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For clinical trials in patients with asthma, chronic obstructive pulmonary disease, and relapsing-remitting multiple sclerosis, regulatory guidelines state that a noninferiority clinical trial is an option. Aiming at establishing assay sensitivity, a three-arm noninferiority trial, including an experimental treatment, a reference treatment, and a placebo, the so-called gold-standard noninferiority trial, is recommended. In addition, in the clinical trials for the above diseases, the number of events per unit time is often used as a primary or key secondary endpoint. There are two issues to be addressed in determining the sample size for gold-standard noninferiority trials: the hypotheses to be tested for assay sensitivity, and overdispersion of the number of events. To address these two issues, we propose a sample size calculation method for gold-standard noninferiority trials with two fixed margins and negative binomial endpoints. In a simulation, we show that the proposed hypothesis-testing method achieves the target power, while controlling the Type I error rate at a nominal level, and that the sample size calculation method has adequate power accuracy. Moreover, we illustrate an application of our proposed method for a clinical trial of mild asthma. [ABSTRACT FROM AUTHOR]

Abstract Background The amino-acid balance in cancer patients often differs from that in healthy individuals, because of metabolic changes. This study investigated the use of plasma amino-acid profiles as a novel marker for screening non-small-cell lung cancer (NSCLC) patients. Methods The amino-acid concentrations in venous blood samples from pre-treatment NSCLC patients (n = 141), and age-matched, gender-matched, and smoking status-matched controls (n = 423), were measured using liquid chromatography and mass spectrometry. The resultant study data set was subjected to multiple logistic regression analysis to identify amino acids related with NSCLC and construct the criteria for discriminating NSCLC patients from controls. A test data set derived from 162 patients and 3,917 controls was used to validate the stability of the constructed criteria. Results The plasma amino-acid profiles significantly differed between the NSCLC patients and the controls. The obtained model (including alanine, valine, isoleucine, histidine, tryptophan and ornithine concentrations) performed well, with an area under the curve of the receiver-operator characteristic curve (ROC_AUC) of >0.8, and allowed NSCLC patients and controls to be discriminated regardless of disease stage or histological type. Conclusions This study shows that plasma amino acid profiling will be a potential screening tool for NSCLC.

A placebo‐controlled randomized clinical trial is required to demonstrate that an experimental treatment is superior to its corresponding placebo on multiple coprimary endpoints. This is particularly true in the field of neurology. In fact, clinical trials for neurological disorders need to show the superiority of an experimental treatment over a placebo in two coprimary endpoints. Unfortunately, these trials often fail to detect a true treatment effect for the experimental treatment versus the placebo owing to an unexpectedly high placebo response rate. Sequential parallel comparison design (SPCD) can be used to address this problem. However, the SPCD has not yet been discussed in relation to clinical trials with coprimary endpoints. In this article, our aim was to develop a hypothesis‐testing method and a method for calculating the corresponding sample size for the SPCD with two coprimary endpoints. In a simulation, we show that the proposed hypothesis‐testing method achieves the nominal type I error rate and power and that the proposed sample size calculation method has adequate power accuracy. In addition, the usefulness of our methods is confirmed by returning to an SPCD trial with a single primary endpoint of Alzheimer disease‐related agitation. [ABSTRACT FROM AUTHOR]

Basket trials simultaneously evaluate the effect of one or more drugs on a defined biomarker, genetic alteration, or molecular target in a variety of disease subtypes, often called strata. A conventional approach for analyzing such trials is an independent analysis of each of the strata. This analysis is inefficient as it lacks the power to detect the effect of drugs in each stratum. To address these issues, various designs for basket trials have been proposed, centering on designs using Bayesian hierarchical models. In this article, we propose a novel Bayesian basket trial design that incorporates predictive sample size determination, early termination for inefficacy and efficacy, and the borrowing of information across strata. The borrowing of information is based on the similarity between the posterior distributions of the response probability. In general, Bayesian hierarchical models have many distributional assumptions along with multiple parameters. By contrast, our method has prior distributions for response probability and two parameters for similarity of distributions. The proposed design is easier to implement and less computationally demanding than other Bayesian basket designs. Through a simulation with various scenarios, our proposed design is compared with other designs including one that does not borrow information and one that uses a Bayesian hierarchical model. [ABSTRACT FROM AUTHOR]

A randomized exploratory clinical trial comparing an experimental treatment with a control treatment on a binary endpoint is often conducted to make a go or no‐go decision. Such an exploratory trial needs to have an adequate sample size such that it will provide convincing evidence that the experimental treatment is either worthwhile or unpromising relative to the control treatment. In this paper, we propose three new sample‐size determination methods for an exploratory trial, which utilize the posterior probabilities calculated from predefined efficacy and inefficacy criteria leading to a declaration of the worthwhileness or unpromisingness of the experimental treatment. Simulation studies, including numerical investigation, showed that all three methods could declare the experimental treatment as worthwhile or unpromising with a high probability when the true response probability of the experimental treatment group is higher or lower, respectively, than that of the control treatment group. [ABSTRACT FROM AUTHOR]

Left ventricle (LV) unloading caused by a left ventricular assist device (LVAD) has been shown to enhance reverse LV remodeling in end‐stage cardiomyopathy. Several reports consistently suggest that a pulsatile‐flow LVAD has more profound effects compared to continuous‐flow LVAD, though the responsible mechanisms are not fully understood. We hypothesized that arterial pulsatility, being affected by the type of LVAD, may affect microvasculature and functional/pathological LV remodeling in end‐stage cardiomyopathy. The study included 18 patients with chronic heart failure who underwent LVAD implantation. Eight patients were implanted with pulsatile‐flow LVAD, and 10 patients were implanted with continuous‐flow LVAD. The results of serial echocardiograms and histopathological assessment of transmural LV tissues, which were collected during the implantation and removal of LVADs, were compared between the groups. The results of echocardiography showed that LV systolic dimension and LV ejection fraction improved greatly in the pulsatile‐flow LVAD group compared to the continuous‐flow LVAD group. Histological analysis showed that in both groups, increased microvasculature density and decreased cardiomyocyte size during LVAD support had no significant difference. In contrast, only the patients with continuous‐flow LVADs had presented with significant increase in α‐smooth muscle actin (α‐SMA)‐positive layer thickness and the number of proliferating cell nuclear antigen (PCNA)‐positive cells of myocardial arterioles. We concluded that the use of long‐term continuous‐flow LVAD support, having less pulsatility, had induced more thickening to the medial layer of myocardial arterioles compared to the use of pulsatile‐flow LVADs. Our findings suggest that the pathological impairment of myocardial microvascular structure during continuous‐flow LVAD support may be a novel mechanism which accounts for the difference in LV remodeling depending on the type of LVAD. [ABSTRACT FROM AUTHOR]

In placebo‐controlled, double‐blinded, randomized clinical trials, the presence of placebo responders reduces the effect size for comparison of the active drug group with the placebo group. An attempt to resolve this problem is to use the sequential parallel comparison design (SPCD). Although there are SPCDs with dichotomous or continuous outcomes, an SPCD with negative binomial outcomes—with which investigators deal eg, in clinical trials involving multiple sclerosis, where the investigators are still concerned about the presence of placebo responders—has not yet been discussed. In this article, we propose a simple test for the treatment effect in clinical trials with an SPCD and negative binomial outcomes. Through simulations, we show that the analysis method achieves the nominal type I error rate and power, whereas the sample size calculation provides the sample size with adequate power accuracy. [ABSTRACT FROM AUTHOR]