Testing the diagnostic accuracy of common questions for seizure diagnosis: Challenges and future directions.

OBJECTIVE: The aim of this study was to evaluate the diagnostic accuracy of common interview questions used to distinguish a diagnosis of epilepsy from seizure mimics including non-epileptic seizures (NES), migraine, and syncope. METHODS: 200 outpatients were recruited with an established diagnosis of focal epilepsy (n = 50), NES (n = 50), migraine (n = 50), and syncope (n = 50). Patients completed an eight-item, yes-or-no online questionnaire about symptoms related to their events. Sensitivity and specificity were calculated. Using a weighted scoring for the questions alone with baseline characteristics, the overall questionnaire was tested for diagnostic accuracy. RESULTS: Of individual questions, the most sensitive one asked if events are sudden in onset (98 % sensitive for epilepsy (95 % CI: 89 %, 100 %)). The least sensitive question asked if events are stereotyped (46 % sensitive for epilepsy (95 % CI: 32 %, 60 %)). Overall, three of the eight questions showed an association with epilepsy as opposed to mimics. These included questions about "sudden onset" (OR 10.76, 95 % CI: (1.66, 449.21) p = 0.0047), "duration < 5 min" (OR 3.34, 95 % CI: (1.62, 6.89), p = 0.0008), and "duration not > 30 min" (OR 4.44, 95 % CI: (1.94, 11.05), p = <0.0001). When individual seizure mimics were compared to epilepsy, differences in responses were most notable between the epilepsy and migraine patients. Syncope and NES were most similar in responses to epilepsy. The overall weighted questionnaire incorporating patient age and sex produced an area under the ROC curve of 0.80 (95 % CI: 0.74, 0.87)). CONCLUSION: In this study, we examined the ability of common interview questions used by physicians to distinguish between epilepsy and prevalent epilepsy mimics, specifically NES, migraines, and syncope. Using a weighted scoring system for questions, and including age and sex, produced a sensitive and specific predictive model for the diagnosis of epilepsy. In contrast to many prior studies which evaluated either a large number of questions or used methods with difficult practical application, our study is unique in that we tested a small number of easy-to-understand "yes" or "no" questions that can be implemented in most clinical settings by non-specialists.

Safety profile of pembrolizumab monotherapy based on an aggregate safety evaluation of 8937 patients.

BACKGROUND: Pembrolizumab has a manageable safety profile as described in its label, which was primarily based on 2799 patients who participated in clinical trials for melanoma or non-small cell lung cancer. Here, we evaluated the safety of pembrolizumab in a broader population of patients from 31 advanced cancer clinical trials across 19 cancer types. METHODS: Safety was analyzed in patients who received at least one dose of pembrolizumab (200 mg every 3 weeks [Q3W], 10 mg/kg Q2W or Q3W, or 2 mg/kg Q3W). Adverse events (AEs) and immune-mediated AEs and infusion reactions were evaluated. RESULTS: Safety data from 8937 patients in 31 trials of pembrolizumab monotherapy were pooled (median, seven administrations; range, 1-59). Median duration on treatment was 4.1 months (range, 0.03-40.1). AEs occurred in 96.6% of patients. Grade 3-5 AEs occurred in 50.6% of patients. AEs led to pembrolizumab discontinuation in 12.7% of patients and death in 5.9%. Immune-mediated AEs and infusion reactions occurred in 23.7% of patients (4.6% experienced multiple immune-mediated AEs/infusion reactions) and led to pembrolizumab discontinuation in 3.6% and death in 0.2%. Grade 3-5 immune-mediated AEs occurred in 6.3% of patients. Serious immune-mediated AEs and infusion reactions occurred in 6.0% of patients. Median time to immune-mediated AE onset was 85 days (range, 13-163). Of 2657 immune-mediated AEs, 22.3% were initially treated with prednisone ≥ 40 mg/day or equivalent, and 8.3% were initially treated with lower steroid doses. CONCLUSIONS: This pooled analysis of 31 clinical trials showed that pembrolizumab has a consistent safety profile across indications.

Universal ophthalmia neonatorum prophylaxis in Ontario: a cost-effectiveness analysis.

BACKGROUND: Although prophylaxis for ophthalmia neonatorum at birth is required by law in Ontario, declining prevalence of disease and efficacy of prophylaxis have called this practice into question. The objective of this modelling study was to assess the cost-effectiveness of universal prophylaxis for ophthalmia neonatorum to inform decision-makers on the potential impact of a change in this policy. METHODS: We compared the cost-effectiveness of prophylaxis for ophthalmia neonatorum with no prophylaxis through cost-utility analysis with a lifetime time horizon, considering a provincial government payer, for a hypothetical population of newborns in Ontario. We assessed both the mean incremental costs of prophylaxis and its mean incremental effectiveness using a hybrid (part decision tree, part Markov) model. We used a scenario analysis to evaluate alternative time horizons and discount rates. We conducted a threshold analysis to evaluate the impact of variations in the cost of prophylaxis and in the prevalence of sexually transmitted infections (gonorrhea and chlamydia). RESULTS: In our model, prophylaxis for ophthalmia neonatorum did not meet a willingness-to-pay threshold of Can$50 000 per quality-adjusted life-year (QALY). Although prophylaxis was effective in reducing morbidity associated with ophthalmia neonatorum, the number needed to treat to prevent 1 case of ophthalmia neonatorum blindness was 500 000, with an associated cost of more than Can$4 000 000. When compared with no prophylaxis, prophylaxis had an incremental cost of Can$355 798 per long-term QALY gained (incremental cost-effectiveness ratio). INTERPRETATION: We found that prophylaxis for ophthalmia neonatorum, although individually inexpensive, leads to very high costs on a population level. These findings contribute to the discussion on mandatory prophylaxis currently underway in several jurisdictions.

Exploratory analyses of clinical trial data used for health technology assessments: a retrospective evaluation.

OBJECTIVES: To examine the validity and statistical limitations of exploratory analyses of clinical trial data commonly requested by agencies responsible for determining which medical products may be financed or reimbursed by a healthcare system. DESIGN: This was a retrospective review of efficacy and safety analyses conducted for German Health Technology Assessment (HTA) evaluations with a decision date between 2015 and 2020, and an illustrative safety-related exploratory analysis of data from two phase III clinical trials of verubecestat (an anti-amyloid drug whose development was stopped for lack of efficacy) as would be mandated by the German HTA agency. RESULTS: We identified 422 HTA evaluations of 404 randomised controlled clinical trials. For 140 trials (34.7%), the evaluation was based on subpopulations of participants in the originating confirmatory trial (175 subpopulations were assessed). In 57% (100 of 175), the subpopulation sample size was 50% or less of the original study population. Detailed analysis of five evaluations based on subpopulations of the original trial is presented. The safety-related exploratory analysis of verubecestat led to 206 statistical analyses for treatments and 812 treatment-by-subgroup interaction tests. Of 31 safety endpoints with an elevated HR (suggesting association with drug treatment), the HR for 81% of these (25 of 31) was not elevated in both trials. Of the 812 treatment-by-subgroup interactions evaluated, 26 had an elevated HR for a subgroup in one trial, but only 1 was elevated in both trials. CONCLUSIONS: Many HTA evaluations rely on subpopulation analyses and numerous post hoc statistical hypothesis tests. Subpopulation analysis may lead to loss of statistical power and uncontrolled influences of random imbalances. Multiple testing may introduce spurious findings. Decisions about benefits of medical products should therefore not rely on exploratory analyses of clinical trial data but rather on prospective clinical studies and careful synthesis of all available evidence based on prespecified criteria.

The language of seizure identification: A qualitative investigation.

OBJECTIVE: Clinical history taking is often the most important factor in seizure recognition and the diagnosis of epilepsy. Apart from subspecialist evaluation, patients frequently present for initial evaluation of seizures in emergency departments, urgent care clinics, and primary care clinics. We utilized qualitative methods to assess the current approaches and language used by both subspecialist and non-specialist physicians when interviewing adult patients with suspected seizures to create a clinical tool to aid in seizure diagnosis. METHODS: We carried out semi- structured interviews with 10 physicians spanning a range of specialties, practice locations, and clinical experience. This included epilepsy specialists and non-specialists in fields where evaluation of new-onset seizures is common: emergency medicine, internal medicine, and family medicine. Thematic analysis was used to develop a "Seizure Identifier" questionnaire, which was subsequently reviewed by five independent experts for content and face validity. RESULTS: Our analysis revealed that across specialties and practice settings, physicians have a structured approach in evaluating patients who present with suspected seizures. Five key characteristics important for identifying seizures emerged across interviews: sudden-onset unprovoked symptoms, short-lasting symptoms, strange or difficult-to-describe symptoms, highly stereotyped symptoms, and postictal symptoms. After independent review, these were translated into an eight-question "Seizure Identifier" tool. SIGNIFICANCE: This study highlights important concepts for clinical practice regarding seizure identification. Using themes from our analysis, we were able to create a tool that may aid non-specialists in the approach to history taking for adult patients who present with suspected seizures and may help improve time to subspecialist evaluation. Importantly, this tool can be tested in future research for improving seizure recognition and improving timely epilepsy diagnosis.

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. 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.

A cross-sectional study of factors associated with unstable housing among marginalized people who use drugs in Ottawa, Canada.

INTRODUCTION: Housing affects an individual's physical and mental health, particularly among people who use substances. Understanding the association between individual characteristics and housing status can inform housing policy and help optimize the care of people who use drugs. The objective of this study was to explore the factors associated with unstable housing among people who use drugs in Ottawa. METHODS: This is a cross-sectional analysis of data from 782 participants in the Participatory Research in Ottawa: Understanding Drugs (PROUD) Study. PROUD is a prospective cohort study of people who use drugs in Ottawa. Between March and December 2013, participants were recruited through peer-based recruitment on the streets and in social services settings and completed a peer-administered questionnaire that explored socio-demographic information, drug use patterns, community integration, experiences with police and incarceration, and access to health care and harm reduction services. Eligibility criteria included age of 16 years or older, self-reported illicit drug use within the past 12 months and having lived in Ottawa for at least 3 months. Housing status was determined by self-report. "Stable housing" was defined as residence in a house or apartment and "unstable housing" was defined as all other residence types. Exploratory multivariable logistic regression analyses of the association between characteristics of people who use drugs and their housing status were conducted. RESULTS: Factors that were associated with unstable housing included: recent incarceration; not having a regular doctor; not having received support from a peer worker; low monthly income; income source other than public disability support payments; and younger age. Gender, language, ethnicity, education level, opioid use and injection drug use were not independently associated with housing status. CONCLUSIONS: People who use drugs face significant barriers to stable housing. These results highlight key areas to address in order to improve housing stability among this community.

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. The seven-item Insomnia Severity Index (ISI) and other subjective and objective assessments were also completed by patients. PGI-S responses were compared primarily with the ISI using descriptive statistics and correlations. The PGI-S demonstrated favourable measurement characteristics (validity, reliability, responsiveness and sensitivity). PGI-S scores decreased from baseline to Month 3 in a similar pattern to the ISI total score, and the Spearman correlation coefficient between PGI-S and the ISI was .73. An improvement of ≥2 points on the PGI-S defined a treatment responder, based on comparison to the ISI definition of a responder (improvement of ≥6 points). Our present findings suggest that the PGI-S is a simple but valid, reliable, responsive, sensitive, and meaningful patient-reported assessment of insomnia severity. The PGI-S may be particularly useful as a companion outcome to sleep monitoring using wearable sleep devices or smartphones in at-home settings.

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. 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.

The effectiveness of substance use interventions for homeless and vulnerably housed persons: A systematic review of systematic reviews on supervised consumption facilities, managed alcohol programs, and pharmacological agents for opioid use disorder.

BACKGROUND: Substance use is disproportionately high among people who are homeless or vulnerably housed. We performed a systematic overview of reviews examining the effects of selected harm reduction and pharmacological interventions on the health and social well-being of people who use substances, with a focus on homeless populations. METHODS AND FINDINGS: We searched MEDLINE, EMBASE, PsycINFO, Joanna Briggs Institute EBP, Cochrane Database of Systematic Reviews and DARE for systematic reviews from inception to August 2019. We conducted a grey literature search and hand searched reference lists. We selected reviews that synthesized evidence on supervised consumption facilities, managed alcohol programs and pharmacological interventions for opioid use disorders. We abstracted data specific to homeless or vulnerably housed populations. We assessed certainty of the evidence using the GRADE approach. Our search identified 483 citations and 30 systematic reviews met all inclusion criteria, capturing the results from 442 primary studies. This included three reviews on supervised consumption facilities, 24 on pharmacological interventions, and three on managed alcohol programs. Supervised consumption facilities decreased lethal overdoses and other high risk behaviours without any significant harm, and improved access to care. Pharmaceutical interventions reduced mortality, morbidity, and substance use, but the impact on retention in treatment, mental illness and access to care was variable. Managed alcohol programs reduced or stabilized alcohol consumption. Few studies on managed alcohol programs reported deaths. CONCLUSIONS: Substance use is a common chronic condition impacting homeless populations. Supervised consumption facilities reduce overdose and improve access to care, while pharmacological interventions may play a role in reducing harms and addressing other morbidity. High quality evidence on managed alcohol programs is limited.

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. Analyses were performed separately for each of the two clinical trial databases. For univariate associations, within-subject correlations were estimated using mixed effect modeling of bi-variate longitudinal data with one variable being a given PSG variable and the other being sQUAL. To evaluate how accurately sQUAL could be predicted by all PSG variables jointly plus patient's age and gender, the Random Forest multivariate technique was used. Random Forest was also used to evaluate the accuracy of sQUAL prediction by subjective sleep measures plus age and gender, and to quantitatively describe the relative importance of each variable for predicting sQUAL. RESULTS: In the univariate analyses, total sleep time (TST) had the largest correlation with sQUAL compared with all other PSG sleep parameters, and the magnitude of the correlation between each PSG sleep architecture parameter and sQUAL generally increased with the strength of their associations with TST. In the multivariate analyses, the overall accuracy of sQUAL prediction, even with the large number of PSG parameters plus patient's age and gender, was moderate (area under the Receiver Operating Characteristic curve (AROC): 71.2-71.8%). Ranking of PSG parameters by their contribution to sQUAL indicated that TST was the most important predictor of sQUAL among all PSG variables. Subjective TST and subjective number of awakenings jointly with patient's age classified sQUAL with higher accuracy (AROC: 78.7-81.7%) than PSG variables plus age and gender. The pattern of findings was consistent across the two clinical trial databases. CONCLUSION: In insomnia patients participating in trials of sleep medications or placebo, PSG variables had a moderate but consistent pattern of association with sQUAL across two separate clinical trial databases. Of the PSG variables evaluated, TST was the best predictor of sQUAL. CLINICAL TRIALS: trial registration at www.clinicaltrials.gov: NCT01097616; NCT01097629; NCT00094627; NCT00094666.

Immunogenicity of pembrolizumab in patients with advanced tumors.

BACKGROUND: Pembrolizumab is a potent, humanized, monoclonal anti-programmed death 1 antibody that has demonstrated effective antitumor activity and acceptable safety in multiple tumor types. Therapeutic biologics can result in the development of antidrug antibodies (ADAs), which may alter drug clearance and neutralize target binding, potentially reducing drug efficacy; such immunogenicity may also result in infusion reactions, anaphylaxis, and immune complex disorders. Pembrolizumab immunogenicity and its impact on exposure, safety, and efficacy was assessed in this study. PATIENTS AND METHODS: Pembrolizumab immunogenicity was assessed in 3655 patients with advanced or metastatic cancer treated in 12 clinical studies. Patients with melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, colorectal cancer, urothelial cancer, and Hodgkin lymphoma were treated with pembrolizumab at 2 mg/kg every 3 weeks, 10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or 200 mg every 3 weeks. An additional study involving 496 patients with stage III melanoma treated with 200 mg adjuvant pembrolizumab every 3 weeks after complete resection was analyzed separately. RESULTS: Of 3655 patients, 2000 were evaluable for immunogenicity analysis, 36 (1.8%) were treatment-emergent (TE) ADA-positive; 9 (0.5%) of these TE-positive patients had antibodies with neutralizing capacity. The presence of pembrolizumab-specific ADAs did not impact pembrolizumab exposure, nor did pembrolizumab immunogenicity affect the incidence of drug-related adverse events (AEs) or infusion-related reactions. There was no clear relationship between the presence of pembrolizumab-specific ADAs and changes in tumor size across treatment regimens. Of the 496 patients treated with pembrolizumab as adjuvant therapy, 495 were evaluable, 17 (3.4%) were TE ADA-positive; none had neutralizing antibodies. CONCLUSIONS: The incidence of TE (neutralizing positive) ADAs against pembrolizumab was low in patients with advanced tumors. Furthermore, immunogenicity did not appear to have any clinically relevant effects on the exposure, safety, or efficacy of pembrolizumab. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01295827 (February 15, 2011), NCT01704287 (October 11, 2012), NCT01866319 (May 31, 2013), NCT01905657 (July 23, 2013), NCT02142738 (May 20, 2014), NCT01848834 (May 8, 2013), NCT02255097 (October 2, 2014), NCT02460198 (June 2, 2015), NCT01953692 (October 1, 2013), NCT02453594 (May 25, 2015), NCT02256436 (October 3, 2014), NCT02335424 (January 9, 2015), NCT02362594 (February 13, 2015).

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. Age-adjusted (non-elderly/elderly) dose-regimes of 40/30 mg and 20/15 mg were evaluated. The ISI, a 7-item self-rated questionnaire with each item rated on 0-4 scale (higher score corresponds to increasing severity), was administered to patients as an exploratory assessment in both studies at baseline and one and three months after randomization. RESULTS: The analysis included 1824 patients. Suvorexant improved change-from-baseline ISI total scores to a greater extent than placebo (Month three: 20/15 mg = -6.2, 40/30 mg = -6.7, placebo = -4.9, p-values for both active arms vs. placebo <0.001) and resulted in a greater proportion of responders than placebo using a variety of definitions (eg, ≥6-point improvement from baseline at Month three: 20/15 mg = 55.5%, 40/30 mg = 54.9%, placebo = 42.2%, p-values for both active arms vs. placebo <0.001). Additionally, the "impact of insomnia" component, which assesses the impact of insomnia on daytime function/quality-of-life, was improved to a greater extent by suvorexant than placebo. CONCLUSIONS: Suvorexant 20/15 mg and 40/30 mg improved sleep to a greater extent than placebo as assessed by the ISI in patients with insomnia. Improvement in sleep onset/maintenance as well as a reduction of the impact of sleep problems on daytime function contributed to the overall improvement observed in ISI total score. CLINICALTRIALS. GOV IDENTIFIER: NCT01097616, NCT01097629.

A New Single-Item Sleep Quality Scale: Results of Psychometric Evaluation in Patients With Chronic Primary Insomnia and Depression.

STUDY OBJECTIVES: A single-item sleep quality scale (SQS) was developed as a simple and practical sleep quality assessment and psychometrically evaluated. METHODS: SQS measurement characteristics were evaluated using the Pittsburgh Sleep Quality Index (PSQI) and morning questionnaire-insomnia (MQI) according to prespecified analysis plans in separate clinical studies of patients with insomnia and depression. Patients with insomnia (n = 70) received 4 weeks' usual care with an FDA-approved hypnotic agent; patients with depression (n = 651) received 8 weeks' active or experimental therapy. RESULTS: Concurrent criterion validity (correlation with measures of a similar construct) was demonstrated by strong (inverse) correlations between the SQS and MQI (week 1 Pearson correlation -.76) and PSQI (week 8 Goodman-Kruskal correlation -.92) sleep quality items in populations with insomnia and depression, respectively. In patients with depression, stronger correlations between the SQS and PSQI core sleep quality components versus other items supported convergent/divergent construct validity (similarity/dissimilarity to related/unrelated measures). Known-groups validity was evidenced by decreasing mean SQS scores across those who sleep normally, those borderline to having sleep problems, and those with problems sleeping. Test-retest reliability (intraclass correlation coefficient) was .62 during a 4-week period of sleep stability in patients with insomnia and .74 in stable patients with depression (1 week). Effect sizes (standardized response means) for change from baseline were 1.32 (week 1) and .67 (week 8) in populations with insomnia and depression, respectively. Mean SQS changes from baseline to week 8 convergently decreased across groups of patients with depression categorized by level of PSQI sleep quality improvement. CONCLUSIONS: The SQS possesses favorable measurement characteristics relative to lengthier or more frequently administered sleep questionnaires in patients with insomnia and depression. CLINICAL TRIAL REGISTRATION: Registry: ClincalTrials.gov, Title: Treatment of Patients With Major Depressive Disorder With MK0869, Identifier: NCT00034983, URL: https://clinicaltrials.gov/ct2/show/NCT00034983.

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. Results: Relative to placebo, suvorexant decreased the number and time spent in long wake bouts (>2 minutes) and increased the number and time spent in short wake bouts (≤2 minutes). The time spent in long wake bouts during Night-1 decreased by 32-54 minutes, whereas the time spent in short wake bouts increased by 2-6 minutes. On average, a patient returned to sleep from his or her longest awakening more than twice as fast on suvorexant than placebo. The reduced time spent in long wake bouts resulted in odds ratios of self-reported good or excellent sleep quality ranging from 1.59 to 2.19 versus placebo. The small increase in time spent in short wake bouts had no effect on odds ratios. Findings were more pronounced for the higher (40/30 mg) doses of suvorexant. The wake and sleep bout characteristics of suvorexant differed from zolpidem which equally decreased the number of wake and sleep bouts of all durations during the early part of the night. Conclusion: Suvorexant reduces WASO by reducing long wake bouts. This reduction has a positive effect on sleep quality. Clinical Trials: Trial registration at www.clinicaltrials.gov NCT01097616; NCT01097629.

Statistical planning in confirmatory clinical trials with multiple treatment groups, multiple visits, and multiple endpoints.

Multiplicity issues can be multidimensional: A confirmatory clinical trial may be designed to have efficacy assessed with two or more primary endpoints, for multiple dose groups, and at several post-baseline visits. Controlling for multiplicity in this situation is challenging because there can be a hierarchy with respect to some but not all measurements. If the higher dose is considered more efficacious, multiplicity approach may evaluate the higher dose with higher priority through a fixed sequential testing framework for dose assessments in combination with a Hochberg approach for endpoints. The lower dose is only assessed when the higher dose has significant results, which reduces the power for detecting signals in the lower dose group. However, in some instances the higher dose may associate with tolerability or safety concerns that preclude regulatory approval. A real confirmatory clinical trial with such challenges is provided as an illustrative example. We discuss closed testing procedures based on multi-way averages of comparisons for this complex multiplicity situation through illustrative case analyses and a simulation study. Such strategies manage the higher dose and the lower dose with equal priority, and they enable evaluation of the multiple endpoints at multiple visits collectively with power being reasonably high.

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. METHODS: Prespecified subgroup analyses of pooled 3-month data from two (efficacy) and three (safety) randomized, double-blind, placebo-controlled, parallel-group trials. In each trial, elderly (≥65 years) patients with insomnia were randomized to suvorexant 30 mg, suvorexant 15 mg, and placebo. By design, fewer patients were randomized to 15 mg. Patient-reported and polysomnographic (subset of patients) sleep maintenance and onset endpoints were measured. RESULTS: Suvorexant 30 mg (N = 319) was effective compared with placebo (N = 318) on patient-reported and polysomnographic sleep maintenance, and onset endpoints at Night 1 (polysomnographic endpoints)/Week 1 (patient-reported endpoints), Month 1, and Month 3. Suvorexant 15 mg (N = 202 treated) was also effective across these measures, although the onset effect was less evident at later time points. The percentages of patients discontinuing because of adverse events over 3 months were 6.4% for 30 mg (N = 627 treated), 3.5% for 15 mg (N = 202 treated), and 5.5% for placebo (N = 469 treated). Somnolence was the most common adverse event (8.8% for 30 mg, 5.4% for 15 mg, 3.2% for placebo). CONCLUSION: Suvorexant generally improved sleep maintenance and onset over 3 months of nightly treatment and was well-tolerated in elderly patients with insomnia (clinicaltrials.gov; NCT01097616, NCT01097629, NCT01021813).

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. Two age-adjusted (non-elderly/elderly) dose regimes of 40/30 and 20/15 mg were evaluated, with fewer patients assigned to 20/15 mg. Efficacy was assessed by patient-reported outcomes (N = 1264 women, 707 men) and by polysomnography endpoints in ~75% of patients. Safety analyses by sex (N = 1744 women, 1065 men) included pooled data from the two 3-month trials plus 3-month data from a safety trial of 40/30 mg. RESULTS: The sex subgroup efficacy analyses mirrored the improvements seen for suvorexant 40/30 and 20/15 mg over placebo on patient-reported outcomes and polysomnography sleep maintenance and onset endpoints in the primary analyses; 95% CIs excluded zero in favor of suvorexant for most endpoints in both sexes, and similar efficacy was observed between sexes (95% CIs overlapped). Suvorexant was well-tolerated in women and men, although women in all treatment groups (including placebo) reported more adverse events than men. The most frequent adverse event was somnolence (women: 11.1% for 40/30 mg, 8.5% for 20/15 mg, 2.3% for placebo; men: 10.1% for 40/30 mg, 3.4% for 20/15 mg, 4.2% for placebo). CONCLUSION: Suvorexant was generally effective and well-tolerated in both women and men with insomnia. ClinicalTrials.gov trial registration numbers: NCT01097616, NCT01097629, NCT01021813.

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. Absolute power in the delta, theta and sigma bands declined with age for both females and males. Females had significantly greater power than males at all ages, and for each band, cohort and part of the night. These sex differences were much greater than differences between patients with insomnia and good sleepers. Compared with good sleepers, patients with insomnia under age 40-45 years had reduced delta band power during Part 1 of the night. Females with insomnia over age 45 years had increased delta and theta band power in Parts 2 and 3 of the night, and males with insomnia under age 40 years had reduced theta power in Part 1. Females with insomnia had increased beta2 power in all parts of the night, and males with insomnia had reduced alpha power during all parts of the night. Relative power (the proportion that an individual frequency band contributes to the total power) decreased in the delta band and increased in all other bands with age for both cohorts, sexes and all parts of the night. This analysis provides a unique resource for quantitative information on the differences in power spectra between patients with insomnia and good sleepers accounting for age, sex and part of the night.