Long-Term Safety and Effectiveness of Tacrolimus in Patients With Lupus Nephritis in Japan: 10-Year Analysis of the Real-World TRUST Study.

OBJECTIVE: To assess the long-term safety and effectiveness of tacrolimus as maintenance therapy in patients with lupus nephritis (LN) receiving treatment in real-world clinical settings in Japan. METHODS: An open-label, noncomparative, observational, prospective postmarketing surveillance study was conducted in 1395 patients with LN receiving maintenance treatment with tacrolimus at 278 medical institutions across Japan over a period of 10 years. Tacrolimus continuation rate and cumulative incidence of adverse drug reactions (ADRs), relapse, progression to renal failure, and progression to dialysis were calculated using Kaplan-Meier analysis. RESULTS: Safety data were available for 1355 patients, almost half (49.3%) of whom remained on tacrolimus for the full 10 years of follow-up. A significant reduction in mean (SD) daily oral corticosteroid dose was observed from 16.0 (9.7) mg/day at 4 weeks after initiation of tacrolimus treatment to 7.2 (4.4) mg/day at year 10 (P < 0.001). The most frequently reported serious ADRs were infections (reported for 131 [9.7%] patients). Except for infections, no marked increase in the incidence of any other ADRs was seen over time, including renal impairment, malignant tumors, and cardiac dysfunction. Renal function was generally well maintained over the 10 years of follow-up. At year 10, cumulative rates of relapse, renal failure, and dialysis were 44.5%, 12.2%, and 4.5%, respectively. CONCLUSION: Tacrolimus was effective and generally well tolerated as maintenance therapy for LN in a large cohort of patients in Japan followed for 10 years, almost half of whom remained on therapy for the entire duration of follow-up. (ClinicalTrials.gov: NCT01410747).

Third nationwide surveillance of bacterial pathogens in patients with acute uncomplicated cystitis conducted by the Japanese surveillance committee during 2020 and 2021: Antimicrobial susceptibility of Escherichia coli, Klebsiella pneumoniae, and Staphylococcus saprophyticus.

The Japanese surveillance committee conducted a third nationwide surveillance of antimicrobial susceptibility of acute uncomplicated cystitis at 55 facilities throughout Japan between April 2020 and September 2021. In this surveillance, we investigated the susceptibility of Escherichia coli (E. coli), Klebsiella pneumoniae (K. pneumoniae), and Staphylococcus saprophyticus (S. saprophyticus) for various antimicrobial agents by isolating and culturing bacteria from urine samples. In total, 823 strains were isolated from 848 patients and 569 strains of target bacteria, including E. coli (n = 529, 92.9 %), K. pneumoniae (n = 28, 4.9 %), and S. saprophyticus (n = 12, 2.2 %) were isolated. The minimum inhibitory concentrations of 18 antibacterial agents were determined according to the Clinical and Laboratory Standards Institute manual. In premenopausal patients, there were 31 (10.5 %) and 20 (6.8 %) fluoroquinolone (FQ)-resistant E. coli and extended-spectrum ß-lactamase (ESBL)-producing E. coli, respectively. On the other hand, in postmenopausal patients, there were 75 (32.1 %) and 36 (15.4 %) FQ-resistant E. coli and ESBL-producing E. coli, respectively. The rate of FQ-resistant E. coli and ESBL-producing E. coli in post-menopausal women was higher than that for our previous nationwide surveillance (20.7 % and 32.1 %: p = 0.0004, 10.0 % and 15.4 %; p = 0.0259). For pre-menopausal women, there was no significant difference in the rate of FQ-resistant E. coli and ESBL-producing E. coli between this and previous reports, but the frequency of FQ-resistant E. coli and ESBL-producing E. coli exhibited a gradual increase. For appropriate antimicrobial agent selection and usage, it is essential for clinicians to be aware of the high rate of these antimicrobial-resistant bacteria in acute uncomplicated cystitis in Japan.

The third nationwide surveillance of antimicrobial susceptibility against Neisseria gonorrhoeae from male urethritis in Japan, 2016-2017.

Neisseria gonorrhoeae is one of the important pathogens of sexually transmitted infections. N. gonorrhoeae is rapidly becoming antimicrobial resistant, and there are few drugs that are effective in the initial treatment of gonorrhea. To understand the trends of antimicrobial susceptibility of N. gonorrhoeae, the Surveillance Committee of the Japanese Society of Infectious Diseases, the Japanese Society for Chemotherapy, and the Japanese Society of Clinical Microbiology conducted the third nationwide antimicrobial susceptibility surveillance of N. gonorrhoeae isolated from male urethritis. The specimens were collected from male patients with urethritis at 30 facilities from May 2016 to July 2017. From the 159 specimens collected, 87 N. gonorrhoeae strains were isolated, and 85 were tested for susceptibility to 21 antimicrobial agents. All strains were non-susceptible to penicillin G. Seven strains (8.2%) were ß-lactamase-producing strains. The rates of susceptibility to cefixime and cefpodoxime were 96.5% and 52.9%, respectively. Three strains were non-susceptible with a minimum inhibitory concentration (MIC) of 0.5 mg/L for cefixime. None of the strains were resistant to ceftriaxone or spectinomycin. The susceptibility rate for ciprofloxacin was 23.5% (20 strains), and no strains showed intermediate susceptibility. The susceptibility rate against azithromycin was 81.2%, with one strain isolated with a MIC of 8 mg/L against azithromycin. The results of this surveillance indicate that ceftriaxone and spectinomycin, which are currently recommended for gonococcal infections in Japan, appear to be effective. It will be necessary to further expand the scale of the next surveillance to understand the current status of drug-resistant N. gonorrhoeae in Japan.

A multicenter, retrospective observational study investigating baseline characteristics and clinical outcomes in patients with hormone-sensitive prostate cancer treated with primary androgen deprivation therapy.

OBJECTIVE: This multicenter, retrospective, observational study investigated baseline characteristics and clinical outcomes in patients with hormone-sensitive prostate cancer who received primary androgen deprivation therapy, using Japan Study Group of Prostate Cancer registry data. METHODS: Among patients in the Japan Study Group of Prostate Cancer registry, those who initiated primary androgen deprivation therapy and were aged 20 years or older were enrolled in this study. The primary endpoint was time to disease progression, defined as time from primary androgen deprivation therapy initiation to either prostate-specific antigen or clinical progression. Secondary endpoints included prostate-specific antigen progression-free survival, prostate-specific antigen response (90% or greater reduction from baseline) and distribution of second-line treatment. RESULTS: Of the 2494 patients (goserelin, n = 564; leuprorelin, n = 1148; surgical castration, n = 161; degarelix, n = 621), those who received degarelix had higher prostate-specific antigen levels and Gleason scores and were at a more advanced clinical stage than those receiving goserelin or leuprorelin. The median time to disease progression (identical to the prostate-specific antigen progression-free survival result) was not reached for goserelin and leuprorelin, 52.7 months for surgical castration and 54.0 months for degarelix. Although baseline prostate-specific antigen values in the degarelix cohort were higher than those of the leuprorelin or goserelin cohorts, prostate-specific antigen responses were not different among the three cohorts. Regarding second-line treatment, the largest patient group received degarelix followed by leuprorelin (n = 195). CONCLUSIONS: This study clarified patient characteristics and long-term effectiveness of primary androgen deprivation therapy in real-world clinical practice. Japanese urologists appear to select appropriate primary androgen deprivation therapy based on patient background and tumour characteristics, with degarelix largely reserved for higher risk patients.

Tacrolimus use and renal function in pregnancy with lupus nephritis: Analysis of post-marketing surveillance data in Japan.

OBJECTIVES: Tacrolimus may be administered to pregnant women with lupus nephritis in Japan if considered therapeutically beneficial, but supporting data are limited. We assessed the safety and effectiveness of tacrolimus before, during, and after pregnancy in women with lupus nephritis receiving tacrolimus. METHODS: This was an ad hoc analysis of data from a post-marketing surveillance study of tacrolimus in patients with lupus nephritis in Japan. Pregnancy outcomes, nephritis status, and adverse events were assessed for up to 2 years postpartum. RESULTS: Data were available for 23 births in 21 patients (two patients had two births each). Tacrolimus for lupus nephritis was continued during 11 births in nine patients (during and after pregnancy) and discontinued in 12 patients (when pregnancy was known or when approaching delivery). Renal function was generally maintained in patients who gave birth while receiving tacrolimus; however, there were cases of increased urine protein and decreased renal function over 2 years. There were no unexpected adverse events/safety concerns. CONCLUSIONS: These data from clinical practice suggest that tacrolimus is a valid treatment option for lupus nephritis in fertile women in Japan and, with careful monitoring, pregnant women with lupus nephritis may continue their tacrolimus treatment.

Health-related quality of life with enzalutamide versus flutamide in castration-resistant prostate cancer from the AFTERCAB study.

BACKGROUND: Patient-reported outcome (PRO) measures can provide valuable information in evaluating patients' health-related quality of life (HRQoL). Post hoc analysis of the AFTERCAB study was conducted to evaluate the HRQoL benefit of enzalutamide plus androgen deprivation therapy (ADT) compared to flutamide plus ADT for the treatment of patients with castration-resistant prostate cancer (CRPC) in Japan. METHODS: The open-label AFTERCAB study was conducted from November 2016 to March 2020 in Japanese men aged ≥ 20 years with asymptomatic or mildly symptomatic CRPC. Patients received enzalutamide plus ADT or flutamide plus ADT, respectively, as first-line alternative androgen therapy (AAT). HRQoL was analyzed through the Functional Assessment of Cancer Therapy-Prostate, EuroQoL 5-Dimension 5-Level instruments, Brief Pain Inventory-Short Form, and Brief Fatigue Inventory. The longitudinal changes in HRQoL, HRQoL deterioration based on minimally important difference (MID), and time to HRQoL deterioration were evaluated for first-line AAT. RESULTS: Overall, HRQoL between the enzalutamide and flutamide groups was similar during first-line treatment. No statistically significant HRQoL difference in change from baseline to week 61 (least square mean difference; p value) was observed. Furthermore, proportions of pain progression, symptom worsening, and HRQoL deterioration based on MID, were not significantly different between groups. CONCLUSIONS: The results were similar in all subscales of each PRO, demonstrating similar HRQoL deterioration based on MID criteria between the enzalutamide and flutamide groups.

Enzalutamide + androgen deprivation therapy (ADT) versus flutamide + ADT in Japanese men with castration-resistant prostate cancer: AFTERCAB study.

Objectives: The objective of the study is to compare the efficacy and safety of alternative androgen therapy (AAT) with enzalutamide + androgen deprivation therapy (ADT) and flutamide + ADT in the treatment of Japanese men with metastatic or nonmetastatic castration-resistant prostate cancer (CRPC) who progressed despite combined androgen blockade (CAB) with bicalutamide + ADT. AAT treatment sequence was also investigated. Materials and methods: The open-label, Phase 4 AFTERCAB study (NCT02918968) was conducted from November 2016 to March 2020 in Japanese men aged ≥20 years with asymptomatic or mildly symptomatic CRPC. Patients were initially randomized to enzalutamide (160 mg/day) + ADT (enzalutamide first) or flutamide (375mg/day [125mg three times daily]) + ADT (flutamide first) as first-line therapy. Following prostate-specific antigen (PSA) progression, other disease progression, or discontinuation of first-line therapy due to an adverse event (AE), patients switched to the other treatment as second-line therapy. The primary endpoint was time to PSA progression with first-line therapy (TTPP1). Secondary endpoints included TTPP2 (TTPP1 + time to PSA progression with second-line therapy). AEs were monitored to assess safety. Results: Overall, 206 men were randomized (enzalutamide first, n = 102; flutamide first, n = 104) and stratified by study site and disease stage; 133 patients transitioned to second-line therapy (enzalutamide first, n = 48; flutamide first, n = 85). TTPP1 was significantly improved with enzalutamide first versus flutamide first (median 21.4 months vs. 5.8 months; hazard ratio [HR] 0.42; 95% confidence interval [CI] [0.29, 0.61]). TTPP2 was numerically improved with enzalutamide first versus flutamide first (median not reached vs. 21.2 months; HR 0.76; 95% CI [0.48, 1.19]). Both treatments were generally well tolerated, with AEs consistent with their known safety profiles. Conclusion: First-line AAT with enzalutamide + ADT provided a significant improvement in time to PSA progression versus flutamide + ADT. Enzalutamide + ADT may therefore be the preferred first-line AAT option in Japanese men with metastatic or nonmetastatic CRPC who progress despite CAB with bicalutamide + ADT.

Tacrolimus in Patients With Interstitial Pneumonia Associated With Polymyositis or Dermatomyositis: Interim Report of Postmarketing Surveillance in Japan.

OBJECTIVE: The calcineurin inhibitor tacrolimus has been approved in Japan for the treatment of interstitial pneumonia (IP) in patients with polymyositis (PM) and dermatomyositis (DM). Postmarketing surveillance was initiated to examine long-term outcomes of immunosuppressive regimens containing tacrolimus in real-world settings. METHODS: Observational, prospective, postmarketing surveillance is ongoing in 179 patients with PM/DM-associated IP initiating treatment with tacrolimus. We report interim findings after 2 years of follow-up. Cumulative overall survival was assessed using Kaplan-Meier analysis. Potential prognostic factors for mortality were assessed by univariate Cox proportional hazards analysis. RESULTS: A total of 170 patients were included in this analysis. At the time of starting treatment with tacrolimus, almost all patients were receiving corticosteroids (98.8%), and cyclophosphamide was additionally used in 42 patients (24.7%). Forty-nine patients (28.8%) discontinued tacrolimus during follow-up, mainly due to loss to follow-up, patient death, and adverse events. Mean (SD) oral corticosteroid dose decreased from 32.4 (21.6) mg/day at baseline to 7.6 (4.2) mg/day at 2 years. Overall survival at 2 years was 90.3%; corresponding progression-free survival was 62.5%. Factors found to be associated with all-cause mortality included diagnosis of clinically amyopathic DM (hazard ratio [HR] 9.04, 95% CI 1.18-69.51 vs PM), ferritin level 500 to < 1500 ng/mL (HR 8.61, 95% CI 2.51-29.45 vs < 500 ng/mL), and presence of antimelanoma differentiation-associated gene 5 antibodies (HR 8.16, 95% CI 1.03-64.47 vs absence). CONCLUSION: Immunosuppressive regimens containing tacrolimus appear useful for the management of IP in patients with PM/DM. [ClinicalTrials.gov: NCT02159651].

Nationwide surveillance of the antimicrobial susceptibility of Chlamydia trachomatis from male urethritis in Japan: Comparison with the first surveillance report.

The Urogenital Sub-committee and the Surveillance Committee of the Japanese Society of Chemotherapy, The Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology conducted the second nationwide surveillance of the antimicrobial susceptibility of Chlamydia trachomatis. In this second surveillance study, clinical urethral discharge specimens were collected from patients with urethritis in 26 hospitals and clinics from May 2016 to July 2017. Based on serial cultures, the minimum inhibitory concentration (MIC) could be determined for 41 isolates; the MICs (MIC90) of ciprofloxacin, levofloxacin, tosufloxacin, sitafloxacin, doxycycline, minocycline, erythromycin, clarithromycin, azithromycin and solithromycin were 2 µg/ml (2 µg/ml), 1 µg/ml (0.5 µg/ml), 0.25 µg/ml (0.25 µg/ml), 0.125 µg/ml (0.063 µg/ml), 0.125 µg/ml (0.125 µg/ml), 0.25 µg/ml (0.25 µg/ml), 0.031 µg/ml (0.031 µg/ml), 0.25 µg/ml (0.125 µg/ml), and 0.016 µg/ml (0.008 µg/ml), respectively. In summary, this surveillance project did not identify any strains resistant to fluoroquinolone, tetracycline, or macrolide agents in Japan. In addition, the MIC of solithromycin was favorable and lower than that of other antimicrobial agents. However, the MIC of azithromycin had a slightly higher value than that reported in the first surveillance report, though this might be within the acceptable margin of error. Therefore, the susceptibility of azithromycin, especially, should be monitored henceforth.

Real-world evidence for long-term safety and effectiveness of ipragliflozin in treatment-naïve versus non-naïve Japanese patients with type 2 diabetes mellitus: subgroup analysis of a 3-year post-marketing surveillance study (STELLA-LONG TERM).

BACKGROUND: STELLA-LONG TERM was a 3-year post-marketing surveillance study that evaluated the long-term safety and effectiveness of ipragliflozin in Japanese patients with type 2 diabetes mellitus (T2DM). This subgroup analysis examined the safety and effectiveness of ipragliflozin in treatment-naïve and non-naïve patients. MATERIALS AND METHODS: Patients were stratified into two subgroups: treatment-naïve (patients who had not received any antidiabetic drugs before starting ipragliflozin monotherapy) and non-naïve (all other patients). Patients who had added or switched antidiabetic drugs during follow-up were excluded from the analysis from that point. The incidence of adverse drug reactions (ADRs) and changes from baseline in glycosylated hemoglobin (HbA1c), body weight, fasting plasma glucose (FPG) and laboratory parameters were assessed. RESULTS: Of the 11,051 patients in the safety analysis set, 1980 patients (17.92%) were treatment-naïve and 9071 (82.08%) were non-naïve. In the safety analysis set, treatment-naïve patients reported significantly lower incidences of ADRs (10.81% vs 20.87%; p < 0.001) and serious ADRs (0.86% vs 2.09%; p < 0.001) compared with non-naïve patients, as well as significantly lower incidences of polyuria/pollakiuria, volume depletion-related events, skin complications and renal disorders. In the effectiveness analysis, sustained and significant reductions from baseline to 36 months were observed in HbA1c, FPG and body weight in both treatment-naïve and non-naïve patients (all p < 0.001 vs baseline). CONCLUSIONS: Over 3 years, ipragliflozin was better tolerated in treatment-naive than in non-naive Japanese patients with T2DM and had similar efficacy in these populations. Therefore, ipragliflozin is a useful first-line treatment option for patients with T2DM. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT02479399. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13340-021-00501-w.

Primary Androgen-Depletion Therapy Prevails Not Only for Metastatic but Also for Nonmetastatic Hormone-Naïve Prostate Cancer in Japan-Recent Trends and Efficacy.

OBJECTIVE: To investigate the real-world use of primary androgen-deprivation therapy(PADT; gonadotropin-releasing hormone agonists[leuprorelin/goserelin]and antagonists[degarelix]/surgical castration), its clinical effectiveness, and the characteristics of Japanese patients with hormone-sensitive prostate cancer treated with PADT. METHODS: In this retrospective, observational study, patients using PADT(≥1 record)in the 2016-2018 Japan Study Group of Prostate Cancer registry were followed up from their initial date of PADT until October 2018. The primary endpoints included prostate-specific antigen( PSA)response rate(PSA<4 ng/mL)and duration of initial treatment. RESULTS: Of 1,895 patients, 47.7%, 24.4%, and 22.0% received leuprorelin, goserelin, and degarelix, respectively; 5.9% underwent surgical castration. The degarelix group had the highest median PSA at diagnosis(116.7 ng/mL)and proportion of patients with clinical Stage Ⅳ prostate cancer (72.9%)and Gleason score 9-10(59.7%). A concomitant antiandrogen was used in >80% and 70% of patients in the leuprorelin/goserelin and degarelix groups, respectively; bicalutamide was used most commonly(99.0%). Median duration of initial treatment was 20.8 months in the degarelix group and not yet reached in the leuprorelin/goserelin groups; continuation rates at 24 months were 44.6% and 81.6%/87.3%, respectively. The PSA response rate was the highest in the leuprorelin group(93.7%); median percentage change in PSA was comparable across all treatment groups(-99.1% to -99.8%). CONCLUSIONS: Real-world use of PADT in patients with hormone-sensitive prostate cancer is likely based on its specific therapeutic attributes and patient characteristics.

Effect of ipragliflozin on liver function in Japanese type 2 diabetes mellitus patients: subgroup analysis of a 3-year post-marketing surveillance study (STELLA-LONG TERM).

The STELLA-LONG TERM prospective post-marketing surveillance study assessed ipragliflozin in Japanese patients with type 2 diabetes mellitus (T2DM). This subgroup analysis of patients with liver impairment used the final 3-year results. Data on patients, adverse drug reactions (ADRs), and changes in glycemic parameters and liver enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], gamma-glutamyl transpeptidase [γ-GTP] and alkaline phosphatase [ALP]) were collected, and the fatty liver index (FLI) was calculated. In the effectiveness analysis (n = 8,763), baseline liver function was normal in 2,605 patients (ALT <31/<21 U/L [men/women]) and abnormal in 3,277 (ALT ≥31/≥21 U/L). The abnormal liver function group had higher mean body weight and BMI than the normal liver function group (p < 0.001). In the safety analysis (n = 11,051), urinary tract infections, genital infections and hepatic disorders were more common in the abnormal than normal liver function group (2.25% vs. 1.07%; 1.78% vs. 1.14% and 1.85% vs. 1.01%). In the abnormal liver function group, there were significant (p < 0.001) decreases from baseline at 36 months in AST and ALT (from 38.8 and 53.7 U/L to 29.3 and 37.7 U/L, respectively), γ-GTP (from 75.4 to 51.7 U/L) and ALP (from 254.8 to 234.5 U/L), which were greater than in the normal liver function group. FLI reductions at 36 months were significant (p < 0.001) in subgroups with baseline FLI of ≥30 or ≥60. In conclusion, ipragliflozin improved liver function over 3 years in patients with impaired liver function, although ADRs occurred more frequently than in the normal liver function group.

Nationwide surveillance of bacterial pathogens isolated from patients with acute uncomplicated cystitis in 2018: Conducted by the Japanese Research Group for Urinary Tract Infections (JRGU).

INTRODUCTION: The aim of this study was to monitor the development of drug-resistant bacteria isolated from acute uncomplicated cystitis (AUC) and to evaluate methodology of the survey conducted by collecting only clinical data. METHODS: We enrolled female patients at least 16 years of age diagnosed with AUC in 2018. Patient information including age, menopausal status, and results of bacteriological examination were collected and analyzed regardless of bacterial identification, antimicrobial susceptibility testing or extended-spectrum ß-lactamase (ESBL) detection method. RESULTS: A total of 847 eligible cases were collected. Escherichia coli (E. coli) was the most frequently isolated bacterial species at about 70%, with proportions of fluoroquinolone-resistant E. coli (QREC) and ESBL-producing E. coli isolates at 15.6% and 9.5% of all E. coli isolates, respectively. The proportion of Staphylococcus saprophyticus (S. saprophyticus) was significantly higher in premenopausal women. Regarding the drug susceptibility of E. coli, isolates from Eastern Japan had significantly higher susceptibility to cefazolin, cefotiam and cefpodoxime and lower susceptibility to levofloxacin in postmenopausal women. ESBL-producing E. coli isolates had a high susceptibility to tazobactam-piperacillin, cefmetazole, carbapenems, aminoglycosides, and fosfomycin. In S. saprophyticus, the susceptibility to ß-lactams including carbapenems was 40-60%. CONCLUSIONS: The proportions of QREC and ESBL-producing E. coli were increasing trends and lower susceptibility to LVFX in postmenopausal women was observed. Such surveillance, consisting of the collecting only clinical data, could be conducted easily and inexpensively. It is expected to be continuously performed as an alternative survey to conventional one collecting bacterial strains.

Safety and Effectiveness of Ipragliflozin in Elderly Versus Non-elderly Japanese Patients with Type 2 Diabetes: Subgroup Analysis of STELLA-LONG TERM.

INTRODUCTION: STELLA-LONG TERM is a post-marketing surveillance study evaluating the safety and effectiveness of ipragliflozin in Japanese patients with type 2 diabetes mellitus. METHODS: Patients were classified by age at ipragliflozin initiation (< 65 and ≥ 65 years), and elderly patients were subclassified by baseline body mass index (BMI) < 25.0 or ≥ 25.0 kg/m2. Incidence of adverse drug reactions (ADRs) and effectiveness were evaluated over 3 years. RESULTS: Among 11,051 patients, 7894 (71.4%) were aged < 65 years and 3157 (28.6%) ≥ 65 years. The 3-year ADR incidence was similar in patients aged ≥ 65 (19.04%) and < 65 years (19.36%; P = 0.701). Serious ADRs were more frequent in the subgroup ≥ 65 years (2.79% vs 1.55%; P < 0.001). In terms of ADRs of special interest, a significantly greater proportion of elderly patients had skin complications (2.22% vs 1.62%, P = 0.033), renal disorders (2.28% vs 1.51%, P = 0.005), hypoglycemia (0.73% vs 0.43%, P = 0.048), or malignant tumors (1.01% vs 0.24%, P < 0.001), while the incidence of polyuria/pollakiuria (5.97% vs 4.47%, P = 0.002) and hepatic disorders (1.39% vs 0.73%, P = 0.004) was significantly higher in non-elderly than elderly patients. In patients aged ≥ 65 years, the incidence of ADRs was higher when baseline BMI was ≥ 25 kg/m2 versus < 25 kg/m2 (24.40% vs 17.68%; P < 0.001). Glycosylated hemoglobin, fasting blood glucose, and body weight significantly decreased from baseline in both age groups at each evaluation up to 3 years (all P < 0.001). CONCLUSIONS: Ipragliflozin was well tolerated and effective for 3 years in routine clinical use in elderly and non-elderly patients, although elderly patients had a higher rate of serious ADRs. No new safety concerns were identified. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02479399.

Safety and effectiveness of ipragliflozin in Japanese patients with type 2 diabetes mellitus and impaired renal function: subgroup analysis of a 3-year post-marketing surveillance study (STELLA-LONG TERM).

STELLA-LONG TERM, a 3-year post-marketing surveillance study, evaluated the safety and effectiveness of the sodium-glucose cotransporter 2 inhibitor ipragliflozin in Japanese type 2 diabetes mellitus (T2DM) patients. Final results in the safety (n = 6697) and effectiveness populations (n = 5625) were analyzed by stratifying patients by baseline estimated glomerular filtration rate (eGFR, mL/min/1.73 m2) into four subgroups (≥ 90, 60 to < 90, 45 to < 60, and < 45) and two subgroups (≥ 60 and < 60). Adverse drug reaction (ADR) incidence, and changes from baseline in glycosylated hemoglobin (HbA1c), bodyweight, and eGFR were assessed. The percentage of patients experiencing ADRs and serious ADRs was similar across most eGFR subgroups. Polyuria/pollakiuria was the most common ADR. Renal disorders and volume depletion ADRs were more frequent in the subgroups with more severe renal impairment at baseline than in those with an eGFR of 60 to < 90 or ≥ 90 mL/min/1.73 m2. Bodyweight and HbA1c decreased in all subgroups, the latter by - 0.91% to - 0.40% (P < 0.05 vs. baseline). eGFR increased in the 45 to < 60 mL/min/1.73 m2 subgroup (+ 1.42 ± 8.77 mL/min/1.73 m2; P = 0.006). It decreased in the ≥ 90 and 60 to < 90 mL/min/1.73 m2 subgroups (- 8.27 ± 13.73 and - 1.22 ± 10.34 mL/min/1.73 m2; P < 0.001), but not to < 60 mL/min/1.73 m2. In conclusion, there were no new or unexpected safety findings in Japanese patients treated with ipragliflozin for T2DM, and long-term sustained improvements in HbA1c and bodyweight were observed regardless of the presence of renal impairment.

Mirabegron Add-On Therapy to Tamsulosin in Men with Overactive Bladder: Post Hoc Analyses of Efficacy from the MATCH Study.

INTRODUCTION: MATCH was a randomized, double-blind, placebo-controlled study enrolling Japanese and Korean men aged ≥ 40 years who still had overactive bladder (OAB) symptoms while receiving tamsulosin. After a 4-week single-blind screening period in which patients received placebo and tamsulosin, patients were randomized to mirabegron 50 mg + tamsulosin or placebo + tamsulosin for 12 weeks (n = 568). This post hoc analysis investigated the proportion of treatment responders for each treatment group and for subgroups stratified by age based on voiding diaries and patient-reported outcomes (PROs). METHODS: Responders were defined as those achieving normalization or clinically meaningful improvements in efficacy, or clinically important differences in PROs [≥ 10-point improvement in OAB questionnaire (OAB-q) symptom bother or total health-related quality of life (HRQoL) subscales at end of treatment (EoT; minimally important difference [MID]) or OAB symptom score (OABSS) total score decreased by ≥ 3 points at EoT [minimally clinically important change (MCIC)]]. RESULTS: At EoT, micturition frequency normalization was achieved by 30.7% of tamsulosin + mirabegron patients and 18.6% of tamsulosin + placebo patients. Normalization of urgency and incontinence was 19.1% and 60.7% for tamsulosin + mirabegron and 18.2% and 60.0% for tamsulosin + placebo. Normalization of OAB symptoms based on OABSS was 17.1% for tamsulosin + mirabegron and 14.5% for tamsulosin + placebo. Higher proportions of patients in the mirabegron add-on group versus the placebo group reported clinically meaningful improvements in micturitions, urgency, and incontinence and in MCIC for OABSS and MID for the OAB-q subscales. Double- and triple-responder findings were as predicted by the results of single-responder analyses. These results were mirrored in the age groups using cut-offs of 65 and 75 years. CONCLUSION: Mirabegron therapy added on to tamsulosin resulted in a higher frequency of responders in terms of normalization (e.g., micturition frequency normalization), clinically meaningful improvements in efficacy (e.g., ≥ 50% decrease in urgency), and minimally important changes in PROs (e.g., MCIC in OABSS). TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02656173.

Long-term Safety and Effectiveness of Tacrolimus in Patients With Lupus Nephritis: 5-year Interim Postmarketing Surveillance Study in Japan (TRUST).

OBJECTIVE: To assess the long-term safety and effectiveness of tacrolimus for treating lupus nephritis (LN) in the real-world clinical setting. METHODS: This is an ongoing, open-label, noncomparative, observational, postmarketing surveillance study conducted across 275 sites in Japan. Registered patients with LN were followed for 10 years. Here we report data relating to 5 years of tacrolimus maintenance therapy at the interim data cutoff in August 2016. RESULTS: Of 1395 registered patients, 1355 received tacrolimus maintenance therapy for LN and provided safety data. The most common serious adverse drug reactions (ADR) included pneumonia (1.1%), herpes zoster (1.0%), cellulitis (1.0%), and diabetes mellitus (1.0%). ADR occurred mainly within the first 28 weeks of tacrolimus treatment, and no marked increase was observed during the follow-up period. Subgroup analyses suggested that risk factors for commonly observed ADR associated with tacrolimus included inpatient management, LN disease severity, increasing age, abnormal renal or hepatic function, and comorbid or previous disease. The cumulative rate of progression to renal failure (based on the attending physician's assessment) was 0.8% at Year 1 and 6.6% at Year 5. Cumulative relapse rates were 7.8% and 30.6%, respectively. Urine protein:creatinine ratio, serum anti-dsDNA antibody levels, complement C3 levels, and steroid-sparing effects were all significantly improved from 4 weeks after tacrolimus treatment initiation (P < 0.001) and were sustained over 5 years. CONCLUSION: Long-term tacrolimus maintenance treatment over 5 years in the real-world clinical setting was well tolerated and effective in a large population of patients with LN (www.ClinicalTrials.gov: NCT01410747).