Confirmatory efficacy testing for individual dose-placebo comparisons using serial gatekeeping procedure in dose-finding trials with multiple comparison procedures-modeling.

Dose-finding trials play a key role in the entire drug development process to determine optimal doses for regulatory approval. We address confirmatory efficacy testing for individual dose-placebo comparisons in the context of a dose-finding trial designed with multiple comparison procedures-modeling (MCP-Mod). An extension of the MCP-Mod, called closed MCP-Mod, has been proposed to carry out the MCP-Mod in conjunction with pairwise dose-placebo comparisons; however, an issue associated with the misspecification of candidate dose-response models remains. We consider another way to combine the MCP-Mod and the individual dose-placebo comparisons using serial gatekeeping procedures with fixed sequence, Holm, Hochberg, and step-down Dunnett procedure. The method controls the family-wise error rate in the strong sense and is simple enough to be implemented by existing software. Simulation studies suggested that the serial gatekeeping procedure was comparable with the closed MCP-Mod in terms of statistical power to detect the efficacy of at least one dose, and both methods were capable of pursuing the efficacy claim rather than just establishing the dose-response signal with less than a 20% increase in sample size when assuming monotonic dose-response shapes. The serial gatekeeping procedure would have advantages in the simplicity of implementation and ease of interpretation. The dose-finding trials aiming to declare the dose-response signal, as well as the efficacy of individual doses, would be worth considering as an option to accelerate the drug development program in certain situations.

Clostridioides (Clostridium) difficile infection in Japanese hospitals 2008-2017: A real-world nationwide analysis of treatment pattern, incidence and testing density.

OBJECTIVE: To characterize treatment pattern, incidence and diagnosis of hospital-onset Clostridioides difficile infection (CDI) in Japan, cases were studied over a 9-year period using a large, administrative database. METHODS: This was a retrospective, cross-sectional analysis of inpatients at 320 Japanese Diagnosis-Procedure Combination (DPC) hospitals. Hospitalizations between April 2008 and March 2017 were extracted for patients aged ≥18 years. CDI was defined as CDI treatment plus CDI diagnosis or positive enzyme immunoassay (EIA) result. Endpoints included treatment (type, route, daily dose, duration), time to CDI onset from admission, and time to recurrence (rCDI) from the end of treatment. Chronological changes were reported for treatment pattern, CDI incidence and EIA testing. RESULTS: The analysis included 11,823 CDI hospitalizations, 1359 with rCDI. Overall, oral metronidazole (MNZ), oral vancomycin (VCM), and intravenous MNZ were used in 50.2%, 42.1% and 1.2% of CDI hospitalizations, respectively. From 2009 to 2017, CDI hospitalizations treated with MNZ more than doubled and VCM more than halved. Median (Q1-Q3) time to CDI and rCDI onset was 25 (11-52) days and 10 (6-17.5) days, respectively. Median treatment duration ranged from 8 to 10 days and median dose was 1 g/day for both MNZ and VCM. CDI incidence remained steady from 2010 until 2017 (0.99/10,000 patient-days) and EIA testing density doubled from 2008 to 2017 (24.46/10,000 patient-days). CONCLUSION: Oral MNZ has become the primary CDI treatment in Japanese DPC hospitals. The treatment duration and dose were aligned to the package insert. CDI diagnostic testing density increased over time, CDI incidence did not. CLINICAL TRIAL REGISTRATION NUMBER: N/A.

Risk stratification and clinical course of hepatitis B virus reactivation in rheumatoid arthritis patients with resolved infection: final report of a multicenter prospective observational study at Japanese Red Cross Hospital.

BACKGROUND: The prophylaxis for hepatitis B virus (HBV) reactivation assumes that hepatic injury after reactivation is often rapidly progressive and can evoke fulminant hepatitis. The incidence and prognosis of reactivation in patients with rheumatoid arthritis (RA) may be different from those receiving organ transplantation and cancer chemotherapy. This study aimed to investigate the incidence, risk factors, and clinical course of HBV reactivation and develop a scoring system for risk stratification in RA patients with resolved infection. METHODS: HBV DNA was measured using real-time polymerase chain reaction, and patient data were collected for 4 years in RA patients with resolved HBV infection who were treated with steroids or synthetic or biologic immunosuppressive drugs. RESULTS: Among 1127 patients, HBV DNA was detected in 57 patients (1.65/100 person-years); none of the reactivated patients exhibited worsening of hepatic function. Multivariate logistical analysis revealed that age > 70 years and HB core antibody (HBcAb) positivity alone were independent risk factors for HBV reactivation. HBV DNA ≥ 2.1 log copies/mL was observed in 15 patients (0.43/100 person-years); seven patients were treated with nucleic acid analogs (NAAs), whereas the remaining eight were observed without treatment. Among reactivated cases, 15 cases changed to HBV DNA-negative status spontaneously, whereas 24 cases remained HBV DNA positive < 2.1 log copies/mL during the observation period. We designed the following scoring system: HBV reactivation risk score = 1 × (age > 70 years) + 2 × (HBcAb positivity alone) + 1 × (treatment other than methotrexate monotherapy). This revealed that patients with the highest score had an odds ratio of 13.01 for HBV reactivation, compared to those with the lowest score. CONCLUSIONS: Rapid progression and poor outcomes after HBV reactivation were not frequent in RA patients with resolved infection. Our new risk scoring system might be useful for screening and optimization of prophylactic treatment by distinguishing patients with significantly lower reactivation risk.

Real-World Effectiveness of Sodium Glucose Co-Transporter-2 Inhibitors in Japanese Patients with Diabetes Mellitus.

INTRODUCTION: Sodium glucose co-transporter-2 inhibitors (SGLT2i) have been on the market for 5 years in Japan. We explored the real-world effectiveness of SGLT2i in Japan. METHODS: We retrospectively analyzed two large Japanese administrative databases from JMDC Inc.: insurance-dataset (I-dataset) and Medical Data Vision Co. Ltd. [hospital-dataset (H-dataset)]. Patients who newly started SGLT2i or other oral antidiabetic drugs (OADs) between 1 April 2014 and 31 March 2016 were selected for this analysis and followed for 1 year from the index date. Changes in glycated hemoglobin (HbA1c), body mass index (BMI), and estimated glomerular filtration rate (eGFR) were evaluated during the 1-year period. RESULTS: A total of 127,961 patients in the H-dataset and 26,436 in the I-dataset were included in this analysis. Baseline HbA1c, BMI, and eGFR levels tended to be higher in SGLT2i users than in other OAD cohorts. After 1 year, 44.3% (I-dataset) and 53.3% (H-dataset) of SGLT2i users and 33.0-44.2% (I-dataset) and 47.0-58.1% (H-dataset) of other users were still on their medications. The mean HbA1c level decreased by - 0.7 to - 0.9% in SGLT2i users versus - 0.4 to - 1.5% in the other cohorts. The mean BMI decreased by - 0.8 kg/m2 in SGLT2i users whereas the change in other cohorts was - 0.5 to 0.4 kg/m2. No clinically relevant changes in eGFR were observed over the period. CONCLUSION: This study showed that around half of the SGLT2i users were still on medication after 1 year from treatment initiation. Initiation of SGLT2i was associated with improvement in HbA1c and BMI, with no abnormal changes in renal function observed in the first year following treatment. These findings support the results from clinical trials and will expand the existing evidence of SGLT2i use in real-life practice in Japan. FUNDING: Astellas Pharma Inc., Tokyo, Japan.

Drug Utilization Patterns in Patients with Diabetes Initiating Sodium Glucose Co-Transporter-2 Inhibitors (SGLT2i) in Japan: A Multi-Database Study (2014-2017).

INTRODUCTION: This study aimed to identify drug utilization patterns in patients initiating sodium glucose co-transporter-2 inhibitors (SGLT2i) in the first 3 years of their launch in Japan. METHODS: This was a retrospective study using three administrative databases in Japan: a pharmacy claims database, a hospital-based database, and an insurance claims database. Prescription data were extracted from adult outpatients with diabetes who started SGLT2i between April 2014 and March 2017 to evaluate pre-index and concomitant medications. For glimepiride and insulin co-users, dose at SGLT2i add-on was also assessed. RESULTS: Data from a total of 14,861 patients in the pharmacy dataset (P-dataset), 27,039 in the hospital dataset (H-dataset), and 12,408 in the insurance dataset (I-dataset) were analyzed. The majority of SGLT2i new users (ca. 70%) were taking one to three concomitant antidiabetic medications. Around half of SGLT2i initiators used dipeptidyl peptidase 4 inhibitors and/or biguanides before using SGLT2i or concomitantly with SGLT2i. The average daily glimepiride dose decreased from 2.1 mg/day during the pre-index period to 1.8 mg/day at SGLT2i add-on in the P-dataset and from 1.9 to 1.7 mg/day in the both H- and I-datasets, respectively, with a decreasing trend observed during the first 3 years of launch. The average daily insulin dose at SGLT2i add-on was higher during the first 15 months of launch and then decreased thereafter. Nearly 40% or more SGLT2i new users were taking at least five concomitant medications: cardiovascular agents were predominantly co-prescribed. CONCLUSION: SGLT2i were frequently used as second- or later-line treatment and as part of a dual, triple, or quadruple regimen, as well as co-prescribed with many other medications in the first 3 years of their launch. For SGLT2i users taking concomitant SU or insulin medications, the average daily doses of SU and insulin at SGLT2i add-on decreased slightly over the study period. FUNDING: Astellas Pharma Inc., Tokyo, Japan.

Open-Label Study to Assess the Efficacy of Ipragliflozin for Reducing Insulin Dose in Patients with Type 2 Diabetes Mellitus Receiving Insulin Therapy.

BACKGROUND AND OBJECTIVE: To avoid insulin-induced hypoglycemia and weight gain, the minimum dose of insulin should be used. In this study, therefore, we examined insulin dose reduction by ipragliflozin add-on therapy in Japanese patients with type 2 diabetes mellitus treated with long-acting basal insulin. METHODS: In this multicenter, open-label study, patients received one ipragliflozin 50-mg tablet once daily in combination with basal insulin for 24 weeks. The primary efficacy endpoint was the change and percent change in insulin dose from baseline to Week 24. Secondary efficacy endpoints included changes in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), glycoalbumin, cholesterol, leptin, adiponectin, C-peptide, glucagon, body weight, and blood pressure, and number of patients achieving withdrawal of insulin at the end of treatment (EOT). Treatment-emergent adverse events (TEAEs) were evaluated for safety. RESULTS: In total, 114 patients were screened, 103 were registered, and 97 completed the study. The mean age was 59 years and 72.8% of patients were male. The mean change in insulin dose from baseline at Week 24 was - 6.6 ± 4.4 units/day (p < 0.001); the mean percent change was - 29.87%. HbA1c, FPG, glycoalbumin, glucagon levels, body weight, and blood pressure significantly decreased from baseline to EOT (p < 0.05). Cholesterol, leptin, and adiponectin were unaffected. One patient was able to stop insulin treatment at Week 16. The incidence of TEAEs was 60.2%. Hypoglycemia (10.7%) and pollakiuria (13.6%) were the most common drug-related TEAEs. Conclusions Once-daily 50-mg ipragliflozin enabled a 30% dose reduction of insulin by Week 24 compared with baseline. No major safety concerns were raised. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT02847091).

Characterization and risk factors for recurrence of Clostridioides (Clostridium) difficile infection in Japan: A nationwide real-world analysis using a large hospital-based administrative dataset.

OBJECTIVE: Recurrent Clostridioides (Clostridium) difficile infection (rCDI) is common and increases healthcare resource utilization. In this study, we assessed rCDI risk factors using an up-to-date, Japanese national hospital-based database. METHODS: C. difficile infection (CDI) episodes, occurring July 2014-June 2017, in patients aged ≥18 years were extracted from the database and a nested case-control analysis was performed. Cases were defined as rCDI episodes which required re-initiation of oral vancomycin or oral/intravenous metronidazole treatment within 8 weeks from the start of initial treatment. Cases were matched to 4 non-rCDI episodes at the timing of rCDI occurrence. Adjusted odds ratios (ORs) were estimated using multivariate conditional logistic regression model. RESULTS: Of 18,246 initial CDI episodes, 3250 (17.8%) had at least one rCDI. Approximately 90% of episodes occurred in inpatients and 65% were treated with metronidazole. Older age (<75 years vs 75-84 years and vs 85 + years) was associated with higher risk of rCDI (OR = 1.27, 95% confidence interval [1.15, 1.41] and 1.45 [1.30, 1.61], respectively). Use of systemic antibiotics (3.16 [2.90, 3.44]), probiotics (2.53 [2.32, 2.77]), chemotherapy (1.28 [1.08, 1.53]), or proton pump inhibitors (PPIs) (1.17 [1.07, 1.28]), and prior CDI history (1.22 [1.03, 1.43]) were also identified as rCDI risk factors. Vancomycin reduced the risk of rCDI compared with metronidazole treatment (0.83 [0.76, 0.91]). CONCLUSION: This large, multicenter, nationwide study confirmed that older age, PPIs, antibiotics, probiotics, chemotherapy, and prior CDI history are risk factors for rCDI in Japan. There was a 17% decrease of rCDI risk with vancomycin vs metronidazole treatment. CLINICAL TRIAL REGISTRATION NUMBER: N/A.

Characteristics of Patients with Diabetes Initiating Sodium Glucose Co-transporter-2 Inhibitors (SGLT2i): Real-World Results from Three Administrative Databases in Japan.

INTRODUCTION: The aim of this study was to evaluate the characteristics of new users of sodium glucose co-transporter-2 inhibitors (SGLT2i) in comparison with those of new users of other oral antidiabetic drugs (OADs) using data retrieved from three administrative databases in Japan. METHODS: This study included adult patients from each database who started an OAD between 2014 and 2017. Outpatients who started SGLT2i therapy were included in the SGLT2i cohort. The remaining outpatients were grouped according to the OAD class of their earliest initial prescription after no use of the index OAD during the 6-month pre-index period. Diabetes-related complications were evaluated using the Diabetes Complication Severity Index. RESULTS: In total, 176,355 patients in the hospital-based administrative database (H-dataset), 98,361 in the pharmacy claims database (P-dataset) and 37,786 in the insurance claims database (I-dataset) were analyzed. In the H-dataset, SGLT2i users, compared with users of other OADs, tended to be younger (mean age at index: 57.7 vs. 60.3-69.2 years) and to have a higher prevalence of hypercholesterolemia (73.5 vs. 55.2-71.4%), a higher mean body weight (74.4 vs. 60.5-70.8 kg), a higher body mass index (27.6 vs. 23.5-26.4 kg/m2) and a higher glycated hemoglobin level (8.4 vs. 7.4-8.1%). There were no distinct differences in the prevalence of complications between SGLT2i users and users of other OADs in the H-dataset. Similar trends were noted in the other datasets. CONCLUSION: Patients initiating SGLT2i therapy differed in several characteristics from new users of other OADs. SGLT2i were prescribed more frequently to younger patients, those at increased cardiovascular risk or those with poorer glycemic control. FUNDING: Astellas Pharma Inc., Tokyo, Japan.

Flexible alpha allocation strategies for confirmatory adaptive enrichment clinical trials with a prespecified subgroup.

Adaptive enrichment designs have recently received considerable attention as they have the potential to make drug development process for personalized medicine more efficient. Several statistical approaches have been proposed so far in the literature and the operating characteristics of these approaches are extensively investigated using simulation studies. In this paper, we improve on existing adaptive enrichment designs by assigning unequal weights to the significance levels associated with the hypotheses of the overall population and a prespecified subgroup. More specifically, we focus on the standard combination test, a modified combination test, the marginal combination test, and the partial conditional error rate approach and explore the operating characteristics of these approaches by a simulation study. We show that these approaches can lead to power gains, compared to existing approaches, if the weights are chosen carefully.

Efficacy of abatacept in patients with rheumatoid arthritis, as assessed by magnetic resonance imaging of bilateral hands.

AIM: To examine the efficacy of abatacept in patients with rheumatoid arthritis (RA) using magnetic resonance imaging (MRI) of bilateral hands. METHOD: This prospective study included 35 RA patients. MRI of bilateral hands was performed at baseline and after 12 months of treatment with intravenous abatacept. MRI images were scored for synovitis, osteitis, erosion and joint space narrowing (JSN) according to the RA MRI Scoring System (RAMRIS). The primary endpoint was the change in RAMRIS score from baseline. Repair of erosion was defined as a negative change in the erosion score that was greater than the smallest detectable changes (SDCs). RESULTS: Thirty-one patients completed the study. Median synovitis and osteitis scores showed statistically significant reductions at Month 12 when compared to baseline (synovitis score, -5.5 [P < 0.0001]; osteitis score, -0.5 [P = 0.03]). However, median erosion and JSN scores did not significantly change. At Month 12, 83% of patients showed no progression of erosion scores and repair of erosion was observed in 11% of patients. All patients with repair of erosion achieved functional remission (Health Assessment Questionnaire-Disability Index ≤ 0.5). The Simplified Disease Activity Index response rate at Month 1 was identified as an independent factor predicting changes in the erosion scores at Month 12. CONCLUSION: Abatacept treatment reduced synovitis and osteitis scores and did not worsen erosion and JSN scores at Month 12. Over 10% of patients experienced repair of erosion.

Incidence of hepatitis B virus reactivation in patients with resolved infection on immunosuppressive therapy for rheumatic disease: a multicentre, prospective, observational study in Japan.

BACKGROUND: Although the reactivation of hepatitis B virus (HBV) is recognised as a serious complication in patients with rheumatic disease (RD) receiving immunosuppressive drugs (ISDs), the incidence and risk factors for reactivation remain controversial. OBJECTIVES: To investigate the incidence and risk factors for HBV reactivation in patients with RD. METHODS: We performed a multicentre, observational, prospective study over 2 years in patients with resolved HBV infection. Patients with RD treated with a dose of ≥5 mg/day prednisolone and/or synthetic or biological ISDs with negative HB virus surface antigen and positive anti-HB virus surface antibody (HBsAb) and/or anti-HB virus core antibody (HBcAb) were enrolled. Quantitative HBV DNA results and related data were regularly recorded. RESULTS: Among 1042 patients, including 959 with rheumatoid arthritis, HBV DNA was detected in 35 (1.93/100 person-years), with >2.1 log copies/mL observed in 10 patients (0.55/100 person-years). None of the reactivated patients, including seven treated with a nucleic acid analogue, showed overt hepatitis. Low HBsAb titres and advanced age seemed to be risk factors for HBV reactivation; however, reactivation was observed in three patients with positive HBsAb and negative HBcAb test results. The risk of reactivation was lower with methotrexate but higher with prednisolone among the different types of ISDs. The intervals from the start of ISD to reactivation were relatively long (3-182 months; median, 66 months). CONCLUSIONS: The incidence of HBV reactivation with ISD use was 1.93/100 person-years in patients with RD with resolved HBV infection. No overt hepatitis was observed in the reactivated patients.

A simple and flexible graphical approach for adaptive group-sequential clinical trials.

In this article, we introduce a graphical approach to testing multiple hypotheses in group-sequential clinical trials allowing for midterm design modifications. It is intended for structured study objectives in adaptive clinical trials and extends the graphical group-sequential designs from Maurer and Bretz (Statistics in Biopharmaceutical Research 2013; 5: 311-320) to adaptive trial designs. The resulting test strategies can be visualized graphically and performed iteratively. We illustrate the methodology with two examples from our clinical trial practice. First, we consider a three-armed gold-standard trial with the option to reallocate patients to either the test drug or the active control group, while stopping the recruitment of patients to placebo, after having demonstrated superiority of the test drug over placebo at an interim analysis. Second, we consider a confirmatory two-stage adaptive design with treatment selection at interim.

Difference in left ventricular mass index between hypertensive patients with and without renal artery stenosis by propensity score analysis.

This study aimed to define the difference in cardiac hypertrophy between hypertensive patients with and without renal artery stenosis (RAS). When cardiac ultrasonographic examination was performed in 971 consecutive hypertensive outpatients, renal peak systolic velocity (PSV) was examined. Compared with patients without RAS, those with RAS (PSV ≥180 cm/s, 4.1%) were significantly older and included a higher proportion of male patients and had a higher left ventricular mass index (LVMI). A stratified analysis in the selected 120 patients showed that the LVMI was significantly higher in patients with RAS than in those without RAS for each confounding factor such as age and blood pressure. RAS was independently associated with a higher LVMI on propensity score analysis and multivariate analysis. Thus, the difference in LVMI between hypertensive patients with and without RAS was confirmed, irrespective of age and blood pressure, by stratified propensity score analysis and multivariate regression analysis.

Renin-angiotensin-aldosterone system polymorphisms and 5-year mortality in survivors of acute myocardial infarction: a report from the Osaka Acute Coronary Insufficiency Study.

This study sought to evaluate whether genetic variants in the renin-angiotensin-aldosterone system (RAAS) have an impact on long-term mortality after acute myocardial infarction (AMI) in the percutaneous coronary intervention (PCI) era. We investigated the impacts of individual and combinations of 4 major RAAS genetic variants, angiotensinogen (AGT) T1311C, angiotensin-converting enzyme (ACE) insertion/deletion (I/D), angiotensin 2 type 1 receptor A1166C, and aldosterone synthase T4660C on 5-year mortality in 3149 post-AMI patients using multivariate Cox regression analysis. The predictive accuracy of all possible RAAS genetic combinations was evaluated using Cox regression analysis, and the best combination that affected prognosis was determined based on the minimal Akaike Information Criterion. There were 220 deaths during a median follow-up of 4.9 years. Independent analyses of any single RAAS variant did not show significant impacts on 5-year mortality. However, analyses in combination revealed that absence of both AGT CC genotype and ACE D allele was associated with lower 5-year mortality (log-rank P = 0.005). Patients with at least either of the AGT CC or ACE D allele had increased mortality with adjusted hazard ratios of 2.07 (95% confidence interval 1.18-3.65, P = 0.012), compared with those with neither the AGT CC nor ACE D allele. Among the 4 RAAS genetic variants examined, a combination of AGT and ACE polymorphisms was associated with 5-year mortality after AMI.

Comparison of 5-year survival after acute myocardial infarction using angiotensin-converting enzyme inhibitor versus angiotensin II receptor blocker.

Few studies have investigated whether angiotensin II receptor blocker (ARB) is a practical alternative to angiotensin-converting enzyme inhibitor (ACEI) for long-term use after acute myocardial infarction (AMI) in real-world practice in the percutaneous coronary intervention era. We compared 5-year survival benefits of ACEI and ARB in patients with AMI registered in the Osaka Acute Coronary Insufficiency Study. Study subjects were divided into 3 groups: ACEI (n = 4,425), ARB (n = 2,158), or patients without either drug (n = 2,442). A total of 661 deaths were recorded. Cox regression analysis revealed that treatment with either ACEI or ARB was associated with reduced 5-year mortality (adjusted hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.58 to 0.83, p <0.001 and HR 0.79, 95% CI 0.64 to 0.98, p = 0.03, respectively). However, Kaplan-Meier estimates and Cox regression analyses based on propensity score revealed that ACEI was associated with better survival than ARB from 2 to 5 years after survival discharge (adjusted HR 0.53, 95% CI 0.38 to 0.74, p <0.001). These findings were confirmed in a propensity score-matched population. In conclusion, treatment with ACEI was associated with better 5-year survival after AMI.

Partition testing in confirmatory adaptive designs with structured objectives.

In this paper, we propose a partition testing for adaptive clinical trials with structured study objectives. The proposed approach is a combination of the graphical approach with partition testing. The proposed approach enables one to handle many types of structured objectives, to tailor a multiple test procedure to given structured objectives, and to draw sensible conclusions in adaptive clinical trials. In addition, the proposed approach reduces to the Bonferroni-based graphical approaches that can allow adaptations such as treatment selection and sample size reassessment during the course of the trial. Some practical aspects of the proposed approach are investigated via a simulation study.