There is a public health need for improved suicide risk assessment tools. This pilot methodology study compared the assay sensitivity of computerized adaptive tests (CAT) of depression and suicidal ideation vs. traditional ratings in a randomized trial subgroup. The last 20 persons to enroll in a published ketamine trial in suicidal depression were studied. This subgroup received traditional and CAT ratings at baseline, 24 h post-infusion and follow-up week 2, 4, and 6: Hamilton Depression Rating Scale, Beck Depression Inventory, and Beck Scale for Suicidal Ideation vs. the CAT-Depression Inventory and CAT-Suicide Scale. Results showed larger effect sizes (ES) for CAT compared with traditional clinician-rated and self-report scales. Coefficients of variation for baseline measurements were lower for CAT compared with traditional scales. This is the first study to show that CAT may have greater assay sensitivity for treatment effects, particularly for suicidal ideation, compared with traditional clinician-rated and non-adaptive self-rated scales in a randomized trial. The findings suggest CAT can enable quick long-term follow-up assessments via cellphone, tablet, or computer while minimizing response bias due to repeated measurement of the same symptom items. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT01700829.

To compare assay sensitivity of the Visual Analogue Scale (VAS) for global osteoarthritis pain and the Western Ontario and McMaster University (WOMAC) pain subscale, and the associated between-trial heterogeneity in effect sizes (ES).
We included trials with placebo, sham or non-intervention control that included at least 100 patients with hip or knee osteoarthritis per arm, reporting both VAS and WOMAC pain scores. ES were calculated as between-group difference in means divided by the pooled standard deviation and compared using a paired t-test. ES and τ2 as a measure of between-trial heterogeneity were combined using random-effects meta-regression with robust variance estimation to account for the correlation of data within trials and meta-analyses.
Twenty-eight trials with 44 randomized comparisons were included. In 28 comparisons (64%), ES from VAS favoured the intervention more than those from WOMAC pain (P = 0.003). Twenty-six p-values (59%) were smaller according to VAS (P = 0.008). The 44 comparisons contributed to 12 meta-analyses. Eleven meta-analyses (92%) showed larger benefits of interventions according to VAS, with a combined overall difference in ES of -0.08 (95% CI -0.14 to -0.02). τ2 was similar for VAS and WOMAC pain (difference in τ2, -0.003, 95% CI -0.009 to 0.004).
The VAS for global pain had slightly higher assay sensitivity at trial and meta-analysis levels than the WOMAC pain subscale without relevant increase in between-trial heterogeneity.

A three-arm trial including an experimental treatment, an active reference treatment and a placebo is often used to assess the non-inferiority (NI) with assay sensitivity of an experimental treatment. Various hypothesis-test-based approaches via a fraction or pre-specified margin have been proposed to assess the NI with assay sensitivity in a three-arm trial. There is little work done on confidence interval in a three-arm trial. This paper develops a hybrid approach to construct simultaneous confidence interval for assessing NI and assay sensitivity in a three-arm trial. For comparison, we present normal-approximation-based and bootstrap-resampling-based simultaneous confidence intervals. Simulation studies evidence that the hybrid approach with the Wilson score statistic performs better than other approaches in terms of empirical coverage probability and mesial-non-coverage probability. An example is used to illustrate the proposed approaches.

Three-arm non-inferiority (NI) trial including the experimental treatment, an active reference treatment, and a placebo where the outcome of interest is binary are considered. While the risk difference (RD) is the most common and well explored functional form for testing efficacy (or effectiveness), however, recent FDA guideline suggested measures such as relative risk (RR), odds ratio (OR), number needed to treat (NNT) among others, on the basis of which NI can be claimed for binary outcome. Albeit, developing test based on these different functions of binary outcome are challenging. This is because the construction and interpretation of NI margin for such functions are non-trivial extensions of RD based approach. A Frequentist test based on traditional fraction margin approach for RR, OR and NNT are proposed first. Furthermore a conditional testing approach is developed by incorporating assay sensitivity (AS) condition directly into NI testing. A detailed discussion of sample size/power calculation are also put forward which could be readily used while designing such trials in practice. A clinical trial data is reanalyzed to demonstrate the presented approach.

A concurrent positive control should be included in a thorough QTc clinical trial to validate the study according to ICH E14 guidance. Some pharmaceutical companies have started to use \"hybrid TQT\" study to meet ICH E14 regulatory requirements since the release of ICH E14 Q&A (R3). The \"hybrid TQT\" study includes the same treatment arms (therapeutic and/or supratherapeutic dose of investigational drug, placebo, and positive control) with sample size less than traditional TQT studies, but use concentration-QTc (C-QTc) analysis as primary analysis and assay sensitivity analysis. To better understand the statistical characteristics of assay sensitivity with a commonly used positive control - Moxifloxacin - in \"hybrid TQT\" studies, we examined the original and subsampled moxifloxacin and placebo data from more than a hundred of TQT studies submitted to FDA. The assay sensitivity results are quite consistent between classical E14 analysis and C-QTc analysis using the original datasets. Performance of assay sensitivity in \"hybrid TQT\" studies using subsampled data depends on number of moxifloxacin subjects, study design (crossover design and parallel design), and C-QTc model. The results presented here can aid the design of future \"hybrid TQT\" studies.

A 3-arm trial design that includes an experimental treatment, an active reference treatment, and a placebo is useful for assessing the noninferiority of an experimental treatment. The inclusion of a placebo arm enables the assessment of assay sensitivity and internal validation, in addition to the testing of the noninferiority of the experimental treatment compared with the reference treatment. In 3-arm noninferiority trials, various statistical test procedures have been considered to evaluate the following 3 hypotheses: (i) superiority of the experimental treatment over the placebo, (ii) superiority of the reference treatment over the placebo, and (iii) noninferiority of the experimental treatment compared with the reference treatment. However, hypothesis (ii) can be insufficient and may not accurately assess the assay sensitivity for the noninferiority of the experimental treatment compared with the reference treatment. Thus, demonstrating that the superiority of the reference treatment over the placebo is greater than the noninferiority margin (the nonsuperiority of the reference treatment compared with the placebo) can be necessary. Here, we propose log-rank statistical procedures for evaluating data obtained from 3-arm noninferiority trials to assess assay sensitivity with a prespecified margin Δ. In addition, we derive the approximate sample size and optimal allocation required to minimize the total sample size and that of the placebo treatment sample size, hierarchically.

With the recent advancement in many therapeutic areas, quest for better and enhanced treatment options is ever increasing. While the \"efficacy\" metric plays the most important role in this development, emphasis on other important clinical factors such as less intensive side effects, lower toxicity, ease of delivery, and other less debilitating factors may result in the selection of treatment options, which may not beat current established treatment option in terms efficacy, yet prove to be desirable for subgroups of patients. The resultant clinical trial by means of which one establishes such slightly less efficacious treatment is known as noninferiority (NI) trial. Noninferiority trials often involve an active established comparator arm, along with a placebo and an experimental treatment arm, resulting into a 3-arm trial. Most of the past developments in a 3-arm NI trial consider defining a prespecified fraction of unknown effect size of reference drug, i.e., without directly specifying a fixed NI margin. However, in some recent developments, more direct approach is being considered with prespecified fixed margin, albeit in the frequentist setup. In this article, we consider Bayesian implementation of such trial when primary outcome of interest is binary. Bayesian paradigm is important, as it provides a path to integrate historical trials and current trial information via sequential learning. We use several approximation-based and 2 exact fully Bayesian methods to evaluate the feasibility of the proposed approach. Finally, a clinical trial example is reanalyzed to demonstrate the benefit of the proposed approach.

BACKGROUND: Inherited antithrombin (AT) deficiency is a heterogeneous disease. Due to low prevalence, only a few studies are available concerning genotype-phenotype associations. The aim was to describe the clinical, laboratory and genetic characteristics of AT deficiency in a large cohort including children and to add further laboratory data on the different sensitivity of functional AT assays.
METHODS: Non-related AT deficient patients (n=156) and their family members (total n=246) were recruited. Clinical and laboratory data were collected, the mutation spectrum of SERPINC1 was described. Three different AT functional assays were explored.
RESULTS: Thirty-one SERPINC1 mutations including 11 novel ones and high mutation detection rate (98%) were detected. Heparin binding site deficiency (type IIHBS) was the most frequent (75.6%) including AT Budapest3 (ATBp3), AT Padua I and AT Basel (86%, 9% and 4% of type IIHBS, respectively). Clinical and laboratory phenotypes of IIHBS were heterogeneous and dependent on the specific mutation. Arterial thrombosis and pregnancy complications were the most frequent in AT Basel and AT Padua I, respectively. Median age at the time of thrombosis was the lowest in ATBp3 homozygotes. The functional assay with high heparin concentration and pH7.4 as assay conditions had low (44%) sensitivity for ATBp3 and it was insensitive for AT Basel and Padua I.
CONCLUSIONS: Type IIHBS deficiencies behave differently in clinical and laboratory phenotypes from each other and from other AT deficiencies. Heparin concentration and pH seem to be the key factors influencing the sensitivity of AT functional assays to IIHBS.

A thorough QT/QTc study in healthy white Caucasian subjects demonstrated that rupatadine has no proarrhythmic potential and raised no cardiac safety concerns. The present phase 1 study aimed to confirm the cardiac safety of rupatadine in healthy Japanese subjects. In this randomized, double-blind, placebo-controlled study, 27 healthy Japanese subjects were administered single and multiple escalating rupatadine doses of 10, 20, and 40 mg or placebo. Triplicate electrocardiogram (ECG) recordings were performed on days -1, 1, and 5 at several points, and time-matched pharmacokinetic samples were also collected. Concentration-effect analysis based on the change in the QT interval corrected using Fridericia\'s formula (QTcF) from average baseline was performed. Data from the formal TQT study in white Caucasian subjects was used for a comparison analysis. The ECG data for rupatadine at doses up to 40 mg did not show an effect on the QTc interval of regulatory concern. The sensitivity of this study to detect small changes in the QTc interval was confirmed by demonstrating a significant shortening of QTcF on days 1 and 5 four hours after a standardized meal. The data from this study exhibited no statistically significant differences in the QTc effect between Japanese and white Caucasian subjects.

We developed a homogeneous bridging anti-drug antibody (ADA) assay on an electro chemiluminescent immunoassay (ECLIA) platform to support the immunogenicity evaluation of a dimeric domain antibody (dAb) therapeutic in clinical studies. During method development we evaluated the impact of different types of acid at various pH levels on polyclonal and monoclonal ADA controls of differing affinities and on/off rates. The data shows for the first time that acids of different pH can have a differential effect on ADA of various affinities and this in turn impacts assay sensitivity and drug tolerance as defined by these surrogate controls. Acid treatment led to a reduction in signal of intermediate and low affinity ADA, but not high affinity or polyclonal ADA. We also found that acid pretreatment is a requisite for dissociation of drug bound high affinity ADA, but not for low affinity ADA-drug complexes. Although we were unable to identify an acid that would allow a 100% retrieval of ADA signal post-treatment, use of glycine pH3.0 enabled the detection of low, intermediate and high affinity antibodies (Abs) to various extents. Following optimization, the ADA assay method was validated for clinical sample analysis. Consistencies within various parameters of the clinical data such as dose dependent increases in ADA rates and titers were observed, indicating a reliable ADA method. Pre- and post-treatment ADA negative or positive clinical samples without detectable drug were reanalyzed in the absence of acid treatment or presence of added exogenous drug respectively to further assess the effectiveness of the final acid treatment procedure. The overall ADA results indicate that assay conditions developed and validated based on surrogate controls sufficed to provide a reliable clinical data set. The effect of low pH acid treatment on possible pre-existing ADA or soluble multimeric target in normal human serum was also evaluated, and preliminary data indicate that acid type and pH also affect drug-specific signal differentially in individual samples. The results presented here represent the most extensive analyses to date on acid treatment of a wide range of ADA affinities to explore sensitivity and drug tolerance issues. They have led to a refinement of our current best practices for ADA method development and provide a depth of data to interrogate low pH mediated immune complex dissociation.