Randomized Trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy-Statin and Eicosapentaenoic Acid (RESPECT-EPA).

BACKGROUND: Low plasma levels of eicosapentaenoic acid (EPA) are associated with cardiovascular events. This trial aimed to assess the clinical benefits of icosapent ethyl in patients with coronary artery disease, a low EPA/arachidonic acid (AA) ratio, and statin treatment. METHODS: In this prospective, multicenter, randomized, open-label, blinded end-point study, patients with stable coronary artery disease and a low EPA/AA ratio (<0.4) were randomized to EPA (1800 of icosapent ethyl administered daily) or control group. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, unstable angina pectoris, and coronary revascularization. The secondary composite end points of coronary events included sudden cardiac death, fatal and nonfatal myocardial infarction, unstable angina requiring emergency hospitalization and coronary revascularization, or coronary revascularization. RESULTS: Overall, 3884 patients were enrolled at 95 sites in Japan. Among them, 2506 patients had a low EPA/AA ratio, and 1249 and 1257 patients were randomized to the EPA and control group, respectively. The median EPA/AA ratio was 0.243 (interquartile range, 0.180-0.314) and 0.235 (interquartile range, 0.163-0.310) in the EPA and control group, respectively. Over a median period of 5 years, the primary end point occurred in 112 of 1225 patients (9.1%) and 155 of 1235 patients (12.6%) in the EPA and control group, respectively (hazard ratio, 0.79 [95% CI, 0.62-1.00]; P=0.055). Meanwhile, the secondary composite end point of coronary events in the EPA group was significantly lower (81/1225 [6.6%] versus 120/1235 [9.7%] patients; hazard ratio, 0.73 [95% CI, 0.55-0.97]). Adverse events did not differ between the groups, but the rate of new-onset atrial fibrillation was significantly higher in the EPA group (3.1% versus 1.6%; P=0.017). CONCLUSIONS: Icosapent ethyl treatment resulted in a numerically lower risk of cardiovascular events that did not reach statistical significance in patients with chronic coronary artery disease, a low EPA/AA ratio, and statin treatment. REGISTRATION: URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000012069.

A bias-reduced generalized estimating equation approach for proportional odds models with small-sample longitudinal ordinal data.

BACKGROUND: Longitudinal ordinal data are commonly analyzed using a marginal proportional odds model for relating ordinal outcomes to covariates in the biomedical and health sciences. The generalized estimating equation (GEE) consistently estimates the regression parameters of marginal models even if the working covariance structure is misspecified. For small-sample longitudinal binary data, recent studies have shown that the bias of regression parameters may result from the GEE and have addressed the issue by applying Firth's adjustment for the likelihood score equation to the GEE as if generalized estimating functions were likelihood score functions. In this manuscript, for the proportional odds model for longitudinal ordinal data, the small-sample properties of the GEE were investigated, and a bias-reduced GEE (BR-GEE) was derived. METHODS: By applying the adjusted function originally derived for the likelihood score function of the proportional odds model to the GEE, we produced the BR-GEE. We investigated the small-sample properties of both GEE and BR-GEE through simulation and applied them to a clinical study dataset. RESULTS: In simulation studies, the BR-GEE had a bias closer to zero, smaller root mean square error than the GEE with coverage probability of confidence interval near or above the nominal level. The simulation also showed that BR-GEE maintained a type I error rate near or below the nominal level. CONCLUSIONS: For the analysis of longitudinal ordinal data involving a small number of subjects, the BR-GEE is advantageous for obtaining estimates of the regression parameters of marginal proportional odds models.

Study protocol and baseline characteristics of Randomized trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy-Statin and Eicosapentaenoic Acid: RESPECT-EPA, the combination of a randomized control trial and an observational biomarker study.

BACKGROUND: Omega-3 polyunsaturated fatty acids (PUFAs) have been a hot topic since the Japan EPA Lipid Intervention Study (JELIS), the first landmark study using a highly purified eicosapentaenoic acid (EPA), indicated that EPA could decrease the incidence of cardiovascular events. Over 20 years have passed since the JELIS was conducted, and the standard treatment for dyslipidemia has altered significantly since then. The JELIS subjects did not undertake the current risk management especially current standard statins and did not exclusively target secondary prevention patients. In addition, the subjects included are relatively high EPA population. Furthermore, the clinical implication of the plasma EPA/arachidonic acid (AA) ratio as a biomarker has not yet been validated. Therefore, the Randomized trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy - Statin and EPA (RESPECT-EPA) was planned and is currently underway in Japan. METHODS: The RESPECT-EPA comprises two parts: the open-label randomized controlled trial (RCT) and biomarker study (prospective cohort study design). The RCT included patients with a low EPA/AA ratio. These patients were then randomized to highly purified EPA (1800 mg/day) or control groups. The primary endpoint was cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, unstable angina pectoris, and clinically indicated coronary revascularization. The biomarker study assesses the EPA/AA ratio's usefulness as a biomarker for cardiovascular events prediction. RESULTS: In the RCT, a total of 2,460 patients were enrolled in 95 sites in Japan. Patients' baseline characteristics were similar between intervention and control groups in the RCT. The baseline median EPA/AA ratio was 0.243 and 0.235, respectively. A total of 1,314 patients were participated in the observational part, and the baseline median EPA/AA ratio was 0.577. CONCLUSIONS: After this study is completed, we will have further evidence on whether a highly purified EPA is effective in reducing cardiovascular events for secondary prevention or not, as well as whether if EPA/AA ratio is a predictor for future cardiovascular events. This study was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN000012069).

Dealing with missing data in laboratory test results used as a baseline covariate: results of multi-hospital cohort studies utilizing a database system contributing to MID-NET® in Japan.

BACKGROUND: To evaluate missing data methods applied to laboratory test results used for confounding adjustment, utilizing data from 10 MID-NET®-collaborative hospitals. METHODS: Using two scenarios, five methods dealing with missing laboratory test results were applied, including three missing data methods (single regression imputation (SRI), multiple imputation (MI), and inverse probability weighted (IPW) method). We compared the point estimates of adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) between the five methods. Hospital variability in missing data was considered using the hospital-specific approach and overall approach. Confounding adjustment methods were propensity score (PS) weighting, PS matching, and regression adjustment. RESULTS: In Scenario 1, the risk of diabetes due to second-generation antipsychotics was compared with that due to first-generation antipsychotics. The aHR adjusted by PS weighting using SRI, MI, and IPW by the hospital-specific-approach was 0.61 [95%CI, 0.39-0.96], 0.63 [95%CI, 0.42-0.93], and 0.76 [95%CI, 0.46-1.25], respectively. In Scenario 2, the risk of liver injuries due to rosuvastatin was compared with that due to atorvastatin. Although PS matching largely contributed to differences in aHRs between methods, PS weighting provided no substantial difference in point estimates of aHRs between SRI and MI, similar to Scenario 1. The results of SRI and MI in both scenarios showed no considerable changes, even upon changing the approaches considering hospital variations. CONCLUSIONS: SRI and MI provide similar point estimates of aHR. Two approaches considering hospital variations did not markedly affect the results. Adjustment by PS matching should be used carefully.

Characteristics of hospital differences in missing of clinical laboratory test results in a multi-hospital observational database contributing to MID-NET® in Japan.

BACKGROUND: In Japan, a multiple-hospital observational database system, the Medical Information Database Network (MID-NET®), was launched for post-marketing drug safety assessments. These assessments will be based on datasets with missing laboratory results. The characteristics of missing data considering hospital differences have not been evaluated. We assessed the missing proportion and the association between missingness and a factor through case studies using a database system, a part of MID-NET®. METHODS: Seven scenarios using laboratory results before the prescription of the assessed drug as baseline covariates and data from 10 hospitals of Tokushukai Medical Group were used. The missing proportion and the association between missingness and patient background were investigated per hospital. The associations were assessed using the log of adjusted odds ratio (log-aOR). Additionally, an ad hoc survey was conducted to explore other factors affecting the missingness. RESULTS: For some laboratory tests, missing proportions varied among hospitals, such as 7.4-44.4% of alkaline phosphatase (ALP) and 8.1-31.2% of triglyceride (TG) among statin users. The association between missingness and affecting factors also differed among hospitals for some factors; example, the log-aOR of hospitalization associated with missingness of TG was - 0.41 (95% CI, - 1.06 to 0.24) in hospital 3 and 1.84 (95% CI, 1.34 to 2.34) in hospital 4. In the ad hoc survey focusing on ALP, hospital-dependent differences in the ordering system settings were observed. CONCLUSIONS: Hospital differences in missing data appeared in some laboratory tests in our multi-hospital observational database, which could be attributed to the affecting factors, including the patient background.

Association of blood cadmium levels in pregnant women with infant birth size and small for gestational age infants: The Japan Environment and Children's study.

BACKGROUND: There is growing evidence of an association between cadmium (Cd) and unfavorable birth outcomes. The effect of Cd exposure on anthropometric measures at birth or small for gestational age (SGA) infants in a large, nationwide Japanese cohort remains to be clarified. OBJECTIVES: To analyze the association between maternal blood Cd levels at different sampling times and sex-dependent infant birth size, weight, body length, chest, and head circumferences, in addition to SGA. METHODS: Data of 17,584 pregnant women in the Japan Environment and Children's Study were analyzed for anthropometric measurements. For SGA determination, 13,969 cases of vaginal delivery were analyzed after excluding infants born by cesarean section. Maternal blood Cd levels were categorized into quartiles (Q1-Q4), and the Q1 was used as a reference. Multiple linear regression analysis was performed for anthropometric measurements, and multiple logistic regression analysis was used to investigate the association of maternal blood Cd levels with the risk of SGA. RESULTS: Birth weight tended to decrease according to the increase in quartiles of blood Cd levels (15.63 g decrease [95% confidence level (CI): -33.26, 2.01] for Q4). The overall analysis revealed no decreases in body length and head and chest circumference, but subgroup analysis revealed that chest circumference tended to decrease according to the increase in quartiles in the female sex/third-trimester stratification (0.16 cm decrease [95% CI: -0.32, 0.00] for Q4). SGA risk was also higher and paralleled the increase in blood Cd levels associated with the female sex/third-trimester group (Odds Ratio 1.90 [95% CI: 1.23, 2.94] for Q4). CONCLUSION: Our results provide further evidence of sex-specific health risks associated with Cd exposure in early life in a large Japanese pregnancy cohort.

Intensive uric acid-lowering therapy in CKD patients: the protocol for a randomized controlled trial.

BACKGROUND: Hyperuricemia would be a risk factor for the development/progression of CKD. However, several studies showed U-shape association between serum uric acid level and renal impairment, suggesting that hypouricemia was rather associated with renal dysfunction. Perhaps, there is the optimal target level of serum UA for renal function. METHODS: The Target-UA study is a multicenter randomized controlled trial. Eligible CKD patients (eGFR ≥ 30, < 60 mL/min/1.73 m2 and urine protein < 0.5 g/gCr or urine albumin to creatinine ratio (ACR) < 300 mg/gCr) with serum UA ≥ 8.0 mg/dL (≥ 7.0 mg/dl: under the treatment) will be enrolled and be randomly assigned to the intensive therapy group (target serum UA level ≥ 4.0 mg/dL, < 5.0 mg/dL) or the standard therapy group (serum UA level ≥ 6.0 mg/dL, < 7.0 mg/dL). Topiroxostat, a new xanthine oxidase inhibitor, will be administered to treat hyperuricemia. The primary endpoint is a change in logarithmic value of urine ACR between baseline and week 52 of treatment. The secondary endpoints include changes in serum UA, eGFR, urine protein, lipid profile, and onset of composite cardiovascular events, renal events, gouty arthritis, and attack of urolithiasis. The number of subjects has been set to be 185 in each group for a total of 370. DISCUSSION: This is the first study, to the best of our knowledge, to determine the optimal target level of serum UA for renal protection and is expected to lead to progress in CKD treatment. TRIAL REGISTRATION: (UMIN000026741 and jRCTs051180146).

Identification of malignant early repolarization pattern by late QRS activity in high-resolution magnetocardiography.

BACKGROUND: The early repolarization pattern (ERP) in electrocardiography (ECG) has been considered as a risk for ventricular fibrillation (VF), but effective methods for identification of malignant ERP are still required. We investigated whether high spatiotemporal resolution 64-channel magnetocardiography (MCG) would enable distinction between benign and malignant ERPs. METHODS: Among all 2,636 subjects who received MCG in our facility, we identified 116 subjects (43 ± 18 years old, 54% male) with inferior and/or lateral ERP in ECG and without structural heart disease, including 13 survivors of VF (ERP-VF(+)) and 103 with no history of VF (ERP-VF(-)). We measured the following MCG parameters in a time-domain waveform of relative current magnitude: (a) QRS duration (MCG-QRSD), (b) root-mean-square of the last 40 ms (MCG-RMS40), and (c) low amplitude (<10% of maximal) signal duration (MCG-LAS). RESULTS: Compared to ERP-VF(-), ERP-VF(+) subjects presented a significantly longer MCG-QRS (108 ± 24 vs. 91 ± 23 ms, p = .02) and lower MCG-RMS40 (0.10 ± 0.08 vs. 0.25 ± 0.20, p = .01) but no difference in MCG-LAS (38 ± 22 vs. 29 ± 23 ms, p = .17). MCG-QRSD and MCG-RMS40 showed significantly larger area under the ROC curve compared to J-peak amplitude in ECG (0.72 and 0.71 vs. 0.50; p = .04 and 0.03). The sensitivity, specificity, and odds ratio for identifying VF(+) based on MCG-QRSD ≥ 100 ms and MCG-RMS40 ≤ 0.24 were 69%, 74%, and 6.33 (95% CI, 1.80-22.3), and 92%, 48%, and 10.9 (95% CI, 1.37-86.8), respectively. CONCLUSION: Magnetocardiography is an effective tool to distinguish malignant and benign ERPs.

Association between blood manganese level during pregnancy and birth size: The Japan environment and children's study (JECS).

BACKGROUND: Manganese (Mn) is both an essential element and a potential toxicant. Although a few studies have suggested a nonlinear relationship between the maternal whole blood Mn level at delivery and infant birth weight, little is known about the effects of Mn levels during pregnancy on fetal growth, particularly with regard to sex-specific differences. METHODS: In this nationwide birth cohort study, we examined the association of maternal blood Mn level during pregnancy with infant birth weight, length, and head circumference in 16,473 mother-infant pairs. Pregnant women living in 15 regions across Japan were recruited between January 2011 and March 2014. The analysis of birth size (8,484 males and 7,989 females) was conducted using a nonlinear spline, followed by the use of quadratic regression or linear regression models. The analysis of small-for-gestational-age (SGA) (6,962 males and 6,528 females born vaginally) was conducted using multivariate logistic regression. Additionally, subgroup analysis was conducted according to the timing of blood sampling. RESULTS: The median maternal blood Mn level during pregnancy (i.e., 2nd and 3rd trimesters) was 16.2 µg/L (range, 4.3-44.5 µg/L). A positive linear association between the log blood Mn level and head circumference was observed in both male and female infants. However, a nonlinear relationship between the log blood Mn level and birth weight was observed only in male infants, such that the birth weight increased up to a blood Mn level of 18.6 µg/L. In the subgroup analysis stratified by the timing of maternal blood sampling, this nonlinear relationship was obvious only when sampling was performed in the 3rd trimester. Male infants in the lowest blood Mn level quartile (≤ 13.2 µg/L) faced an increased risk of SGA (odds ratio [95% confidence interval] = 1.35 [1.04-1.74]), as did those in the highest blood Mn level quartile (≥ 21.0 µg/L) when sampling was performed during the 3rd trimester (odds ratio [95% confidence interval] = 1.62 [1.10 to 2.39]), compared to those in the third blood Mn level quartile (the category including 18.6 µg/L). No association of blood Mn level with birth weight was observed among female infants, and blood Mn level was not associated with birth length in either male or female infants. CONCLUSION: A low blood Mn level during pregnancy or a high blood Mn level during the 3rd trimester was associated with a lower birth weight and increased risk of SGA in male infants, but not in female infants. A low blood Mn level was found to correlate slightly with a small head circumference among infants of both sexes.

A multicenter Phase II study of sorafenib in Japanese patients with advanced hepatocellular carcinoma and Child Pugh A and B class.

OBJECTIVE: To evaluate prospectively the efficacy and safety of sorafenib, which has been the first-line treatment for advanced hepatocellular carcinoma (HCC), in Japanese HCC patients (pts) with not only Child-Pugh (C-P) A class but also C-P B class. METHODS: Sorafenib was administered orally at the dose of 400 mg twice daily for pts with HCC and liver function of C-P score of 5-8. Administration was continued until the detection of disease progression or appearance of unacceptable toxicity. The primary endpoint was time to progression (TTP), and toxicity and the secondary endpoints included objective response, overall survival (OS). RESULTS: Forty C-P A pts and 12 C-P B pts were enrolled. The median TTP in the C-P A pts and C-P B pts was 3.3 months and 3.2 months, respectively. Among the pts with C-P A, complete response, partial response, and stable disease were achieved for 2.5%, 7.5% and 47.5%. Among the pts with C-P B, there were no treatment responses, 66.7% of pts had stable disease. The median OS in the C-P A pts and C-P B pts was 13.4 months and 7.4 months, respectively. With regard to toxicities, fewer C-P A pts experienced Grade 3/4 toxicities than C-P B pts (77.5% vs. 91.6%). There were no treatment-related deaths in either group of patients. CONCLUSIONS: This study shows sorafenib has similar effectiveness in the recent post-approval studies and is well-tolerated in Japanese pts with HCC and Child Pugh A class. Sorafenib should be used with great care for Child Pugh class B pts.

A Bayesian meta-analytic approach for safety signal detection in randomized clinical trials.

BACKGROUND/AIM: Meta-analyses are frequently performed on adverse event data and are primarily used for improving statistical power to detect safety signals. However, in the evaluation of drug safety for New Drug Applications, simple pooling of adverse event data from multiple clinical trials is still commonly used. We sought to propose a new Bayesian hierarchical meta-analytic approach based on consideration of a hierarchical structure of reported individual adverse event data from multiple randomized clinical trials. METHODS: To develop our meta-analysis model, we extended an existing three-stage Bayesian hierarchical model by including an additional stage of the clinical trial level in the hierarchical model; this generated a four-stage Bayesian hierarchical model. We applied the proposed Bayesian meta-analysis models to published adverse event data from three premarketing randomized clinical trials of tadalafil and to a simulation study motivated by the case example to evaluate the characteristics of three alternative models. RESULTS: Comparison of the results from the Bayesian meta-analysis model with those from Fisher's exact test after simple pooling showed that 6 out of 10 adverse events were the same within a top 10 ranking of individual adverse events with regard to association with treatment. However, more individual adverse events were detected in the Bayesian meta-analysis model than in Fisher's exact test under the body system "Musculoskeletal and connective tissue disorders." Moreover, comparison of the overall trend of estimates between the Bayesian model and the standard approach (odds ratios after simple pooling methods) revealed that the posterior median odds ratios for the Bayesian model for most adverse events shrank toward values for no association. Based on the simulation results, the Bayesian meta-analysis model could balance the false detection rate and power to a better extent than Fisher's exact test. For example, when the threshold value of the posterior probability for signal detection was set to 0.8, the false detection rate was 41% and power was 88% in the Bayesian meta-analysis model, whereas the false detection rate was 56% and power was 86% in Fisher's exact test. LIMITATIONS: Adverse events under the same body system were not necessarily positively related when we used "system organ class" and "preferred term" in the Medical Dictionary for Regulatory Activities as a hierarchical structure of adverse events. For the Bayesian meta-analysis models to be effective, the validity of the hierarchical structure of adverse events and the grouping of adverse events are critical. CONCLUSION: Our proposed meta-analysis models considered trial effects to avoid confounding by trial and borrowed strength from both within and across body systems to obtain reasonable and stable estimates of an effect measure by considering a hierarchical structure of adverse events.

Differentiation-defective phenotypes revealed by large-scale analyses of human pluripotent stem cells.

We examined the gene expression and DNA methylation of 49 human induced pluripotent stem cells (hiPSCs) and 10 human embryonic stem cells and found overlapped variations in gene expression and DNA methylation in the two types of human pluripotent stem cell lines. Comparisons of the in vitro neural differentiation of 40 hiPSCs and 10 human embryonic stem cells showed that seven hiPSC clones retained a significant number of undifferentiated cells even after neural differentiation culture and formed teratoma when transplanted into mouse brains. These differentiation-defective hiPSC clones were marked by higher expression levels of several genes, including those expressed from long terminal repeats of specific human endogenous retroviruses. These data demonstrated a subset of hiPSC lines that have aberrant gene expression and defective potential in neural differentiation, which need to be identified and eliminated before applications in regenerative medicine.

Postoperative radiotherapy is effective for thymic carcinoma but not for thymoma in stage II and III thymic epithelial tumors: the Japanese Association for Research on the Thymus Database Study.

BACKGROUND: The efficacy of postoperative radiotherapy (PORT) for thymic epithelial tumors is still controversial. Using the Japanese Association for Research on the Thymus (JART) database, this study was aimed at clarifying the efficacy of PORT for Masaoka stage II and III thymic carcinoma and thymoma. METHODS: The JART database registered the records of 2835 patients collected from 32 Japanese institutions from 1991 to 2010. Thymic carcinoma and thymoma at stage II or III were extracted. The efficacy of PORT with respect to relapse-free survival (RFS) and overall survival (OS) was evaluated with the Kaplan-Meier method and Cox regression analysis. RESULTS: There were 1265 patients in all: 155 thymic carcinoma cases (12.3%) and 1110 thymoma cases (87.7%). Eight hundred ninety-five (70.8%) were at stage II, and 370 (29.2%) were at stage III. Four hundred three cases (31.9%) underwent PORT. PORT for stage II and III thymic carcinoma was associated with increasing RFS (hazard ratio, 0.48; 95% confidence interval, 0.30-0.78; P = .003) but was not associated with OS (hazard ratio, 0.94; 95% confidence interval, 0.51-1.75; P = .536). PORT for stage II and III thymoma was not associated with RFS or OS (P = .350). A subgroup analysis of stage III thymoma showed no factor associated with the efficacy of PORT. CONCLUSIONS: In this study, PORT did not increase RFS or OS for stage II or III thymoma but increased RFS for stage II and III thymic carcinoma.

Patterns of Sensitization to Inhalant Allergens in Japanese Lower-Grade Schoolchildren and Related Factors.

OBJECTIVE: This study clarified sensitization patterns to house dust mite (HDM) and Japanese cedar pollen (JCP) in Japanese lower-grade schoolchildren. We also explored factors associated with allergic sensitization. METHODS: This cross-sectional study used a database from the Study on Respiratory Disease and Automobile Exhaust (SORA), a Japanese health study project. The subjects comprised 8,815 pupils aged 6-9 years. We obtained the distribution of HDM- and JCP-specific IgE, respectively, as a marker of sensitization. To determine factors associated with sensitization, we used logistic regression and calculated adjusted odds ratios (AORs) for the relative prevalence of sensitization. The cut-off point for specific IgE levels was 0.35 kU/l. RESULTS: Sensitization to HDM and JCP was detected in 51 and 39% of subjects, respectively, occurring more often in boys and at older ages. In addition, AORs of sensitization to HDM/JCP were higher in subjects with a history of bronchitis, parental asthma, parental atopic eczema and parental pollinosis. In contrast, AORs for sensitization were lower in those subjected to maternal passive smoking as well as among boys with pets. AORs of sensitization to JCP alone were lower in those with a history of otitis media, those who had been bottle milk fed, and those who were not the firstborn and who lived near a busy road. CONCLUSION: Sensitization to HDM and JCP was detected in 51 and 39% of lower-grade schoolchildren, respectively.

Impact of medication adherence on renal function in comorbid patients with type 2 diabetes and depression: protocol for a cohort study.

BACKGROUND: Prevention, or slowing the progression, of diabetic nephropathy is one of the important goals in diabetes care. Although the impact of depression is a concern in patients with diabetes, it is unknown whether there is an association between adherence to hypoglycemic medication and the decline of renal function in comorbid patients with diabetes and depression. We will conduct a cohort study aimed at examining (1) depression as a predictor of renal function decline, and (2) how adherence to hypoglycemic medication relates to depression and renal function decline in patients with type 2 diabetes. METHODS/DESIGN: In this multicenter cohort study, 550 patients with type 2 diabetes aged 20 years and older will be recruited at 20 outpatient clinics in general medicine and psychiatry. We will measure depression (Patient Health Questionnaire), medication adherence (medication possession ratio, Morisky Medication Adherence Scale, and one-item hypoglycemic medication adherence scale), and renal function (urinary albumin-creatinine ratio and estimated glomerular filtration rate) at baseline and at the 12-month follow-up. The primary endpoint is decline of renal function at 12 months. The secondary endpoints include clinical variables, quality of life, and the attitude of professionals toward depression. We will perform multivariable linear regression analysis to evaluate the effects of medication adherence on the decline of renal function in comorbid patients with type 2 diabetes and depression. DISCUSSION: To our knowledge, this will be the first study to examine how adherence to hypoglycemic medication relates to the decline of renal function in comorbid patients with type 2 diabetes and depression. The results of the study will have implications for practitioners of diabetes care, policy makers, and researchers for the prevention and treatment of diabetic nephropathy. TRIAL REGISTRATION: UMIN000017513 (Registered on May 22, 2015).

Practical approaches for design and analysis of clinical trials of infertility treatments: crossover designs and the Mantel-Haenszel method are recommended.

Crossover designs have some advantages over standard clinical trial designs and they are often used in trials evaluating the efficacy of treatments for infertility. However, clinical trials of infertility treatments violate a fundamental condition of crossover designs, because women who become pregnant in the first treatment period are not treated in the second period. In previous research, to deal with this problem, some new designs, such as re-randomization designs, and analysis methods including the logistic mixture model and the beta-binomial mixture model were proposed. Although the performance of these designs and methods has previously been evaluated in large-scale clinical trials with sample sizes of more than 1000 per group, the actual sample sizes of infertility treatment trials are usually around 100 per group. The most appropriate design and analysis for these moderate-scale clinical trials are currently unclear. In this study, we conducted simulation studies to determine the appropriate design and analysis method of moderate-scale clinical trials for irreversible endpoints by evaluating the statistical power and bias in the treatment effect estimates. The Mantel-Haenszel method had similar power and bias to the logistic mixture model. The crossover designs had the highest power and the smallest bias. We recommend using a combination of the crossover design and the Mantel-Haenszel method for two-period, two-treatment clinical trials with irreversible endpoints.

Satisfying the needs of Japanese cancer patients: a comparative study of detailed and standard informed consent documents.

BACKGROUND: Simplified informed consent forms have been successful in improving patient satisfaction and decreasing patient anxiety. However, unsolved problems remain about whether these documents improve comprehension and satisfaction of patients with standard literacy skills. PURPOSE: s To investigate whether a detailed consent form explaining the key elements of informed consent, in comparison to a standard consent form, would increase the comprehension and satisfaction of adult cancer patients. METHODS: Patients who were eligible for the National Surgical Adjuvant Study of Breast Cancer (protocol 01(N-SAS/BC-01)) were randomly selected to receive one of the following four versions: detailed document with graphics, detailed document without graphics, standard document with graphics, and standard document without graphics. The forms were written in plain language from the patients' point of view. A total of 85 patients were administered questionnaires via interview to assess levels of comprehension, satisfaction, and anxiety. RESULTS: Patients demonstrated a strong understanding of information regarding treatment and research. Patient comprehension did not differ significantly between the detailed document arms and the standard document arms. Patient satisfaction level increased according to the amount of information presented in the consent form; most patients preferred the detailed document with graphics. Anxiety and accrual rates in the parent study were not affected by informed consent procedures. LIMITATIONS: Findings were limited to adults who had standard literacy skills and may not be generalizable to a population with lower literacy. CONCLUSION: Informed consent can be a significant experience for a population with standard literacy skills, as long as the document is easily comprehensible. Such information should be provided in a format that corresponds with patient needs, education levels, and preferences.

Favorable effect of CD26/DPP-4 inhibitors on postoperative outcomes after lung transplantation: A propensity-weighted analysis.

BACKGROUND: We have shown the efficacy of CD26/dipeptidyl peptidase 4 (CD26/DPP-4) inhibitors, antidiabetic agents, in allograft protection after experimental lung transplantation (LTx). We aimed to elucidate whether CD26/DPP-4 inhibitors effectively improve postoperative outcomes after clinical LTx. METHODS: We retrospectively reviewed the records of patients undergoing LTx at our institution between 2010 and 2021 and extracted records of patients with diabetes mellitus (DM) at 6 months post-LTx. The patient characteristics and postoperative outcomes were analyzed. We established 6 months post-LTx as the landmark point for predicting overall survival (OS) and chronic lung allograft dysfunction (CLAD)-free survival. Hazard ratios were estimated by Cox regression after propensity score weighting, using CD26/DPP-4 inhibitor treatment up to 6 months post-LTx as the exposure variable. We evaluated CLAD samples pathologically, including for CD26/DPP-4 immunohistochemistry. RESULTS: Of 102 LTx patients with DM, 29 and 73 were treated with and without CD26/DPP-4 inhibitors, respectively. Based on propensity score adjustment using standardized mortality ratio weighting, the 5-year OS rates were 77.0% and 44.3%, and the 5-year CLAD-free survival rates 77.8% and 49.1%, in patients treated with and without CD26/DPP-4 inhibitors, respectively. The hazard ratio for CD26/DPP-4 inhibitor use was 0.34 (95% confidence interval (CI) 0.14-0.82, p = 0.017) for OS and 0.47 (95% CI 0.22-1.01, p = 0.054) for CLAD-free survival. We detected CD26/DPP-4 expression in the CLAD grafts of patients without CD26/DPP-4 inhibitors. CONCLUSIONS: Analysis using propensity score weighting showed that CD26/DPP-4 inhibitors positively affected the postoperative prognosis of LTx patients with DM.

Multicenter Phase II Trial of Lenvatinib plus Hepatic Intra-Arterial Infusion Chemotherapy with Cisplatin for Advanced Hepatocellular Carcinoma: LEOPARD.

Introduction: Hepatic arterial infusion chemotherapy (HAIC) with cisplatin and lenvatinib exhibits strong antitumor effects against advanced hepatocellular carcinoma (HCC). Higher antitumor activity is expected for the combination treatment. The aim of this trial was to evaluate the efficacy and safety of lenvatinib in combination with HAIC using cisplatin in patients with advanced HCC. Methods: In this multicenter, open-labeled, single-arm, phase II trial, patients with advanced HCC categorized as Child-Pugh class A with no prior history of systemic therapy were enrolled. Patients received lenvatinib plus HAIC with cisplatin (lenvatinib: 12 mg once daily for patients ≥60 kg, 8 mg once daily for patients <60 kg; HAIC with cisplatin: 65 mg/m2, day 1, every 4-6 weeks, maximum of six cycles). The primary endpoint was the objective response rate (ORR) assessed using modified RECIST by the Independent Review Committee. The secondary endpoints were the ORR assessed using RECIST v1.1, progression-free survival, overall survival, and frequency of adverse events associated with the treatment. Results: A total of 36 patients were enrolled between September 2018 and March 2020. In the 34 evaluable patients, the ORR assessed by the Independent Review Committee using modified RECIST and RECIST v1.1 were 64.7% (95% confidence interval [CI]: 46.5-80.3%) and 45.7% (95% CI: 28.8-63.4%), respectively. The median progression-free survival and overall survival were 6.3 months (95% CI: 5.1-7.9 months) and 17.2 months (95% CI: 10.9 - not available, months), respectively. The main grade 3-4 adverse events were increased aspartate aminotransferase (34%), leukopenia (22%), increased alanine aminotransferase (19%), and hypertension (11%). Conclusion: Lenvatinib plus HAIC with cisplatin yielded a favorable ORR and overall survival and was well tolerated in patients with advanced HCC. Further evaluation of this regimen in a phase III trial is warranted.

A Randomized Controlled Trial of Betamethasone on Fatigue in Patients With Advanced Cancer.

CONTEXT: Fatigue is one of the most uncomfortable physical symptoms seen in patients with advanced cancer. Previous studies have reported on the efficacy of corticosteroids from Western countries. OBJECTIVES: To assess the effectiveness of 4mg betamethasone improving fatigue among Japanese patients with advanced cancer. METHODS: A randomized, double-blind, placebo-controlled trial enrolled eligible patients with advanced cancer expected to survive 1-2 months, with an Eastern Cooperative Oncology Group Performance Status of 2-3, and experiencing fatigue according to the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-15-palliative criteria. Participants received twice-daily oral administration of 2 mg betamethasone (4 mg/d) or placebo for seven days, with fatigue assessed using EORTC QLQ-C15-PAL subscale and numerical rating scale (NRS) score (at baseline and day seven). The trial was registered under the University Hospital Medical Information Network (UMIN)000011913. RESULTS: Among the 267 screened patients, 81 were eligible, of which 70 were evaluable (betamethasone, 33; placebo, 37). The mean difference in the EORTC-QLQ-C15-PAL fatigue subscale was -8.2 (95% CIs: -22.3, 0.0; P = 0.178) and in a NRS for fatigue was -1.2 (95% CIs: -2.5, -0.01; P = 0.048), respectively. Emotional function, appetite loss, and global-health were slightly better in the betamethasone group than in the placebo group. CONCLUSION: The impact of betamethasone 4 mg/d on alleviating fatigue in patients with advanced cancer in the last weeks of life did not reach statistical significance in the EORTC-QLQ-C15-PAL as the primary endpoint, however, it was significant in the NRS, the secondary endpoint.