Moderately hypofractionated proton beam therapy for localized prostate cancer: 5-year outcomes of a phase II trial.

The usefulness of moderately hypofractionated radiotherapy for localized prostate cancer has been extensively reported, but there are limited studies on proton beam therapy (PBT) using similar hypofractionation schedules. The aim of this prospective phase II study is to confirm the safety of a shortened PBT course using 70 Gy relative biological effectiveness (RBE) in 28 fractions. From May 2013 to June 2015, 102 men with localized prostate cancer were enrolled. Androgen deprivation therapy was administered according to risk classification. Toxicity was assessed using Common Terminology Criteria for Adverse Events version 4.0. Of the 100 patients ultimately evaluated, 15 were classified as low risk, 43 as intermediate risk, and 42 as high risk. The median follow-up time of the surviving patients was 96 months (range: 60-119 months). The 5-year cumulative incidences of grade 2 gastrointestinal/genitourinary adverse events were 1% (95% CI: 0.1-6.9) and 4% (95% CI: 1.5-10.3), respectively; no grade ≥ 3 gastrointestinal/genitourinary adverse events were observed. The current study revealed a low incidence of late adverse events in prostate cancer patients treated with moderately hypofractionated PBT of 70 Gy (RBE) in 28 fractions, indicating the safety of this schedule.

Preoperative albumin-bilirubin score and liver resection percentage determine postoperative liver regeneration after partial hepatectomy.

BACKGROUND: The success of liver resection relies on the ability of the remnant liver to regenerate. Most of the knowledge regarding the pathophysiological basis of liver regeneration comes from rodent studies, and data on humans are scarce. Additionally, there is limited knowledge about the preoperative factors that influence postoperative regeneration. AIM: To quantify postoperative remnant liver volume by the latest volumetric software and investigate perioperative factors that affect posthepatectomy liver regeneration. METHODS: A total of 268 patients who received partial hepatectomy were enrolled. Patients were grouped into right hepatectomy/trisegmentectomy (RH/Tri), left hepatectomy (LH), segmentectomy (Seg), and subsegmentectomy/nonanatomical hepatectomy (Sub/Non) groups. The regeneration index (RI) and late regeneration rate were defined as (postoperative liver volume)/[total functional liver volume (TFLV)] × 100 and (RI at 6-months - RI at 3-months)/RI at 6-months, respectively. The lower 25th percentile of RI and the higher 25th percentile of late regeneration rate in each group were defined as "low regeneration" and "delayed regeneration". "Restoration to the original size" was defined as regeneration of the liver volume by more than 90% of the TFLV at 12 months postsurgery. RESULTS: The numbers of patients in the RH/Tri, LH, Seg, and Sub/Non groups were 41, 53, 99 and 75, respectively. The RI plateaued at 3 months in the LH, Seg, and Sub/Non groups, whereas the RI increased until 12 months in the RH/Tri group. According to our multivariate analysis, the preoperative albumin-bilirubin (ALBI) score was an independent factor for low regeneration at 3 months [odds ratio (OR) 95%CI = 2.80 (1.17-6.69), P = 0.02; per 1.0 up] and 12 months [OR = 2.27 (1.01-5.09), P = 0.04; per 1.0 up]. Multivariate analysis revealed that only liver resection percentage [OR = 1.03 (1.00-1.05), P = 0.04] was associated with delayed regeneration. Furthermore, multivariate analysis demonstrated that the preoperative ALBI score [OR = 2.63 (1.00-1.05), P = 0.02; per 1.0 up] and liver resection percentage [OR = 1.02 (1.00-1.05), P = 0.04; per 1.0 up] were found to be independent risk factors associated with volume restoration failure. CONCLUSION: Liver regeneration posthepatectomy was determined by the resection percentage and preoperative ALBI score. This knowledge helps surgeons decide the timing and type of rehepatectomy for recurrent cases.

Multivariate generalized mixed-effects models for screening multiple adverse drug reactions in spontaneous reporting systems.

Introduction: For assessing drug safety using spontaneous reporting system databases, quantitative measurements, such as proportional reporting rate (PRR) and reporting odds ratio (ROR), are widely employed to assess the relationship between a drug and a suspected adverse drug reaction (ADR). The databases contain numerous ADRs, and the quantitative measurements need to be calculated by performing the analysis multiple times for each ADR. We proposed a novel, simple, and easy-to-implement method to estimate the PRR and ROR of multiple ADRs in a single analysis using a generalized mixed-effects model for signal detection. Methods: The proposed method simultaneously analyzed the association between any drug and numerous ADRs, as well as estimated the PRR and ROR for a specific combination of drugs and suspected ADRs. Furthermore, the proposed method was applied to detect drug-drug interactions associated with the concurrent use of two or more drugs. Results and discussion: In our simulation studies, the false-positive rate and sensitivity of the proposed method were similar to those of the traditional PRR and ROR. The proposed method detected known ADRs when applied to the Food and Drug Administration Adverse Event Reporting System database. As an important advantage, the proposed method allowed the simultaneous evaluation of several ADRs using multiple drugs.

Relationship between changes in pulmonary function and patient-reported outcomes of lung cancer surgery.

PURPOSE: To investigate the relationship between changes in pulmonary function (PF) and patient-reported outcomes (PROs) of lung cancer surgery. METHODS: We recruited 262 patients who underwent lung resection for lung cancer, to evaluate the PROs, using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 and the Lung Cancer 13-question supplement (LC13). The patients underwent PF tests and PRO assessments preoperatively (Pre) and 1 year after surgery (Y1). Changes were calculated by subtracting the value at Pre from the value at Y1. We set two cohorts: patients under the ongoing protocol (Cohort 1) and patients who were eligible for lobectomy with clinical stage I lung cancer (Cohort 2). RESULTS: Cohorts 1 and 2 comprised 206 and 149 patients, respectively. In addition to dyspnea, changes in PF were also correlated with scores for global health status, physical and role function scores, fatigue, nausea and vomiting, pain, and financial difficulties. Absolute correlation coefficient values ranged from 0.149 to 0.311. Improvement of emotional and social function scores was independent of PF. Sublobar resection preserved PF more than lobectomy did. Wedge resection mitigated dyspnea in both cohorts. CONCLUSION: The correlation between PF and PROs was found to be weak; therefore, further studies are needed to improve the patient's postoperative experience.

Estimating the minimal clinically important difference of upper extremity outcome measures in chronic stroke patients with moderate to severe impairment: a cross-sectional study.

BACKGROUND: Approximately 70% of chronic stroke patients experience upper extremity (UE) functional impairments, and UE outcome measures are often used as quality-of-life indicators. OBJECTIVE: The purpose of this study was to estimate minimal clinically important difference (MCID) values for UE outcome measures in chronic stroke patients with moderate to severe UE hemiplegia. METHODS: This study was a cross-sectional study, conducted as a secondary analysis of data from the ReoGo-J study, a multicenter, prospective, randomized, parallel-group trial of robot-assisted self-training for UE hemiplegia in chronic stroke. The patients were randomized to 1 of 3 treatment groups. Treatment was provided 3 times a week for 10 weeks, and UE outcome measures were evaluated before and after treatment. The anchor-based method was used to estimate MCID values for UE outcome measures, with Stroke Impact Scale (SIS) subscales as anchors. MCID values were estimated by identifying cutoff values in a receiver operating characteristic (ROC) curve. RESULTS: Between-group comparisons of UE outcome measures, based on the clinically important difference (CID) values of SIS subscales, revealed significant differences in both the Amount of Use (AOU) and Quality of Movement (QOM) components of the Motor Activity Log (MAL)-14. The estimated MCID values were 0.89 for the AOU component and 0.77 for the QOM component. CONCLUSIONS: The estimated MCID values for the MAL-14 not only add information regarding the clinical characteristics of the MAL-14 but also facilitate interpretations of changing scores in chronic stroke patients with moderate to severe UE hemiplegia undergoing rehabilitation therapy. STUDY REGISTRATION: https://www.umin.ac.jp/ctr/index.htm (UMIN000022509; 1 July 2016).

Effect of cardiopulmonary bypass on coagulation factors II, VII and X in a primate model: an exploratory pilot study.

OBJECTIVES: The use of cardiopulmonary bypass (CPB) in cardiac surgery is a major risk factor for postoperative bleeding. We hypothesized that consumptive coagulopathy and haemodilution influence the coagulation factors; therefore, we aimed to estimate the activity profiles of coagulation factors II, VII and X during CPB circulation. METHODS: A 120-min bypass was surgically established in cynomolgus monkeys (n = 7). Activities of coagulation factors II, VII and X were measured at 6 time points during the experiment (baseline, 0, 30, 60, 120 min of bypass and 60 min after bypass). To assess the influence of consumptive coagulopathy, the values were adjusted for haemodilution using the haematocrit values. Data were expressed as mean (standard deviation). RESULTS: Activities of coagulation factors decreased during the experiment. In particular, the activities for II, VII and X were decreased the most by 44.2% (5.0), 61.4% (4.3) and 49.0% (3.7) at 30 min following CPB initiation (P < 0.001, P < 0.001 and P < 0.001, respectively). Following adjustments for haemodilution, change magnitudes lessened but remained significant for factor VII. The adjusted concentration of factor VII was observed to decrease from the baseline to the initiation of bypass circulation. CONCLUSIONS: In conclusion, coagulation factor II, VII and X concentrations decreased during CPB. Following adjustment for haemodilution, a decrease in concentration was observed with factor VII.

Continuous glucose monitoring-derived time in range and CV are associated with altered tissue characteristics of the carotid artery wall in people with type 2 diabetes.

AIMS/HYPOTHESIS: Previous studies have suggested that glucose variability may accelerate atherosclerosis progression in people with type 2 diabetes. Current guidelines recommend assessing glycaemic control using continuous glucose monitoring (CGM), which provides a comprehensive glycaemic profile to supplement HbA1c measurement. However, the association between CGM-derived metrics and atherosclerosis progression is not entirely clear. METHODS: This exploratory study used baseline data and data obtained after 104 weeks from an ongoing prospective, multicentre, observational study. Six hundred study participants with type 2 diabetes and no apparent history of symptomatic cardiovascular disease underwent CGM and ultrasonographic atherosclerosis measurements of the carotid arteries, including the intima-media thickness (IMT) and grey-scale median (GSM), at baseline and 104 weeks. Non-invasive ultrasonic tissue characterisation of the carotid artery wall or plaque using the GSM reflects vascular composition. Multivariate regression models were used to analyse the association between CGM-derived indices, mainly time in range (TIR) and CV, and changes in carotid atherosclerosis index values. RESULTS: Over the 104-week study period, there were modest increases in mean IMT (from 0.759±0.153 to 0.773±0.152 mm, p<0.001) and thickened-lesion GSM (from 43.5±19.5 to 53.9±23.5 units, p<0.001), but no significant changes in common carotid artery maximum-IMT (from 1.109±0.442 to 1.116±0.469 mm, p=0.453) or mean GSM (from 48.7±19.3 to 49.8±20.8 units, p=0.092). In a linear regression model with adjustment for possible atherosclerotic risk factors, including HbA1c, TIR and CV at baseline were significantly associated with the annual change in mean GSM (regression coefficient per 10% increase in TIR 0.52; 95% CI 0.06, 0.98; Hochberg-adjusted p value 0.038; regression coefficient per 1% increase in CV -0.12; 95% CI -0.22, -0.02; Hochberg-adjusted p value 0.038). TIR and CV at baseline were also significantly associated with the annual change in thickened-lesion GSM (regression coefficient per 10% increase in TIR 0.95; 95% CI 0.12, 1.79; Hochberg-adjusted p value 0.038; regression coefficient per 1% increase in CV -0.19; 95% CI -0.36, -0.01; Hochberg-adjusted p value 0.038). Participants who achieved target CGM-derived metrics at baseline, as proposed by an international consensus, showed significant annual changes in mean GSM compared with those who did not (0.94±6.88 vs -0.21±6.19 units/year, p=0.007). CONCLUSIONS/INTERPRETATION: TIR and CV were significantly associated with changes in the tissue characteristics of the carotid artery wall. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry, number UMIN000032325.

Long-term efficacy and safety of early alogliptin initiation in subjects with type 2 diabetes: an extension of the SPEAD-A study.

We previously reported in the study of preventive effects of alogliptin on diabetic atherosclerosis (SPEAD-A) that alogliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, attenuated the progression of carotid atherosclerosis in subjects with type 2 diabetes and no history of cardiovascular disease. This extension study of the SPEAD-A trial investigated whether early alogliptin initiation improved long-term cardiovascular outcomes. The SPEAD-A trial randomized 341 subjects with type 2 diabetes to either alogliptin or conventional treatment to investigate the effects of alogliptin on atherosclerosis. All subjects who completed that trial were eligible for this prospective, observational cohort study. The primary endpoint was the first occurrence of a major cardiovascular event, defined as death due to any cause, acute myocardial infarction, or stroke. During the 520-week follow-up period, composite primary outcome events occurred in only a few subjects in each group [8 (5.4%) in the alogliptin group and 9 in the conventional treatment group (5.9%)]. There were no significant differences in the incidence rate of the primary outcome between the two groups. Post hoc Poisson regression analysis showed no significant difference between the two groups in the incidence rate of composite recurrence events for the same outcomes as the primary endpoint. On the other hand, this incidence rate was significantly lower in subjects who received DPP-4 inhibitors before an initial cardiovascular event than in those who did not (5.8 vs. 13.3 per 1000 person-years, respectively, p = 0.04). Early initiation of alogliptin was not associated with a reduced risk of composite cardiovascular disease, which could be attributed to fewer events and/or the addition of DPP-4 inhibitors during the follow-up period.

Kenward-Roger-type corrections for inference methods of network meta-analysis and meta-regression.

Network meta-analysis has been an essential methodology of systematic reviews for comparative effectiveness research. The restricted maximum likelihood (REML) method is one of the current standard inference methods for multivariate, contrast-based meta-analysis models, but recent studies have revealed the resultant confidence intervals of average treatment effect parameters in random-effects models can seriously underestimate statistical errors; that is, the actual coverage probability of a true parameter cannot retain the nominal level (e.g., 95%). In this article, we provided improved inference methods for the network meta-analysis and meta-regression models using higher-order asymptotic approximations based on the approach of Kenward and Roger (Biometrics 1997;53:983-997). We provided two corrected covariance matrix estimators for the REML estimator and improved approximations for its sample distribution using a t-distribution with adequate degrees of freedom. All of the proposed procedures can be implemented using only simple matrix calculations. In simulation studies under various settings, the REML-based Wald-type confidence intervals seriously underestimated the statistical errors, especially in cases of small numbers of trials meta-analyzed. By contrast, the proposed Kenward-Roger-type inference methods consistently showed accurate coverage properties under all the settings considered in our experiments. We also illustrated the effectiveness of the proposed methods through applications to two real network meta-analysis datasets.

MEF2C/p300-mediated epigenetic remodeling promotes the maturation of induced cardiomyocytes.

Cardiac transcription factors (TFs) directly reprogram fibroblasts into induced cardiomyocytes (iCMs), where MEF2C acts as a pioneer factor with GATA4 and TBX5 (GT). However, the generation of functional and mature iCMs is inefficient, and the molecular mechanisms underlying this process remain largely unknown. Here, we found that the overexpression of transcriptionally activated MEF2C via fusion of the powerful MYOD transactivation domain combined with GT increased the generation of beating iCMs by 30-fold. Activated MEF2C with GT generated iCMs that were transcriptionally, structurally, and functionally more mature than those generated by native MEF2C with GT. Mechanistically, activated MEF2C recruited p300 and multiple cardiogenic TFs to cardiac loci to induce chromatin remodeling. In contrast, p300 inhibition suppressed cardiac gene expression, inhibited iCM maturation, and decreased the beating iCM numbers. Splicing isoforms of MEF2C with similar transcriptional activities did not promote functional iCM generation. Thus, MEF2C/p300-mediated epigenetic remodeling promotes iCM maturation.

A comparison of bias-adjusted generalized estimating equations for sparse binary data in small-sample longitudinal studies.

Using a generalized estimating equation (GEE) can lead to a bias in regression coefficients for a small sample or sparse data. The bias-corrected GEE (BCGEE) and penalized GEE (PGEE) were proposed to resolve the small-sample bias. Moreover, the standard sandwich covariance estimator leads to a bias of standard error for small samples; several modified covariance estimators have been proposed to address this issue. We review the modified GEEs and modified covariance estimators, and evaluate their performance in sparse binary data from small-sample longitudinal studies. The simulation results showed that GEE and BCGEE often failed to achieve convergence, whereas the convergence proportion for PGEE was quite high. The bias for the regression coefficients was generally in the ascending order of PGEE < $$ < $$ BCGEE < $$ < $$ GEE. However, PGEE and BCGEE did not sufficiently remove the bias involving 20-30 subjects with unequal exposure levels with a 5% response rate. The coverage probability (CP) of the confidence interval for BCGEE was relatively poor compared with GEE and PGEE. The CP with the sandwich covariance estimator deteriorated regardless of the GEE methods under the small sample size and low response rate, whereas the CP with the modified covariance estimators-such as Morel's method-was relatively acceptable. PGEE will be the reasonable way for analyzing sparse binary data in small-sample studies. Instead of using the standard sandwich covariance estimator, one should always apply the modified covariance estimators for analyzing these data.

Bias in Odds Ratios From Logistic Regression Methods With Sparse Data Sets.

BACKGROUND: Logistic regression models are widely used to evaluate the association between a binary outcome and a set of covariates. However, when there are few study participants at the outcome and covariate levels, the models lead to bias of the odds ratio (OR) estimated using the maximum likelihood (ML) method. This bias is known as sparse data bias, and the estimated OR can yield impossibly large values because of data sparsity. However, this bias has been ignored in most epidemiological studies. METHODS: We review several methods for reducing sparse data bias in logistic regression. The primary aim is to evaluate the Bayesian methods in comparison with the classical methods, such as the ML, Firth's, and exact methods using a simulation study. We also apply these methods to a real data set. RESULTS: Our simulation results indicate that the bias of the OR from the ML, Firth's, and exact methods is considerable. Furthermore, the Bayesian methods with hyper-É¡ prior modeling of the prior covariance matrix for regression coefficients reduced the bias under the null hypothesis, whereas the Bayesian methods with log F-type priors reduced the bias under the alternative hypothesis. CONCLUSION: The Bayesian methods using log F-type priors and hyper-É¡ prior are superior to the ML, Firth's, and exact methods when fitting logistic models to sparse data sets. The choice of a preferable method depends on the null and alternative hypothesis. Sensitivity analysis is important to understand the robustness of the results in sparse data analysis.

Prediction of early graft function after living donor kidney transplantation by quantifying the "nephron mass" using CT-volumetric software.

Early renal function after living-donor kidney transplantation (LDKT) depends on the "nephron mass" in the renal graft. In this study, as a possible donor-recipient size mismatch parameter that directly reflects the "nephron mass," the cortex to recipient weight ratio (CRWR) was calculated by CT-volumetric software, and its ability to predict early graft function was examined. One hundred patients who underwent LDKT were enrolled. Patients were classified into a developmental cohort (n = 79) and a validation cohort (n = 21). Using the developmental cohort, the correlation coefficients between size mismatch parameters, including CRWR, and the posttransplantation estimated glomerular filtration rate (eGFR) were calculated. Multiple regression analysis was conducted to define a formula to predict eGFR 1-month posttransplantation. Using the validation cohort, the validity of the formula was examined. The correlation coefficient was the highest for CRWR (1-month r = 0.66, p < 0.001). By multiple regression analysis, eGFR at 1-month was predicted using the linear model: 0.23 × donor preoperative eGFR + 17.03 × CRWR + 8.96 × preemptive transplantation + 5.10 (adjusted coefficient of determination = 0.54). In most patients in the validation cohort, the observed eGFR was within a 10 ml/min/1.73 m2 margin of the predicted eGFR. CRWR was the strongest parameter to predict early graft function. Predicting renal function using this formula could be useful in clinical application to select proper donors and to avoid unnecessary postoperative medical interventions.

A Smartphone Healthcare Application, CALO mama Plus, to Promote Weight Loss: A Randomized Controlled Trial.

Mobile applications are increasingly used in healthcare. We have developed a smartphone healthcare application, CALO mama Plus, that can register daily diet, exercise, mood, and sleep quality, calculate dietary intake, and provide advice using artificial intelligence technology. This 3-month randomized controlled trial tested the hypothesis that CALO mama Plus could promote body weight reduction in Japanese adults with overweight or obesity. We recruited office workers as participants. The key eligibility criteria were an age of 20-65 years and a body mass index of 23-40 kg/m2. The primary outcome was body weight change over 3 months. We enrolled 141 participants and randomly assigned them to the intervention (n = 72) and control (n = 69) groups. The intervention group used CALO mama Plus, and the control group did not receive any intervention. The change in body weight was -2.4 ± 4.0 kg and -0.7 ± 3.3 kg in the intervention and control groups, respectively. An analysis of covariance adjusted for related variables showed a significant between-group difference in body weight change (-1.60 kg; 95% confidence interval -2.83 to -0.38; p = 0.011). The present study suggests that CALO mama Plus effectively promotes weight loss.

Real-World Investigation on Anticoagulation Management Before and After Catheter Ablation for Atrial Fibrillation in Japan　- Periprocedural and Long-Term Outcomes.

BACKGROUND: Optimal periprocedural oral anticoagulant (OAC) therapy before catheter ablation (CA) for atrial fibrillation (AF) and the safety profile of OAC discontinuation during the remote period (from 31 days and up to 1 year after CA) have not been well defined.Methods and Results: The RYOUMA registry is a prospective multicenter observational study of Japanese patients who underwent CA for AF in 2017-2018. Of the 3,072 patients, 82.3% received minimally interrupted direct-acting OACs (DOACs) and 10.2% received uninterrupted DOACs. Both uninterrupted and minimally interrupted DOACs were associated with an extremely low thromboembolic event rate. Female, long-standing persistent AF, low creatinine clearance, hepatic disorder, and high intraprocedural heparin dose were independent factors associated with periprocedural major bleeding. At 1 year after CA, DOAC was continued in 55.9% of patients and warfarin in 56.4%. The incidence of thromboembolic and major bleeding events for 1 year was 0.3% and 1.2%, respectively. Age ≥73 years, dementia, and AF recurrence were independently associated with major bleeding events. Univariate analyses revealed that warfarin continuation and off-label overdose of DOACs were risk factors for major bleeding after CA. CONCLUSIONS: High intraprocedural dose of heparin was associated with periprocedural major bleeding events. At 1 year after CA, over half of the patients had continued OAC therapy. Thromboembolic events were extremely low; however, major bleeding occurred in 1.2%. Age ≥73 years, dementia, and AF recurrence were independently associated with major bleeding after CA.

The Importance of Continuous Glucose Monitoring-derived Metrics Beyond HbA1c for Optimal Individualized Glycemic Control.

CONTEXT: Current guidelines recommend assessing glycemic control using continuous glucose monitoring (CGM) and hemoglobin A1c (HbA1c) measurement. OBJECTIVE: This study aimed to clarify the characteristics of patients who might benefit from CGM metrics in addition to HbA1c monitoring. METHODS: CGM metrics, specifically time in range (TIR), time below range (TBR), and time above range (TAR), were determined in 999 outpatients with type 2 diabetes and compared between HbA1c categories (HbA1c < 53 mmol/mol [7.0%, HbA1c <  53], HbA1c 53-63 mmol/mol [7.0-7.9%, HbA1c 53-63], HbA1c 64-74 mmol/mol [8.0-8.9%, HbA1c 64-74], and HbA1c ≥ 75 mmol/mol [9.0%, HbA1c ≥  75]) and between patients with identical HbA1c categories who were stratified by age, types of antidiabetic agents, and renal function. RESULTS: For HbA1c <  53 category, patients aged ≥ 65 years had a significantly higher nocturnal TBR than those aged < 65 years. For HbA1c <  53 and HbA1c 53-63 categories, patients receiving insulin and/or sulfonylureas had a significantly higher TAR and TBR, and a lower TIR than those not receiving these drugs, and for HbA1c 64-74 category, they had a significantly higher TBR. For HbA1c <  53, HbA1c 53-63, and HbA1c 64-74 categories, patients with an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 had a significantly higher TBR during some periods than those with an eGFR ≥ 60. CONCLUSION: Higher HbA1c levels do not always protect against hypoglycemic episodes. Our data demonstrate that using CGM metrics to complement HbA1c monitoring is beneficial, especially in older people, users of insulin and/or sulfonylureas, and patients with chronic kidney disease.

Statistical tests for two-stage adaptive seamless design using short- and long-term binary outcomes.

The adaptive seamless design combining phases II and III into a single trial has been shown growing interest for improving the efficiency of drug development, becoming the most frequent adaptive design type. It typically consists of two stages, the trial objectives being often different in each stage. The primary objectives are to select optimal experimental treatment group(s) in the first stage and compare the efficacy between the selected treatment and control groups in the second stage. In this article, we focus on a two-stage adaptive seamless design, for which treatment selection is based on the short-term binary endpoint and treatment comparison is based on the long-term binary endpoint. We thus propose an exact conditional test as a final analysis, based on the bivariate binomial distribution and given the selected treatment with the most promising short-term endpoint response rate from an interim analysis. Additionally, the mid- p $$ p $$ approach is incorporated to improve conservativeness for an exact test. Simulation studies were conducted to compare the proposed methods with a method based on the combination test. The proposed exact method controlled for type I error rate at the nominal level, regardless of the number of initial treatments or the correlation between short- and long-term endpoints. In terms of the treatment comparison power, the proposed methods are more powerful than that based on the combination test in the scenarios, with only one treatment being effective.

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.

Increased risk of urinary tract infection and pyelonephritis under concomitant use of sodium-dependent glucose cotransporter 2 inhibitors with antidiabetic, antidyslipidemic, and antihypertensive drugs: An observational study.

Urinary tract infection (UTI) and pyelonephritis cause urosepsis, which can become life threating. Sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors, a class of oral anti-diabetic drugs, may increase the risk of UTI and pyelonephritis, as observed from their mechanism of action. Patients with diabetes receiving SGLT2 inhibitors are often concomitantly administered other antidiabetic, antidyslipidemic, or antihypertensive drugs. To determine if drug-drug interactions (DDIs) between SGLT2 inhibitors and these medications increased the risk of UTI and pyelonephritis, we analyzed the Food and Drug Administration Adverse Event Reporting System (FAERS) database. We applied Norén's and Gosho's methods for detecting DDIs. FAERS contains records describing 14 526 398 patient characteristics, 54 290 663 drug properties, and 47 252 416 reactions/events. We found 23 drug combinations that could induce UTI and pyelonephritis, such as SGLT2 inhibitors administered with dipeptidyl peptidase-4 inhibitors, thiazolidinediones, glinides, statins, angiotensin II receptor blockers, and calcium channel blockers. Combination therapy with the drugs detected in our analyses would show potential interactions that could result in UTI and pyelonephritis in patients with diabetes mellitus. However, owing to various limitations, these results must be confirmed by additional analyses.