Rationale and Design of Prospective, Multicenter, Double-Arm Clinical Trial to Investigate the Efficacy of Tofogliflozin on Left Ventricular Diastolic Dysfunction in Patients with Heart Failure with Preserved Ejection Fraction and Type 2 Diabetes Mellitus (TOP-HFPEF Trial).

BACKGROUND: Recent large clinical trials have revealed that sodium-glucose cotransporter 2 (SGLT2) inhibitors improve cardiovascular outcomes not only in patients with heart failure with reduced ejection fraction, but also in patients with heart failure with mildly reduced or preserved ejection fraction (HFpEF). However, the effect of SGLT2 inhibitors on left ventricular (LV) diastolic function is still controversial. METHODS AND RESULTS: The TOP-HFPEF trial (Efficacy of Tofogliflozin on Left Ventricular Diastolic Dysfunction in Patients with Heart Failure with Preserved Ejection Fraction and Type 2 Diabetes Mellitus) is a multicenter, double-arm, open-label, confirmatory, investigator-initiated clinical study to investigate the effect of SGLT2 inhibitor on LV diastolic function in patients with HFpEF and type 2 diabetes mellitus. The participants are randomly assigned (1:1) to the tofogliflozin group (20 mg once daily) or the control group (administration or continuation of antidiabetic drugs other than SGLT2 inhibitors). The estimated number of patients to be enrolled in this trial is 90 in total (45 in each group). The participants are followed up for 52 weeks with tofogliflozin or control drugs. The primary endpoint is the change in E/e' assessed by echocardiography from the baseline to the end of this study (52 weeks). This trial will also evaluate the effects of tofogliflozin on cardiovascular events, biomarkers, other echocardiographic parameters, the occurrence of atrial fibrillation, and renal function. CONCLUSIONS: The TOP-HFPEF trial will clarify the efficacy of an SGLT2 inhibitor, tofogliflozin, on LV diastolic function in patients with HFpEF and type 2 diabetes mellitus.

Improvement of Midpoint Imputation for Estimation of Median Survival Time for Interval-Censored Time-to-Event Data.

BACKGROUND: Progression-free survival (PFS) is used to evaluate treatment effects in cancer clinical trials. Disease progression (DP) in patients is typically determined by radiological testing at several scheduled tumor-assessment time points. This produces a discrepancy between the true progression time and the observed progression time. When the observed progression time is considered as the true progression time, a positively biased PFS is obtained for some patients, and the estimated survival function derived by the Kaplan-Meier method is also biased. METHODS: While the midpoint imputation method is available and replaces interval-censored data with midpoint data, it unrealistically assumes that several DPs occur at the same time point when several DPs are observed within the same tumor-assessment interval. We enhanced the midpoint imputation method by replacing interval-censored data with equally spaced timepoint data based on the number of observed interval-censored data within the same tumor-assessment interval. RESULTS: The root mean square error of the median of the enhanced method is almost always smaller than that of the midpoint imputation regardless of the tumor-assessment frequency. The coverage probability of the enhanced method is close to the nominal confidence level of 95% in most scenarios. CONCLUSION: We believe that the enhanced method, which builds upon the midpoint imputation method, is more effective than the midpoint imputation method itself.

Associations of age-adjusted coefficient of variation of R-R intervals with autonomic and peripheral nerve function in non-elderly persons with diabetes.

AIMS/INTRODUCTION: Early diagnosis of diabetes-associated cardiac autonomic neuropathy using the coefficient of variation of R-R intervals (CVRR) may improve outcomes for individuals with diabetes. The present study examined the associations of decreased CVRR at rest and during deep breathing (DB) with other autonomic nerve function parameters. MATERIALS AND METHODS: The electronic records of 141 inpatients with diabetes (22-65 years) admitted to our hospital between March 2015 and March 2019 were analyzed retrospectively. After assessment by exclusion criteria, 51 inpatients were included. All inpatients were assessed for peripheral and autonomic nerve function, clinical characteristics, and physical abilities. RESULTS: Inpatients with decreased CVRR at rest (n = 9 (17.6%)) and during DB (n = 12 (23.5%)) had a longer duration of known diabetes, a higher prevalence of diabetic retinopathy, lower body mass index (BMI), skeletal mass index (SMI), and knee extension strength, and a higher proportion of impaired standing balance. Decreased CVRR at rest was associated with a greater fall in diastolic BP from supine to standing, higher resting HR, longer QTc, longer time of voiding, and sensory symptoms. CONCLUSIONS: Decreased CVRR at rest and during deep breathing was associated with lower BMI, SMI, and knee strength and a higher proportion of impaired standing balance among non-elderly inpatients with diabetes. Decreased CVRR at rest appeared more strongly associated with a greater orthostatic BP decline, higher resting heart rate, longer QTc, lower urinary tract dysfunction, and sensory symptoms than a decreased CVRR during deep breathing.

Use of clinical variables for preoperative prediction of lymph node metastasis in endometrial cancer.

OBJECTIVE: Endometrial cancer is the most common gynaecological cancer, and most patients are identified during early disease stages. Noninvasive evaluation of lymph node metastasis likely will improve the quality of clinical treatment, for example, by omitting unnecessary lymphadenectomy. METHODS: The study population comprised 611 patients with endometrial cancer who underwent lymphadenectomy at four types of institutions, comprising seven hospitals in total. We systematically assessed the association of 18 preoperative clinical variables with postoperative lymph node metastasis. We then constructed statistical models for preoperative lymph node metastasis prediction and assessed their performance with a previously proposed system, in which the score was determined by counting the number of high-risk variables among the four predefined ones. RESULTS: Of the preoperative 18 variables evaluated, 10 were significantly associated with postoperative lymph node metastasis. A logistic regression model achieved an area under the curve of 0.85 in predicting lymph node metastasis; this value is significantly higher than that from the previous system (area under the curve, 0.74). When we set the false-negative rate to ~1%, the new predictive model increased the rate of true negatives to 21%, compared with 6.8% from the previous one. We also provide a spreadsheet-based tool for further evaluation of its ability to predict lymph node metastasis in endometrial cancer. CONCLUSIONS: Our new lymph node metastasis prediction method, which was based solely on preoperative clinical variables, performed significantly better than the previous method. Although additional evaluation is necessary for its clinical use, our noninvasive system may help improve the clinical treatment of endometrial cancer, complementing minimally invasive sentinel lymph node biopsy.

The inter-laboratory validation study of EpiSensA for predicting skin sensitization potential.

The Epidermal Sensitization Assay (EpiSensA) is a reconstructed human epidermis (RhE)-based gene expression assay for predicting the skin sensitization potential of chemicals. Since the RhE model is covered by a stratified stratum corneum, various kinds of test chemicals, including lipophilic ones and pre-/pro-haptens, can be tested with a route of exposure akin to an in vivo assay and human exposure. This article presents the results of a formally managed validation study of the EpiSensA that was carried out by three participating laboratories. The purpose of this validation study was to assess transferability of the EpiSensA to new laboratories along with its within- (WLR) and between-laboratory reproducibility (BLR). The validation study was organized into two independent stages. As demonstrated during the first stage, where three sensitizers and one non-sensitizer were correctly predicted by all participating laboratories, the EpiSensA was successfully transferred to all three participating laboratories. For Phase I of the second stage, each participating laboratory performed three experiments with an identical set of 15 coded test chemicals resulting in WLR of 93.3%, 93.3%, and 86.7%, respectively. Furthermore, when the results from the 15 test chemicals were combined with those of the additional 12 chemicals tested in Phase II of the second stage, the BLR for 27 test chemicals was 88.9%. Moreover, the predictive capacity among the three laboratories showed 92.6% sensitivity, 63.0% specificity, 82.7% accuracy, and 77.8% balanced accuracy based on murine local lymph node assay (LLNA) results. Overall, this validation study concluded that EpiSensA is easily transferable and sufficiently robust for assessing the skin sensitization potential of chemicals.

Efficacy of azilsartan on left ventricular diastolic dysfunction compared with candesartan: J-TASTE randomized controlled trial.

Characterized by ventricular and vascular stiffness, heart failure with preserved ejection fraction (HFpEF) has led to high morbidity and mortality. As azilsartan is an angiotensin receptor blocker with the highest myocardial and vascular affinities, azilsartan may improve the left ventricular (LV) diastolic function in patients with hypertension and either HFpEF or HF with mildly reduced ejection fraction (HFmrEF) more than candesartan. In this randomized, open-label trial, we randomly assigned 193 hypertensive patients with HF and LV ejection fraction ≥ 45% to 20 mg of azilsartan (n = 95) or 8 mg of candesartan (n = 98), once daily for 48 weeks. After the initiation of treatment, changes in the doses of the study drugs were permitted based on the patient's conditions, including blood pressure (median dose at 48 weeks: azilsartan 20.0 mg/day, candesartan 8.0 mg/day). The primary endpoint was the baseline-adjusted change in the ratio of peak early diastolic transmitral flow velocity (E) to early diastolic mitral annular velocity (e') (E/e'). Adjusted least-squares mean (LSM) change in E/e' was - 0.8 (95% confidence interval [CI] - 1.49 to - 0.04) in the azilsartan group and 0.2 (95% CI - 0.49 to 0.94) in the candesartan group, providing the LSM differences of - 1.0 (95% CI - 2.01 to 0.03, P = 0.057). The median change in left atrial volume index was - 2.7 mL/m2 with azilsartan vs 1.4 mL/m2 with candesartan (P = 0.091). The frequency of adverse events related to hypotension and hyperkalemia did not differ between the groups. The current study did not provide strong evidence that azilsartan improves LV diastolic dysfunction, and further confirmatory study is required.

Optimal dose escalation methods using deep reinforcement learning in phase I oncology trials.

In phase I trials of a novel anticancer drug, one of the most important objectives is to identify the maximum tolerated dose (MTD). To this end, a number of methods have been proposed and evaluated under various scenarios. However, the percentages of correct selection (PCS) of MTDs using previous methods are insufficient to determine the dose for late-phase trials. The purpose of this study is to construct an action rule for escalating or de-escalating the dose and continuing or stopping the trial to increase the PCS as much as possible. We show that deep reinforcement learning with an appropriately defined state, action, and reward can be used to construct such an action selection rule. The simulation study shows that the proposed method can improve the PCS compared with the 3 + 3 design, CRM, BLRM, BOIN, mTPI, and i3 + 3 methods.

Intravenous Tranexamic Acid in Percutaneous Kidney Biopsy: A Randomized Controlled Trial.

BACKGROUND: Tranexamic acid is frequently reported to reduce bleeding-related complications in major surgery and trauma. We aimed to investigate whether tranexamic acid reduced hematoma size after percutaneous kidney biopsy. METHODS: We conducted a double-blind, parallel three-group, randomized placebo-controlled trial at a teaching hospital in Japan between January 2016 and July 2018. Adult patients with clinical indication for ultrasound-guided percutaneous biopsy of a native kidney were included. Participants were randomly assigned into three groups: high-dose tranexamic acid (1,000 mg in total), low-dose tranexamic acid (500 mg in total), or placebo (counterpart saline). Intervention drugs were intravenously administered twice, as a bolus just before the biopsy and as a continuous infusion initiated just after the biopsy. Primary outcome was post-biopsy perirenal hematoma size as measured by ultrasound on the morning after the biopsy. RESULTS: We assessed 90 adult patients for study eligibility, of whom 56 were randomly allocated into the three groups: 20 for high-dose tranexamic acid, 19 for low-dose tranexamic acid, and 17 for placebo. The median size of perirenal hematoma was 200 mm2 (interquartile range, 21-650) in the high-dose tranexamic acid group, 52 mm2 (0-139) in the low-dose tranexamic acid group, and 0 mm2 (0-339) in the placebo group (p = 0.048 for high-dose tranexamic acid vs. placebo). CONCLUSION: In this trial, the median size of post-kidney biopsy hematoma was unexpectedly larger in the high-dose tranexamic acid group than in the placebo group. Although our results do not support the routine use of tranexamic acid in percutaneous kidney biopsy at present, further studies are needed to confirm the results.

Identification of High-Risk Groups in Urinalysis: Lessons from the Longitudinal Analysis of Annual Check-Ups.

BACKGROUND: For effective screening in urinalysis, information on high-risk groups is needed; however, there is a lack of evidence in young adults in particular. The aim of this study was to provide information on urinalysis in young adults and to identify high-risk groups of urinalyses using multi-year data obtained from annual large-scale check-ups. METHOD: We used annual health check-up data collected from 2011 to 2016 at Kyoto University in Japan. Eligible participants were those aged 18-39 years who underwent annual health check-ups for four consecutive years between 2011 and 2016. We conducted descriptive analyses and calculated the risk ratios (RRs) for urinary abnormalities in the fourth year of urinalysis. RESULTS: In total, 13,640 participants (10,877 men, 79.7%) met the eligibility criteria. The mean prevalence rates of proteinuria, haematuria and glucosuria were 1.61% (men: 1.63%; women: 1.53%), 1.48% (men: 0.53%; women: 5.22%) and 0.46% (men: 0.52%; women: 0.25%), respectively. Participants with urinary abnormalities at least once in the initial 3 years had a higher risk of urinary abnormalities in the fourth year than participants with no abnormal findings in the initial 3 years; the risk ratios (RRs) of proteinuria, haematuria and glucosuria were 3.5 (95% confidence interval (CI) = 3.2-3.7), 12.2 (95% CI = 11.7-12.7) and 42.6 (95% CI = 37.7-48.1), respectively. The RRs of all urinary abnormalities in the fourth year increased as the frequency of urinary abnormalities over the preceding 3 years increased. In haematuria, differences of the RR were observed between men and women. CONCLUSION: We clarified the prevalence of urinary abnormalities in young adults and high-risk groups of urinary abnormalities. Our findings support the need for multi-year annual urinalysis.

Using horseshoe prior for incorporating multiple historical control data in randomized controlled trials.

Meta-analytic approaches and power priors are often used to incorporate historical controls into the analysis of a current randomized controlled trial. In this study, we propose a method for incorporating multiple historical controls based on a horseshoe prior, which is a type of global-local shrinkage prior. The method assumes that historical controls follow the same distribution as the current control. In the case in which only a few historical controls are heterogeneous, we consider them to follow a potentially biased distribution from the distribution of the current control. We analyze two clinical trial examples with binary and time-to-event endpoints and conduct simulation studies to compare the performance of the proposed and existing methods. In the analysis of the clinical trial example, the posterior standard deviation of the treatment effect is decreased by the proposed method by considering the bias between the current control and heterogeneous historical control. In the scenarios in which the current and historical controls follow the same distribution, the statistical power using the proposed method is higher than that using existing methods. The proposed method is advantageous when few or no heterogeneous historical controls are expected.

Group Cognitive-Behavioral Therapy With Interoceptive Exposure for Drug-Refractory Irritable Bowel Syndrome: A Randomized Controlled Trial.

INTRODUCTION: Few people can access psychotherapy for irritable bowel syndrome (IBS). Group cognitive-behavioral therapy (GCBT) may be efficient, but the evidence for its efficacy is weak and limited. We aimed to assess the efficacy and safety of GCBT with interoceptive exposure (GCBT-IE), a novel form of GCBT for drug-refractory IBS. METHODS: A single-center, open-label, randomized, controlled trial was conducted in Japan among people aged 18-75 years with moderate-to-severe drug-refractory IBS. Participants were stratified by IBS severity and allocated 1:1 to 10-week GCBT-IE or waiting list (WL) in a blockwise randomization by independent staff. Both arms practiced self-monitoring and received treatment as usual. Multiple primary outcomes were changes from baseline to week 13 in the IBS Symptom Severity Score and the IBS Quality of Life Measure (IBS-QOL), assessed in the intention-to-treat sample. RESULTS: A total of 114 people with drug-refractory IBS were randomized to GCBT-IE (n = 54) or WL (n = 60). Forty-nine participants (90.7%) in the GCBT-IE arm and 58 (96.7%) in the WL arm completed the week 13 assessment. Participants in the GCBT-IE arm reported greater improvements in both IBS symptom severity and quality of life compared with the WL arm, with -115.8 vs -29.7 on the IBS Symptom Severity Score (a difference of -86.1, 95% confidence interval -117.3 to -55.0), and 20.1 vs -0.2 on the IBS-QOL (a difference of 20.3, 95% confidence interval 15.2-25.3), respectively. Six unexpected serious adverse events were reported but were judged as unrelated to the interventions. DISCUSSION: GCBT-IE is an efficacious, safe, and efficient treatment option for people with drug-refractory IBS.

Within- and between-laboratory reproducibility and predictive capacity of amino acid derivative reactivity assay (ADRA) using a 0.5 mg/mL test chemical solution: Results of the study for reproducibility confirmation implemented in five participating laboratories.

The amino acid derivative reactivity assay (ADRA) is an in chemico alternative assay for skin sensitization listed in OECD test guideline 442C. ADRA evaluates the reactivity of sensitizers to proteins, which is key event 1 in the skin sensitization adverse outcome pathway. Although the current key event 1 evaluation method is a simple assay that evaluates nucleophile and test chemical reactivity, mixtures of unknown molecular weights cannot be evaluated because a constant molar ratio between the nucleophile and test chemical is necessary. In addition, because the nucleophile is quantified by HPLC, the frequency of co-eluting the test chemical and nucleophile increases when measuring multi-component mixtures. To solve these issues, test conditions have been developed using a 0.5 mg/mL test chemical solution and fluorescence-based detection. Since the practicality of these methods has not been substantiated, a validation test to confirm reproducibility was conducted in this study. The 10 proficiency substances listed in the ADRA guidelines were tested three times at five different laboratories. The results of both within- and between-laboratory reproducibility were 100%, and the results of ultraviolet- and fluorescence-based measurements were also consistent. In addition to the proficiency substances, a new positive control, squaric acid diethyl ester, was tested three times at the five laboratories. The results showed high reproducibility with N-(2-(1-naphthyl)acetyl)-l-cysteine depletion of 37%-52% and α-N-(2-(1-naphthyl)acetyl)-l-lysine depletion of 99%-100%. Thus, high reproducibility was confirmed in both evaluations of the 0.5 mg/mL test chemical and the fluorescence-based measurements, validating the practicability of these methods.

Longitudinal effects of one-leg standing time on neuropathy outcomes in association with glycemic control in non-elderly patients with type 2 diabetes.

AIMS/INTRODUCTION: Diabetic neuropathy leads to postural instability. This study compared longitudinal changes in neuropathy outcomes relative to long-term glycemic control in patients aged <60 years with uncontrolled type 2 diabetes with and without a short one-leg standing time (OLST <60 s). MATERIALS AND METHODS: In this retrospective study, 58 hospitalized patients with type 2 diabetes (glycated hemoglobin [HbA1c] >7.0%; aged 17-59 years), who underwent re-evaluation of neuropathic sensory symptoms, ankle reflexes and nerve conduction attributes, and cardiac autonomic function (R-R interval), >1 year after discharge were divided into OLST <60 and ≥60 s groups. Patients were followed up every 2-3 months for HbA1c levels for up to 8 years. Neuropathy outcomes relative to OLST and HbA1c levels at baseline and over follow up were compared. RESULTS: Additional development of sensory symptoms (one patient) and abnormal ankle reflexes (five patients) were identified during follow up, and decreased peripheral and cardiac autonomic function at both baseline and follow up, only in patients with OLST <60 s. Mean HbA1c levels were significantly higher in patients with OLST <60 s versus ≥60 s (7.8 ± 0.9% vs 7.2 ± 1.2%; P = 0.022). Better glycemic control during follow up was associated with better neuropathy outcomes only in patients with OLST ≥60 s. CONCLUSION: Non-elderly type 2 diabetes patients with OLST <60 s and decreased peripheral nerve function at baseline are at increased risk for intractable diabetic neuropathy. Better glycemic control alone might not improve neuropathy outcomes in these patients.

Flexible use of copula-type model for dose-finding in drug combination clinical trials.

Identification of the maximum tolerated dose combination (MTDC) of cancer drugs is an important objective in phase I oncology trials. Numerous dose-finding designs for drug combination have been proposed over the years. Copula-type models exhibit distinctive advantages in this task over other models used in existing competitive designs. For example, their application enables the consideration of dose-limiting toxicities attributable to one of two agents. However, if a particular combination therapy demonstrates extremely synergistic toxicity, copula-type models are liable to induce biases in toxicity probability estimators due to the associated Fréchet-Hoeffding bounds. Consequently, the dose-finding performance may be worse than those of other competitive designs. The objective of this study is to improve the performance of dose-finding designs based on copula-type models while maintaining their advantageous properties. We propose an extension of the parameter space of the interaction term in copula-type models. This releases the Fréchet-Hoeffding bounds, making the estimation of toxicity probabilities more flexible. Numerical examples in various scenarios demonstrate that the performance (e.g., the percentage of correct MTDC selection) of the proposed method is better than those exhibited by existing copula-type models and comparable with those of other competitive designs, irrespective of the existence of extreme synergistic toxicity. The results obtained in this study could motivate the real-world application of the proposed method in cases requiring the utilization of the properties of copula-type models.

Optimal adaptive allocation using deep reinforcement learning in a dose-response study.

Estimation of the dose-response curve for efficacy and subsequent selection of an appropriate dose in phase II trials are important processes in drug development. Various methods have been investigated to estimate dose-response curves. Generally, these methods are used with equal allocation of subjects for simplicity; nevertheless, they may not fully optimize performance metrics because of nonoptimal allocation. Optimal allocation methods, which include adaptive allocation methods, have been proposed to overcome the limitations of equal allocation. However, they rely on asymptotics, and thus sometimes cannot efficiently optimize the performance metric with the sample size in an actual clinical trial. The purpose of this study is to construct an adaptive allocation rule that directly optimizes a performance metric, such as power, accuracy of model selection, accuracy of the estimated target dose, or mean absolute error over the estimated dose-response curve. We demonstrate that deep reinforcement learning with an appropriately defined state and reward can be used to construct such an adaptive allocation rule. The simulation study shows that the proposed method can successfully improve the performance metric to be optimized when compared with the equal allocation, D-optimal, and TD-optimal methods. In particular, when the mean absolute error was set to the metric to be optimized, it is possible to construct a rule that is superior for many metrics.

The within- and between-laboratories reproducibility and predictive capacity of Amino acid Derivative Reactivity Assay using 4 mM test chemical solution: Results of ring study implemented at five participating laboratories.

Amino acid derivative reactivity assay (ADRA) for skin sensitization was adopted as an alternative method in the 2019 OECD Guideline for the Testing of Chemicals (OECD TG 442C). The molar ratio of the nucleophilic reagent to the test chemicals in the reaction solution was set to 1:50. Imamura et al. reported that changing this molar ratio from 1:50 to 1:200 reduced in false negatives and improved prediction accuracy. Hence, a ring study using ADRA with 4 mM of a test chemical solution (ADRA, 4 mM) was conducted at five different laboratories to verify within- and between-laboratory reproducibilities (WLR and BLR, respectively). In this study, we investigated the WLR and BLR using 14 test chemicals grouped into three classes: (1) eight proficiency substances, (2) four test chemicals that showed false negatives in the ADRA with 1 mM test chemical solution (ADRA, 1 mM), but correctly positive in ADRA (4 mM), and (3) current positive control (phenylacetaldehyde) and a new additional positive control (squaric acid diethyl ester). The results showed 100% reproducibility and 100% accuracy for skin sensitization. Hence, it is clear that the ADRA (4 mM) is an excellent test method in contrast to the currently used ADRA (1 mM). We plan to resubmit the ADRA (4 mM) test method to the OECD Test Guideline Group in the near future so that OECD TG 442C could be revised for the convenience and benefit of many ADRA users.

Matrix decomposition in meta-analysis for extraction of adverse event pattern and patient-level safety profile.

The purpose of assessing adverse events (AEs) in clinical studies is to evaluate what AE patterns are likely to occur during treatment. In contrast, it is difficult to specify which of these patterns occurs in each patient. To tackle this challenging issue, we constructed a new statistical model including nonnegative matrix factorization by incorporating background knowledge of AE-specific structures such as severity and drug mechanism of action. The model uses a meta-analysis framework for integrating data from multiple clinical studies because insufficient information is derived from a single trial. We demonstrated the proposed method by applying it to real data consisting of three Phase III studies, two mechanisms of action, five anticancer treatments, 3317 patients, 848 AE types, and 99,546 AEs. The extracted typical treatment-specific AE patterns coincided with medical knowledge. We also demonstrated patient-level safety profiles using the data of AEs that were observed by the end of the second cycle.

Predicting study duration in clinical trials with a time-to-event endpoint.

In event-driven clinical trials comparing the survival functions of two groups, the number of events required to achieve the desired power is usually calculated using the Freedman formula or the Schoenfeld formula. Then, the sample size and the study duration derived from the required number of events are considered; however, their combination is not uniquely determined. In practice, various combinations are examined considering the enrollment speed, study duration, and the cost of enrollment. However, effective methods for visually representing their relationships and evaluating the uncertainty in study duration are insufficient. We developed a graphical approach for examining the relationship between sample size and study duration. To evaluate the uncertainty in study duration under a given sample size, we also derived the probability density function of the study duration and a method for updating the probability density function according to the observed number of events (ie, information time). The proposed methods are expected to improve the operation and management of clinical trials with a time-to-event endpoint.

Study Designs in Multi-arm Trials for Breast Cancer: A Systematic Literature Review of Major Journals.

BACKGROUND: Several articles showed that statistical efficiency of multi-arm randomized clinical trials (RCTs) is much better than conventional two-arm RCTs. Multi-arm RCTs attract interest mainly when the experimental treatment regimen is not optimized or several pipelines under development exist. Breast cancer is a possible candidate disease. Our aim was to elucidate the current study designs and multiplicity adjustment methods in multi-arm RCTs. METHODS: A search of the PubMed database revealed 468 articles on breast cancer RCTs published from 2010 to 2016. Information on study designs and analysis methods was collected from 4 major journals. RESULTS: A total of 202 RCTs were selected, 48 were multi-arm and 29 were three-arm RCTs. In two of the target journals, multi-arm RCTs have been increasingly reported since 2013. Compared with two-arm RCTs, three-arm RCTs were frequently conducted in neoadjuvant settings (7.7% vs 33.3%). The number of trials performed in perioperative settings was 46 in two-arm and 15 in three-arm RCTs. Of these, the proportion of industry-sponsored trials in two-arm and three-arm RCTs was 26.1% and 53.3%, respectively. Shared control designs (SCDs) which randomized to a common control arm and multiple experimental arms comprised 54.2% of 48 multi-arm RCTs. For SCDs, detailed information on multiplicity adjustment methods was seldom reported. The Bonferroni adjustment method together with alpha-spending functions was commonly used. CONCLUSION: Breast cancer multi-arm RCTs have been increasingly reported. The majority of multi-arm RCTs are industry-sponsored trials using SCDs in neoadjuvant settings. Detailed description about multiplicity adjustment methods is required for multi-arm RCTs.

Association of One-Leg Standing Time with Discontinuation of Injectable Medications During Hospitalization Among Patients with Type 2 Diabetes.

INTRODUCTION: Persons with type 2 diabetes (T2D) are known to experience impaired physical ability even at the early stages of the disease. However, less attention has been paid to increasing physical ability than to increasing physical activity in the treatment of T2D. The aim of this study was to assess whether improved physical ability parameters are associated with the discontinuation of injectable medications once glycemic targets have been achieved among inpatients with inadequately controlled T2D across a wide range of ages. METHODS: Forty-three patients with glycated hemoglobin levels of ≥ 7.5% (58 mmol/mol) aged between 19 and 82 years who received insulin, glucagon-like peptide-1 receptor agonists or both at admission were enrolled in the study. Muscle strength for knee extension, one-leg standing time with eyes open test(OLST), whole-body reaction time and maximal oxygen uptake were assessed as parameters of physical ability. RESULTS: At admission, patients who during hospitalization discontinued injectable medications (n = 29; Discontinued group) had a shorter duration of diabetes, lower fat mass and higher skeletal muscle mass and performed better on all of the physical ability test parameters than those who continued on injectable medications during hospitalization (n = 14; Continued group). At discharge, patients in the Discontinued group had achieved better glycemic control than those in the Continued group, as indicated by lower mean plasma glucose levels according to the 7-point profile. Stepwise logistic regression analysis that included those variables that were significantly different between the Continued group and the Discontinued group, with the aim to identify candidate(s) of explanatory variables, revealed that only OLST was significantly associated with the discontinuation of injectable medication. Patients with an OLST of ≥ 60 s were more likely to discontinue injectable medication than those with an OLST of < 60 s (odds ratio 18.9; 95% confidence interval 2.0-178.8; p = 0.011). CONCLUSIONS: Among inpatients with inadequately controlled T2D diabetes, longer OLST appear to be associated with discontinuing injectable medications during hospitalization. OLST could possibly be useful as a novel patient factor to consider in de-intensifying injectable medication.