Effects of solriamfetol on on-the-road driving in participants with narcolepsy: A randomised crossover trial.

OBJECTIVE: To evaluate the impact of solriamfetol, a dopamine and norepinephrine reuptake inhibitor, on on-the-road driving performance in participants with narcolepsy. METHODS: In this randomised, double-blind, placebo-controlled, crossover study, driving performance during a 1 h on-road driving test was assessed at 2 and 6 h post-dose following 7 days of treatment with solriamfetol (150 mg/day for 3 days, followed by 300 mg/day for 4 days) or placebo. The primary endpoint was standard deviation of lateral position (SDLP) at 2 h post-dose. RESULTS: The study included 24 participants (54% male; mean age, 40 years); 22 had evaluable SDLP data. At 2 h post-dose, median SDLP was significantly lower (improved) with solriamfetol compared with placebo (19.08 vs. 20.46 cm [median difference, -1.9 cm], p = 0.002). Four participants on solriamfetol and 7 on placebo had incomplete driving tests. At 6 h post-dose, median SDLP was not statistically significantly different with solriamfetol compared with placebo (19.59 vs. 19.78 cm [median difference, -1.1 cm], p = 0.125). Three participants on solriamfetol and 10 on placebo had incomplete driving tests. Common adverse events (≥5%) included headache, decreased appetite, and somnolence. CONCLUSIONS: Solriamfetol 300 mg/day improved on-the-road driving performance, at 2 h post-administration in participants with narcolepsy.

Effects of solriamfetol on on-the-road driving performance in participants with excessive daytime sleepiness associated with obstructive sleep apnoea.

OBJECTIVE: To evaluate the impact of solriamfetol, a dopamine and norepinephrine reuptake inhibitor, on on-the-road driving in participants with excessive daytime sleepiness (EDS) associated with obstructive sleep apnoea (OSA). METHODS: Eligible participants were aged 21-75 years with OSA and EDS (Maintenance of Wakefulness Test mean sleep latency <30 minutes and Epworth Sleepiness Scale score ≥10). Participants were randomised 1:1 to solriamfetol (150 mg/day [3 days], then 300 mg/day [4 days]) or placebo for 7 days, before crossover to the other treatment paradigm. On Day 7 of each period, standardised on-road driving tests occurred (2 and 6 hours postdose). Standard deviation of lateral position (SDLP) was the primary endpoint. RESULTS: Solriamfetol significantly reduced SDLP at 2 (n = 34; least squares mean difference, -1.1 cm; 95% CI, -1.85, -0.32; p = 0.006) and 6 hours postdose (n = 32; least squares mean difference, -0.8 cm; 95% CI, -1.58, -0.03; p = 0.043). Two hours postdose, 4 placebo-treated and 1 solriamfetol-treated participants had incomplete driving tests; 6 hours postdose, 7 and 3 participants, respectively, had incomplete tests. Common treatment-emergent adverse events included headache, nausea, and insomnia. CONCLUSIONS: Solriamfetol 300 mg/day significantly improved on-the-road driving performance in participants with EDS associated with OSA.

A single test for rejecting the null hypothesis in subgroups and in the overall sample.

In clinical trials, some patient subgroups are likely to demonstrate larger effect sizes than other subgroups. For example, the effect size, or informally the benefit with treatment, is often greater in patients with a moderate condition of a disease than in those with a mild condition. A limitation of the usual method of analysis is that it does not incorporate this ordering of effect size by patient subgroup. We propose a test statistic which supplements the conventional test by including this information and simultaneously tests the null hypothesis in pre-specified subgroups and in the overall sample. It results in more power than the conventional test when the differences in effect sizes across subgroups are at least moderately large; otherwise it loses power. The method involves combining p-values from models fit to pre-specified subgroups and the overall sample in a manner that assigns greater weight to subgroups in which a larger effect size is expected. Results are presented for randomized trials with two and three subgroups.

Robust inference for group sequential trials.

For ethical reasons, group sequential trials were introduced to allow trials to stop early in the event of extreme results. Endpoints in such trials are usually mortality or irreversible morbidity. For a given endpoint, the norm is to use a single test statistic and to use that same statistic for each analysis. This approach is risky because the test statistic has to be specified before the study is unblinded, and there is loss in power if the assumptions that ensure optimality for each analysis are not met. To minimize the risk of moderate to substantial loss in power due to a suboptimal choice of a statistic, a robust method was developed for nonsequential trials. The concept is analogous to diversification of financial investments to minimize risk. The method is based on combining P values from multiple test statistics for formal inference while controlling the type I error rate at its designated value.This article evaluates the performance of 2 P value combining methods for group sequential trials. The emphasis is on time to event trials although results from less complex trials are also included. The gain or loss in power with the combination method relative to a single statistic is asymmetric in its favor. Depending on the power of each individual test, the combination method can give more power than any single test or give power that is closer to the test with the most power. The versatility of the method is that it can combine P values from different test statistics for analysis at different times. The robustness of results suggests that inference from group sequential trials can be strengthened with the use of combined tests.

Clinical pharmacology of AMG 181, a gut-specific human anti-α4ß7 monoclonal antibody, for treating inflammatory bowel diseases.

AIMS: AMG 181 pharmacokinetics/pharmacodynamics (PK/PD), safety, tolerability and effects after single subcutaneous (s.c.) or intravenous (i.v.) administration were evaluated in a randomized, double-blind, placebo-controlled study. METHODS: Healthy male subjects (n= 68) received a single dose of AMG 181 or placebo at 0.7, 2.1, 7, 21, 70 mg s.c. (or i.v.), 210 mg s.c. (or i.v.), 420 mg i.v. or placebo. Four ulcerative colitis (UC) subjects (n= 4, male : female 2:2) received 210 mg AMG 181 or placebo s.c. (3:1). AMG 181 concentration, anti-AMG 181-antibody (ADA), α4 ß7 receptor occupancy (RO), target cell counts, serum C-reactive protein, fecal biomarkers and Mayo score were measured. Subjects were followed 3-9 months after dose. RESULTS: Following s.c. dosing, AMG 181 was absorbed with a median tmax ranging between 2-10 days and a bioavailability between 82% and 99%. Cmax and AUC increased dose-proportionally and approximately dose-proportionally, respectively, within the 70-210 mg s.c. and 70-420 mg i.v. ranges. The linear ß-phase t1/2 was 31 (range 20-48) days. Target-mediated disposition occurred at serum AMG 181 concentrations of less than 1 µg ml(-1) . The PD effect on α4 ß7 RO showed an EC50 of 0.01 µg ml(-1) . Lymphocytes, eosinophils, CD4+ T cells and subset counts were unchanged. AMG 181-treated UC subjects were in remission with mucosal healing at weeks 6, 12 and/or 28. The placebo-treated UC subject experienced colitis flare at week 6. No ADA or AMG 181 treatment-related serious adverse events were observed. CONCLUSIONS: AMG 181 has PK/PD, safety, and effect profiles suitable for further testing in subjects with inflammatory bowel diseases.

Inference from blinded data in randomized clinical trials.

BACKGROUND: With blinded data, several authors have concluded that there is a negligible chance of inferring a non-null treatment effect. The recent Food and Drug Administration (FDA) draft guidance document on adaptive trials, by encouraging blinded sample size reestimation, implies the same. PURPOSE: We derive methods to investigate whether the probability of inferring a treatment effect is much larger than previously thought, and whether that is of concern. METHODS: A statistic is developed that contributes to improving signal detection. Additionally, trials that are overpowered, for reasons external to powering the primary objective, further strengthen the chance of finding a signal. RESULTS: An example of data from a clinical trial shows how revealing a blinded analysis can be. The ability to infer a non-null effect while a blinded trial is ongoing is a serious matter. LIMITATIONS: The methods apply to superiority trials and are of limited use for non-inferiority or equivalence trials. CONCLUSION: It is important, therefore, that guidance documents include clear language to limit or prevent inference from blinded data to maintain trial integrity. Simple steps are proposed to make inference difficult.

A randomized, double-blind, placebo-controlled, phase 2b study of the efficacy and safety of velusetrag in subjects with diabetic or idiopathic gastroparesis.

BACKGROUND: This study assessed the efficacy and safety of velusetrag-a 5-HT4 agonist with pan-gastrointestinal prokinetic activity-for gastroparesis symptom management and gastric emptying (GE). METHODS: In this multicenter, double-blind, randomized, placebo-controlled study, subjects with diabetic or idiopathic gastroparesis received velusetrag 5, 15, or 30 mg or placebo for 12 weeks. The primary efficacy outcome was a 7-day mean Gastroparesis Cardinal Symptom Index 24-h composite score (GCSI-24H) change from baseline at week 4; GE was evaluated using scintigraphy (GES) and breath tests, and safety from adverse events (AEs). KEY RESULTS: 232 subjects (183 females; 113 idiopathic gastroparesis) received treatment from February 2015 through June 2017. Least-squares mean improvement from baseline GCSI-24H (primary endpoint) at week 4 was -1.5 following velusetrag 5 mg vs -1.1 following placebo (treatment difference, -0.4; 95% confidence interval, -0.75 to -0.03; nominal p = 0.0327; Hochberg-adjusted p = 0.0980 [not significant]). Symptom improvement from baseline was achieved only with velusetrag 5 mg, which resulted in greater improvement from baseline vs placebo in all gastroparesis core symptoms, especially in subjects with idiopathic gastroparesis. Improvement from baseline GE by GES was greater in subjects receiving velusetrag (all doses) vs placebo; >70% of subjects receiving velusetrag 30 mg had GE normalization at 4 h. Treatment-emergent AEs were generally mild. CONCLUSIONS AND INFERENCES: Velusetrag treatment was generally well-tolerated and associated with improved GE vs placebo in subjects with diabetic or idiopathic gastroparesis; however, only the lowest dose, velusetrag 5 mg, was associated with short-term improvement in gastroparesis symptoms. CLINICALTRIALS: GOV: NCT02267525.

The benefit of stratification in clinical trials revisited.

Stratification is common in clinical trials because it can reduce the variance of the estimated treatment effect. The traditional demonstration of variance reduction relies on the assumption of stratum sizes being fixed quantities. However, in practice, to speed up enrollment, and to obtain a study population with a similar distribution as the overall population, the stratum sizes are allowed to vary. Under the condition that the total sample size is fixed and that the stratum sizes have a multinomial distribution, the criterion changes for achieving a reduction in variance. The relationship between the stratified and unstratified variances is established and shown to be approximately the same for prestratified and post-stratified trials. It is demonstrated why stratification may actually increase the variance compared with no stratification even when the mean square error is reduced on account of stratification. Data from a real clinical trial will be used for illustration. The benefit attributed to stratification needs to be re-examined in light of the findings presented, particularly given its widespread use.

Safety, Pharmacokinetics, and Pharmacodynamics of TD-0714, a Novel Potent Neprilysin Inhibitor in Healthy Adult and Elderly Subjects.

TD-0714 is an orally active, potent, and selective inhibitor of human neprilysin (NEP) in development for the treatment of chronic heart failure. Oral administration of TD-0714 in rats resulted in dose-dependent and sustained increases in plasma cyclic guanosine monophosphate (cGMP) over 24 hours consistent with NEP target engagement. Randomized, double-blind, placebo controlled, single ascending dose (50-600 mg TD-0714) and multiple ascending dose (10-200 mg TD-0714 q.d. for 14 days) studies were conducted in healthy volunteers. TD-0714 was generally well-tolerated and no serious adverse events or clinically significant effects on vital signs or electrocardiogram parameters were observed. TD-0714 exhibited dose-proportional pharmacokinetics (PKs) with high oral bioavailability, minimal accumulation after once daily dosing, and negligible renal elimination. Pharmacodynamic (PD) responses were observed at all dose levels studied, as reflected by statistically significant increases in plasma cGMP concentrations. The increases in cGMP were significantly above the baseline (~ 50-100%) on day 14 for the entire 24-hour interval indicating that sustained cGMP elevations are achieved at steady-state. Maximal steady-state cGMP response was observed in plasma and urine at doses ≥ 50 mg. The TD-0714 PK-PD relationship and safety profile were similar in elderly vs. younger adult subjects. The TD-0714 PK and PD profiles support further clinical development of TD-0714 and suggest the potential for once-daily administration and predictable exposure in patients with cardiorenal diseases regardless of their renal function.

A Network Reduction-Based Multiobjective Evolutionary Algorithm for Community Detection in Large-Scale Complex Networks.

Evolutionary algorithms have been demonstrated to be very competitive in the community detection for complex networks. They, however, show poor scalability to large-scale networks due to the exponential increase of search space. In this paper, we suggest a network reduction-based multiobjective evolutionary algorithm for community detection in large-scale networks, where the size of the networks is recursively reduced as the evolution proceeds. In each reduction of the network, the local communities found by the elite individuals in the population are identified as nodes of the reduced network for further evolution, thereby considerably reducing the search space. A local community repairing strategy is also suggested to correct the misidentified nodes after each network reduction during the evolution. Experimental results on synthetic and real-world networks demonstrate the superiority of the proposed algorithm over several state-of-the-art community detection algorithms for large-scale networks, in terms of both computational efficiency and detection performance.

Minimal Residual Disease Status as a Surrogate Endpoint for Progression-free Survival in Newly Diagnosed Multiple Myeloma Studies: A Meta-analysis.

BACKGROUND: Therapeutic advances have greatly extended survival times in patients with multiple myeloma, necessitating increasingly lengthy trials when using survival outcomes as primary endpoints. A surrogate endpoint that can more rapidly predict survival could accelerate drug development. We conducted a meta-analysis to evaluate minimal residual disease (MRD) status as a valid progression-free survival (PFS) surrogate in patients with newly diagnosed multiple myeloma (NDMM). MATERIALS AND METHODS: We searched abstracts in PubMed, The American Society of Hematology, and the European Hematology Association for "myeloma," "minimal residual disease," and "clinical trial." Because of the need to evaluate the treatment effect on MRD response, only randomized studies for subjects with NDMM were included. Details on the MRD-tested populations were required. The meta-analysis was performed by principles outlined at the 2013 United States Food and Drug Administration workshop on MRD in acute myeloid leukemia.42 For samples that were not measured for MRD and within the subset specified for MRD assessment, their MRD status was imputed from the samples that had known MRD status. Patients that were excluded from planned MRD assessment were considered MRD-positive. RESULTS: Six randomized studies, representing 3283 patients and 2208 MRD samples, met analysis inclusion criteria. MRD negativity rates ranged from 0.06 to 0.70. The treatment effect on the odds ratio for MRD-negative response strongly correlated with the hazard ratio for PFS with a coefficient of determination for the weighted regression line of 0.97. Our meta-analysis suggested that MRD status met both the Prentice criteria for PFS surrogacy. CONCLUSIONS: These results support the claim that MRD status can be used as a surrogate for PFS in NDMM.

Alcohol use, comorbidity, and mortality.

OBJECTIVES: To examine the combined influence of alcohol use and comorbidity on 20-year mortality in older adults (average age 66 at the time of the baseline survey). DESIGN: Longitudinal analysis of a national probability sample-based cohort study. SETTING: Data sources were the National Health and Nutrition Examination Survey I (NHANES I), 1971-1974, and the NHANES Epidemiologic Followup Survey, 1992. PARTICIPANTS: Four thousand six hundred ninety-one adults aged 60 and older who provided data on alcohol use. MEASUREMENTS: The prevalence of at-risk drinking in older adults in the United States and the 20-year all-cause mortality risk associated with it. At-risk drinking status was determined from amount of alcohol consumed and comorbidities, using a previously validated method. RESULTS: The prevalence of at-risk drinking in the United States between 1971 and 1974 in older adults was 10% (18% of men, 5% of women). The majority of at-risk drinkers were identified as such because of their use of alcohol in amounts deemed risky in the presence of relevant comorbidities (69%) (e.g., drinking 2-3 drinks per day and having gout or anxiety or taking a medication for pain). In men, at-risk drinking was associated with higher mortality rates than not-at-risk drinking (hazard ratio=1.20, 95% confidence interval=1.01-1.41); abstinence was not associated with greater mortality. In women, neither abstinence nor at-risk drinking was associated with greater mortality rates. CONCLUSION: In this first, large population-based study of older adults examining the mortality risks of alcohol use and comorbidity, at-risk drinking was associated with greater mortality rates in men. These findings suggest that a lower threshold of alcohol use should be recommended for older adults with specific comorbidities to reduce mortality risks.

Longitudinal trajectories of heavy drinking in adults in the United States of America.

AIMS: To estimate age, period, cohort and other demographic influences on heavy alcohol consumption and trajectories of heavy drinking in American adults. DESIGN: Prospective cohort of 14 127 participants, aged 25-74 years at baseline. Generalized estimating equations to model longitudinal change in the probability of heavy drinking and its association with demographic factors. Setting National, population-based sample of non-institutionalized civilians. MEASUREMENTS: Heavy alcohol consumption (usual number of drinks per occasion >or= five for men; >or= four for women) at baseline (1971-74) and three follow-ups until 1992. FINDINGS: Heavy alcohol consumption declined with increasing age (age effect) and tracked national average consumption (period effect). There was no cohort effect. Higher probability of heavy drinking was associated with male gender (relative risk: RR = 2.4), being not married (RR = 1.4), having less than high school education (RR = 1.7), having annual income below the median (RR = 1.5), not living in the South-east (RR = 1.7), and smoking (RR = 3.4). Getting married and quitting smoking during the study were each associated with reduction in heavy drinking (RR = 0.55 and 0.61, respectively). Slower age-related decline in the probability of heavy drinking was seen in men (P < 0.0001), married individuals (P = 0.03), and smokers (P = 0.05). CONCLUSIONS: Demographic predictors of trends in heavy drinking are different from those for trends in average alcohol consumption. The likelihood of heavy drinking declined more slowly with increasing age in men and smokers, suggesting that the negative health effects of alcohol in older ages may be greatest in these groups.

The effects of megestrol acetate suspension for elderly patients with reduced appetite after hospitalization: a phase II randomized clinical trial.

OBJECTIVES: To provide preliminary evidence on the effectiveness and optimal dosage of megestrol acetate for older persons with impaired appetite after hospitalization. DESIGN: Randomized clinical trial. SETTING: Acute care hospital. PARTICIPANTS: Forty-seven older persons (mean age 83) who were recently discharged from an acute care hospital and had fair or poor appetite. INTERVENTION: Participants were randomized to placebo or megestrol acetate suspension 200 mg, 400 mg, or 800 mg daily for 9 weeks. MEASUREMENTS: Appetite, health-related quality of life, and adverse effects were measured at baseline and 20, 42, and 63 days. Serum nutritional markers were measured at baseline and 20 and 63 days. RESULTS: During the course of the study, there were no significant differences between treatment groups on any of the appetite questions, although participants in the 400-mg and 800-mg groups demonstrated significant improvement from baseline on some questions. At 20 days, prealbumin increased in a dose-response relationship across the four groups (by 0.4, 5.1, 7.5, and 9.0 mg/dL, respectively). Participants in the 400-mg and 800-mg groups demonstrated greater improvement in prealbumin levels at 20 days than those receiving placebo (P=.009 and P=.004, respectively) and those in the 400-mg group also demonstrated improvement at 63 days (P=.02). At 20 days, no participant taking placebo had a morning serum cortisol level less than 8 ng/mL (the lower limit of normal). In contrast, 33%, 70%, and 78% of those taking 200 mg, 400 mg and 800 mg, respectively, had values below this level; by 63 days, these percentages were 11%, 30%, 56%, and 37%, respectively. No patient reported clinical symptoms of adrenal insufficiency. Diarrhea developed in three subjects, and thromboembolism occurred in two receiving active treatment. CONCLUSION: Megestrol acetate at doses of 400 mg and 800 mg increases prealbumin in recently hospitalized older persons. Cortisol suppression is common at higher doses and may be persistent. In this small study, the drug did not confer benefit on other nutritional or clinical outcomes.

A Unified Approach to Nonparametric Comparison of Receiver Operating Characteristic Curves for Longitudinal and Clustered Data.

We present a unified approach to nonparametric comparisons of receiver operating characteristic (ROC) curves for a paired design with clustered data. Treating empirical ROC curves as stochastic processes, their asymptotic joint distribution is derived in the presence of both between-marker and within-subject correlations. A Monte Carlo method is developed to approximate their joint distribution without involving nonparametric density estimation. The developed theory is applied to derive new inferential procedures for comparing weighted areas under the ROC curves, confidence bands for the difference function of ROC curves, confidence intervals for the set of specificities at which one diagnostic test is more sensitive than the other, and multiple comparison procedures for comparing more than two diagnostic markers. Our methods demonstrate satisfactory small-sample performance in simulations. We illustrate our methods using clustered data from a glaucoma study and repeated-measurement data from a startle response study.

Longitudinal patterns and predictors of alcohol consumption in the United States.

OBJECTIVES: We examined demographic predictors of longitudinal patterns in alcohol consumption. METHODS: We used mixed-effects models to describe individual alcohol consumption and change in consumption with age, as well as the associations between consumption and birth year, national alcohol consumption, and demographic factors, among 14 105 adults from the National Health and Nutrition Examination Survey I Epidemiologic Follow-Up Study. RESULTS: Alcohol consumption declined with increasing age, and individual consumption mirrored national consumption. Higher consumption was associated with male gender, being White, being married, having a higher educational level, having a higher income, being employed, and being a smoker. Faster age-related decline in consumption was associated with earlier cohorts, being male, being married, having a lower educational level, and being a smoker. CONCLUSIONS: Compared with alcohol consumption among earlier cohorts, that among recent cohorts declined more slowly with increasing age, suggesting that negative health effects of alcohol could increase in the future.