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Objectives: We compared the incidences of four opportunistic infections (OIs) in patients with rheumatoid arthritis (RA) treated with molecular-targeted drugs from big claims data. Materials and Methods: We identified 205,906 patients with RA who were prescribed molecular-targeted drugs in 2010-17 from the National Database of Japan and calculated the incidence of four OIs (Pneumocystis pneumonia, tuberculosis, nontuberculous mycobacterial infection, and herpes zoster). Results: The total number of Pneumocystis pneumonia, tuberculosis, nontuberculous mycobacterial infection, and herpes zoster patients with biological disease-modifying antirheumatic drugs or tofacitinib treatment history in RA was 765, 1158, 834, and 18,336, respectively. The incidence rates of each OI for all biological disease-modifying antirheumatic drugs were 0.14, 0.14, 0.09, and 2.40 per 100 person-years, respectively, while for tofacitinib they were 0.22, 0.22, 0.07, and 7.00 per 100 person-years. No big difference was observed among biological disease-modifying antirheumatic drugs. All OIs showed higher incidence in those >65 years, but Pneumocystis pneumonia, nontuberculous mycobacterial infection, and herpes zoster showed no difference between those 65-74 years old and those >75 years old. The median of occurrence was the third, seventh, ninth, and thirteenth month after treatment, respectively. Conclusions: We counted real incidence rates of OIs for the whole nation from big claims data. [ABSTRACT FROM AUTHOR]

Objectives: The objective of the study was to determine the seasonal changes in the initiation of biological disease-modifying antirheumatic drugs (bDMARDs) and methotrexate (MTX) using big claims data. Methods: We counted the monthly number of initial administrations of each bDMARD and MTX in patients with rheumatoid arthritis (RA) between April 2010 and March 2017. Data were collected from the National Database of Health Insurance Claims and Specific Health Checkups of Japan. This database covers more than 95% of Japanese citizens. Seasonal changes in the number of initiations were determined. Patient claims were also classified according to drugs, districts, gender, and ages. Results: The initiation of bDMARDs and MTX administration varied according to the season in a sine curve shape, with the highest numbers in May to July and the lowest numbers in November to January. The same changing pattern was observed among each bDMARD, district, gender, and age groups particularly when the number was on the higher side. Conclusion: We noted an apparent seasonal change in the number of bDMARDs initiated, with a peak during spring, suggesting an exacerbation of RA in the spring in Japan. These changes are overlooked in daily practice and are only visible using big data. [ABSTRACT FROM AUTHOR]

Objectives: To describe the real-world prescription and treatment retention of molecular-targeted drugs for rheumatoid arthritis (RA) in Japan. Methods: A total of 204,416 patients with RA were prescribed at least one of the eight molecular-targeted drugs in 7 years from the National Database of Health Insurance Claims and Specific Health Checkups of Japan covering 98.3% of the Japanese population. The retention rates of each drug as well as head-to-head comparisons were estimated by Kaplan-Meier method. Results: A total of 121,131 RA patients were prescribed any molecular-targeted drug for the first time, while 36,633 uses of molecular-targeted drug were switched from another (switch use). The overall retention rates of molecular-targeted drugs at 12, 36, and 60 months were 0.64, 0.42, and 0.32 for the naïve use and 0.59, 0.40, and 0.31 for the switch use, respectively. Non-tumour necrosis factor (TNF)-inhibitor molecular-targeted drugs, particularly tocilizumab and tofacitinib, had higher retention rates than TNF inhibitors for both naïve and switch uses regardless of the previous drug and showed higher retention rates in head-to-head comparisons between eight molecular-targeted drugs. Conclusions: Our data reveal that the real-world drug retention is overall lower than previously reported and higher with non-TNF inhibitors than with TNF inhibitors. [ABSTRACT FROM AUTHOR]

Introduction Progestin therapy is the only fertility-sparing treatment option for patients with atypical endometrial hyperplasia (AEH) and endometrial cancer (EC). However, the results of three meta-analyses revealed a high remission rate, as well as an association with a high rate of relapse. We previously conducted a phase II of medroxyprogesterone acetate (MPA) plus metformin as a fertility-sparing treatment for AEH and EC patients, and reported that metformin inhibited disease relapse after remission. Methods and analysis A randomised, open, blinded-endpoint design phase IIb dose response trial was planned to commence in July 2019. The trial aims to identify the appropriate dose of metformin to be combined with MPA therapy for fertility-sparing treatment of patients with AEH and EC. The primary endpoint of the trial is the 3-year relapse-free survival (RFS) rate. The secondary endpoints are RFS rate, the overall rate of response to MPA therapy, the conception rate after treatment, the outcome of pregnancy, toxicity evaluation and changes in insulin resistance and body mass index. A total of 120 patients will be enrolled from 15 Japanese institutions within a 2.5-year period and followed up for at least 3 years. Ethics and dissemination The protocol was approved by the institutional review board at Chiba University Hospital and boards at 14 other institutions. The trial will be conducted according to the principles of the World Medical Association’s Declaration of Helsinki and in accordance with Good Clinical Practice (GCP) standards. The trial findings will be published in a peer-reviewed journal. [ABSTRACT FROM AUTHOR]

Introduction Insomnia has severe consequences for health. Primary care physicians in Japan commonly provide hypnotics, which is far from optimal. The recommended treatment for insomnia is cognitive–behavioural therapy (CBT). Access to trained therapists, however, is limited. Rather than face-to-face CBT, several researchers have studied internet-delivered computerised CBT (ICBT). This paper describes the study protocol for a randomised controlled trial (RCT) to evaluate effectiveness and feasibility of our newly developed five-step ICBT as an adjunct to usual care (UC) compared with UC alone for patients with insomnia who remain symptomatic following hypnotics. Methods and analysis This proposed exploratory RCT comprises two parallel groups (ICBT+UC and UC alone) consisting of 15 participants each (n=30) diagnosed with insomnia who remain symptomatic after pharmacotherapy. We aim to evaluate the effectiveness of six intervention weeks. The primary outcome of insomnia severity will be the Pittsburgh Sleep Quality Index (PSQI) at week 6. Secondary outcomes include sleep onset latency, total sleep time, sleep efficiency extracted from PSQI, current feeling of refreshment and perceived soundness of sleep measured using visual analogue scale, number of awakenings, anxiety by Hospital Anxiety and Depression Scale, depression by Center for Epidemiologic Studies Depression Scale and quality of life by Euro Qol-5D. All measures will be assessed at weeks 0 (baseline), 6 (postintervention) and 12 (follow-up), and intention-to-treat analysis will be applied. The statistical analysis plan has been developed considering design of field materials. Ethics and dissemination This study will be conducted at the academic outpatient clinic of Chiba University Hospital, Japan. Ethics approval was granted by the Institutional Review Board of Chiba University Hospital. All participants will be required to provide written informed consent. The trial will be implemented and reported in accordance with Consolidated Standards of Reporting Trials recommendations. [ABSTRACT FROM AUTHOR]

Introduction Antineutrophil cytoplasm antibody-associated vasculitis (AAV) is a form of systemic vasculitis. The current standard induction therapy with the combination of high-dose glucocorticoids and cyclophosphamide or rituximab has high remission rates of 80%–90%. However, it is also associated with various side effects, including death due to infection or cardiovascular disease. There is an unmet medical need of a new therapy to reduce side effects. Methods and analysis This is a phase IV multicentre, open-label, randomised controlled trial that aims to evaluate the efficacy and safety of a new remission induction regimen with the combination of low-dose glucocorticoids and rituximab. Newly diagnosed patients with AAV will be assessed for eligibility at 34 tertiary rheumatology/nephrology centres in Japan. One hundred and forty patients will be randomised (1:1) to receive low-dose prednisolone (0.5 mg/kg daily) plus rituximab (375 mg/m2 weekly) or high-dose prednisolone (1 mg/kg daily) plus rituximab. The trial consists of remission induction and maintenance phases. The primary endpoint of the study is the remission rate at 6 months (induction phase). Relapse and long-term safety profile will also be assessed until 24 months (maintenance phase).Ethics and dissemination The protocol was first approved by the Institutional Review Board of Chiba University Hospital (reference number: G25051), and then approved by each participating site. The trial was registered at the University hospital Medical Information Network (UMIN) clinical registry (UMIN000014222) and ClinicalTrials.gov registry (NCT02198248). The Low-dose Glucocorticoid Vasculitis Induction Study (LoVAS) trial is currently ongoing and is due to finish in September 2019. The findings of this trial will be disseminated to participants through peer-reviewed publications and presented at national and international conferences in accordance with the Consolidated Standards of Reporting Trials (CONSORT) Statement. [ABSTRACT FROM AUTHOR]

Introduction: Nicorandil has vasodilatory effects on both the epicardial coronary arteries and the coronary microvasculature, thereby increasing coronary blood flow. Intravenous administration of nicorandil can be applicable for fractional flow reserve (FFR) measurement as a hyperaemic agent and a possible alternative to adenosine. However, the effectiveness of intravenous nicorandil infusion for FFR measurement is largely unclear. Methods and analysis: This crossover randomised study is being performed to investigate the efficacy of intravenous administration of nicorandil for FFR measurement. Patients with an intermediate coronary artery stenosis who satisfy the eligibility criteria undergo FFR measurement with a consecutive randomised order of patient-blind infusions of continuous intravenous administration of adenosine and a single bolus intravenous administration of nicorandil. The primary end point of the study is the agreement between the FFR values obtained by the intravenous nicorandil and those obtained by the intravenous adenosine. Recruitment of this trial started in November 2015 and will end in March 2017, or until a total of 50 participants have been recruited. Ethics and dissemination: The protocol was approved by the Institutional Review Board at Chiba University Hospital. Study findings will be published in peer-reviewed journals. [ABSTRACT FROM AUTHOR]

Introduction: Kawasaki disease (KD) is an acute, self-limited vasculitis of unknown aetiology that predominantly affects infants and young children. We hypothesise that cyclosporin A (CsA) may be effective in treating KD by regulating the Ca2+/NFAT signalling pathway. This trial compares the current standard therapy of intravenous immunoglobulin (IVIG) and the combined IVIG+CsA therapy in paediatric patients with severe KD. Methods and analysis: This trial is a phase III, multicentre, randomised, open-label, blinded-end point trial that evaluates the efficacy and safety of IVIG+CsA therapy. Patients with severe KD who satisfy the eligibility criteria are randomised (1:1) to receive either CsA (5 mg/kg/day for 5 days; Neoral) plus high-dose IVIG (2 g/kg for 24 h and aspirin 30 mg/kg/day), or high-dose IVIG alone (2 g/kg for 24 h and aspirin 30 mg/kg/day). The primary end point is the frequency of occurrence of coronary artery abnormalities during the trial period. An independent end point review committee will be in charge of the trial assessment. Ethics and dissemination: The protocol was approved by the Institutional Review Board of each institution. The trial was notified and registered at the Pharmaceutical and Medical Devices Agency, in Japan. The trial is currently on-going and is scheduled to finish in April 2017. The findings will be disseminated through peer-reviewed publications and conference presentations. [ABSTRACT FROM AUTHOR]

Introduction: Polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes (POEMS) syndrome is a fatal systemic disorder associated with plasma cell dyscrasia and the overproduction of the vascular endothelial growth factor (VEGF). Recently, the prognosis of POEMS was substantially improved by introduction of therapeutic intervention for myeloma. However, no randomised clinical trial has been performed because of the rarity and severity of the disease. Methods and analysis: The Japanese POEMS syndrome with Thalidomide ( J-POST) Trial is a phase II/ III multicentre, double-blinded, randomised, controlled trial that aims to evaluate the efficacy and safety of a 24- week treatment with thalidomide in POEMS syndrome, with an additional 48-week open-label safety study. Adults with POEMS syndrome who have no indication for transplantation are assessed for eligibility at 12 tertiary neurology centres in Japan. Patients who satisfy the eligibility criteria are randomised (1:1) to receive thalidomide (100-300 mg daily) plus dexamethasone (12 mg/m² on days 1-4 of a 28-day cycle) or placebo plus dexamethasone. Both treatments were administered for 24 weeks (six cycles; randomised comparative study period). Patients who complete the randomised study period or show subacute deterioration during the randomised period participate in the subsequent 48-week open-label safety study (long-term safety period). The primary end point of the study is the reduction rate of serum VEGF levels at 24 weeks. Ethics and dissemination: The protocol was approved by the Institutional Review Board of each hospital. The trial was notified and registered at the Pharmaceutical and Medical Devices Agency, Japan (No. 22-1716). The J-POST Trial is currently ongoing and is due to finish in August 2015. The findings of this trial will be disseminated through peer-reviewed publications and conference presentations and will also be disseminated to participants. [ABSTRACT FROM AUTHOR]

Introduction: Despite the encouraging results from several randomised controlled trials (RCTs) and meta-analyses, the ability of home telemonitoring for heart failure (HF) to improve patient outcomes remains controversial as a consequence of the two recent large-scale RCTs. However, it has been suggested that there is a subgroup of patients with HF who may benefit from telemonitoring. The aim of the present study was to investigate whether an HF management programme using telemonitoring could improve outcomes in patients with HF under the Japanese healthcare system. Methods and analysis: The Home Telemonitoring Study for Japanese Patients with Heart Failure (HOMES-HF) study is a prospective, multicentre RCT to investigate the effectiveness of home telemonitoring on the primary composite endpoint of all-cause death and rehospitalisation due to worsening HF in recently admitted HF patients (aged 20 and older, New York Heart Association classes II-III). The telemonitoring system is an automated physiological monitoring system including body weight, blood pressure and pulse rate by full-time nurses 7 days a week. Additionally, the system was designed to make it a high priority to support patient's self-care instead of an early detection of HF decompensation. A total sample size of 420 patients is planned according to the Schoenfeld and Richter method. Eligible patients are randomly assigned via a website to either the telemonitoring group or the usual care group by using a minimisation method with biased-coin assignment balancing on age, left ventricular ejection fraction and a history of ischaemic heart disease. Participants will be enrolled until August 2013 and followed until August 2014. Time to events will be estimated using the Kaplan-Meier method, and HRs and 95% CIs will be calculated using the Cox proportional hazards models with stratification factors. [ABSTRACT FROM AUTHOR]