with insomnia (EI).

Methods: Sleep laboratory baseline PSG data from participants age 55-80 years from 2 trials in people with insomnia and a trial in people with ADI were included. ADI participants had dementia of mild-to-moderate severity.

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.

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.

Effects of Bedtime Dosing With Suvorexant and Zolpidem on Balance and Psychomotor Performance in Healthy Elderly Participants During the Night and in the Morning.

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.

BACE inhibition causes rapid, regional, and non-progressive volume reduction in Alzheimer's disease brain.

In the phase 3 EPOCH trial (Clinicaltrials.gov; NCT01739348), treatment with the BACE inhibitor verubecestat failed to improve cognition in patients with mild-to-moderate Alzheimer's disease, but was associated with reduced hippocampal volume after 78 weeks as assessed by MRI. The aims of the present exploratory analyses were to: (i) characterize the effect of verubecestat on brain volume by evaluating the time course of volumetric MRI changes for a variety of brain regions; and (ii) understand the mechanism through which verubecestat might cause hippocampal (and other brain region) volume loss by assessing its relationship to measures of amyloid, neurodegeneration, and cognition.

Use of the single-item Patient Global Impression-Severity scale as a self-reported assessment of insomnia severity.

We evaluated a single-item Patient Global Impression-Severity (PGI-S) scale for assessing insomnia severity during the clinical development programme for suvorexant. The analyses used data from two randomised, double-blind, placebo-controlled, 3-month, Phase III clinical trials of suvorexant in patients with Diagnostic and Statistical Manual of Mental Disorders IV criteria insomnia. Patients assessed insomnia severity during the previous week using the PGI-S, a one-item questionnaire containing six response options ranging from 0 (none) to 5 (very severe), at baseline and at Week 2, and Months 1, 2, and 3 after randomisation.

Cognitive outcomes in trials of two BACE inhibitors in Alzheimer's disease.

Introduction: The APECS and AMARANTH trials showed that beta-secretase (BACE) inhibitors verubecestat and lanabecestat failed to slow cognitive and functional decline in individuals with prodromal or early Alzheimer's disease. Here, the performance on secondary and exploratory cognitive measures in both studies is reported.

Methods: APECS (verubecestat) and AMARANTH (lanabecestat) were randomized, double-blind, placebo-controlled, parallel-group, 104-week clinical trials conducted by different sponsors.

Polysomnographic assessment of suvorexant in patients with probable Alzheimer's disease dementia and insomnia: a randomized trial.

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.

How well can a large number of polysomnography sleep measures predict subjective sleep quality in insomnia patients?

Objective: The determinants of sleep quality (sQUAL) are poorly understood. We evaluated how well a large number of objective polysomnography (PSG) parameters can predict sQUAL in insomnia patients participating in trials of sleep medications or placebo.

Methods: PSG recordings over multiple nights from two clinical drug development programs involving 1158 insomnia patients treated with suvorexant or placebo and 903 insomnia patients treated with gaboxadol or placebo were used post-hoc to analyze univariate and multivariate associations between sQUAL and 98 PSG sleep parameters plus patient's age and gender.

Further analyses of the safety of verubecestat in the phase 3 EPOCH trial of mild-to-moderate Alzheimer's disease.

Background: Verubecestat, a BACE1 inhibitor that reduces Aβ levels in the cerebrospinal fluid of humans, was not effective in a phase 3 trial (EPOCH) of mild-to-moderate AD and was associated with adverse events. To assist in the development of BACE1 inhibitors, we report detailed safety findings from EPOCH.

Methods: EPOCH was a randomized, double-blind, placebo-controlled 78-week trial evaluating verubecestat 12 mg and 40 mg in participants with mild-to-moderate AD diagnosed clinically.

Effects of suvorexant on the Insomnia Severity Index in patients with insomnia: analysis of pooled phase 3 data.

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.

Insight Into Reduction of Wakefulness by Suvorexant in Patients With Insomnia: Analysis of Wake Bouts.

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.

A Phase Ib Randomized Controlled Study to Evaluate the Effectiveness of a Single-Dose of the NR2B Selective N-Methyl-D-Aspartate Antagonist MK-0657 on Levodopa-Induced Dyskinesias and Motor Symptoms in Patients With Parkinson Disease.

Objectives: Blockade of N-methyl-D-aspartate receptors containing the NR2B subunit has been shown to be therapeutic in animal models of Parkinson disease (PD). However, findings with investigational NR2B receptor antagonists in PD patients have been mixed. The objective of this study was to evaluate the effects of the NR2B selective N-methyl-D-aspartate receptor antagonist MK-0657 on levodopa-induced dyskinesias and motor symptoms in PD patients.

Phase II Proof-of-Concept Trial of the Orexin Receptor Antagonist Filorexant (MK-6096) in Patients with Major Depressive Disorder.

Background: We evaluated the orexin receptor antagonist filorexant (MK-6096) for treatment augmentation in patients with major depressive disorder.

Methods: 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.

Randomized trial of preladenant, given as monotherapy, in patients with early Parkinson disease.

Objective: To evaluate the adenosine 2a receptor antagonist preladenant as a nondopaminergic drug for the treatment of Parkinson disease (PD) when given as monotherapy.

Methods: This was a randomized, 26-week, placebo- and active-controlled, parallel-group, multicenter, double-blind trial conducted in adults diagnosed with PD for <5 years who were not yet receiving l-dopa or dopamine agonists. Patients with a Unified Parkinson's Disease Rating Scale (UPDRS) part 3 (motor function) score ≥10 and Hoehn & Yahr score ≤3 were randomized 1:1:1:1:1 to preladenant 2, 5, or 10 mg twice daily, rasagiline 1 mg (active-control) once daily, or placebo.

Suvorexant in Elderly Patients with Insomnia: Pooled Analyses of Data from Phase III Randomized Controlled Clinical Trials.

Objective: Suvorexant is an orexin receptor antagonist approved for treating insomnia at doses of 10-20 mg. Previously reported phase III results showed that suvorexant was effective and well-tolerated in a combined-age population (elderly and nonelderly adults). The present analysis evaluated the clinical profile of suvorexant specifically in the elderly.

Clinical profile of suvorexant for the treatment of insomnia over 3 months in women and men: subgroup analysis of pooled phase-3 data.

Rationale: Sex-related differences in the clinical profiles of some insomnia medications have been previously reported.

Objective: To evaluate the clinical profile of suvorexant, a novel orexin receptor antagonist approved for treating insomnia at doses up to 20 mg, by sex subgroups.

Methods: Efficacy analyses by sex were based on pooled data from two similar phase 3, randomized, double-blind, placebo-controlled, 3-month trials in elderly (≥65 years) and non-elderly (18-64 years) insomnia patients.

EEG spectral analysis of NREM sleep in a large sample of patients with insomnia and good sleepers: effects of age, sex and part of the night.

Previous studies of the differences between patients with insomnia and good sleepers with regard to quantitative electroencephalographic measures have mostly utilized small samples and consequently had limited ability to account for potentially important confounding factors of age, sex and part of the night. We conducted a power spectral analysis using a large database of sleep electroencephalographic recordings to evaluate differences between patients with insomnia (N = 803) and good sleepers (N = 811), while simultaneously accounting for these factors and their interaction. Comparisons of power as a function of age and part of the night were made between cohorts (patients with insomnia versus good sleepers) by sex.

Suvorexant in Patients with Insomnia: Pooled Analyses of Three-Month Data from Phase-3 Randomized Controlled Clinical Trials.

Study Objectives: 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.

Effects of suvorexant on sleep architecture and power spectral profile in patients with insomnia: analysis of pooled phase 3 data.

Background: The orexin receptor antagonist, suvorexant, is approved for treating insomnia at a maximum dose of 20 mg. We evaluated its effects on sleep architecture.

Methods: The analyses included pooled polysomnography data from two similar randomized, double-blind, placebo-controlled, 3-month trials evaluating two age-adjusted (non-elderly/elderly) dose regimes of 20/15 mg and 40/30 mg in 1482 patients with insomnia.

Preladenant as an Adjunctive Therapy With Levodopa in Parkinson Disease: Two Randomized Clinical Trials and Lessons Learned.

Importance: Preladenant is an adenosine 2A receptor antagonist that reduced "off" time in a placebo-controlled phase 2b trial in patients with Parkinson disease (PD). We sought to confirm its efficacy in phase 3 trials.

Objective: To evaluate preladenant as an adjunct to levodopa in patients with PD and motor fluctuations.

Effects of Suvorexant, an Orexin Receptor Antagonist, on Respiration during Sleep In Patients with Obstructive Sleep Apnea.

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 randomized, double-blind, placebo-controlled, 2-period (4 days per period), crossover, sleep laboratory study. Twenty-six patients aged 18-65 years with mild (apnea-hypopnea index [AHI] ≥ 5 and < 15) to moderate (AHI ≥ 15 and < 30) OSA were randomized to receive suvorexant 40 mg or placebo in period-1 and then crossed over to the other treatment in period-2.

Randomized controlled trial of the CGRP receptor antagonist telcagepant for prevention of headache in women with perimenstrual migraine.

Aim: The aim of this article is to evaluate the safety and efficacy of perimenstrual telcagepant, a CGRP receptor antagonist, for headache prophylaxis.

Methods: We conducted a randomized, double-blind, placebo-controlled, six-month trial in women with migraine for ≥ 3 months who experienced perimenstrual headaches. Women were randomized to telcagepant 140 mg or placebo (2:1 ratio) for seven consecutive days perimenstrually.