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Although the “drug lag”—namely, the delay in drug approval time in Japan relative to the United States and/or European Union (US/EU)—has been shortened for drugs approved in Japan, there remain many new drugs that have been approved in the US/EU, but not in Japan. To assess the possibility of a future drug lag, this study has examined the current lag in drug development in Japan based on “ClinicalTrials.gov” data from multiregional clinical trials (MRCTs) conducted in the US/EU and East Asia. Among 828 MRCTs registered as of April 5th, 2021, the percentage of MRCTs in which Japan participated (jMRCTs) was 57.1%. jMRCTs were common for some diseases such as “nervous system” and “visual system” disorders, but less common for “neoplasm,” infection,” “mental,” and “circulatory” disorders. Regarding the investigational drugs in non-jMRCTs (i.e., MRCTs without Japanese participation) in the latter four therapeutic areas (i.e., neoplasm, infection, mental and circulatory disorders), approximately 80% (313/399) of drugs were not being developed in Japan. Furthermore, many of these drugs were being developed by the top 50 pharmaceutical companies by sales, and the majority would be recognized as a new active ingredient with a new mode of action in Japan. This study has highlighted the possibility of a future drug lag in Japan, especially in the therapeutic areas of neoplasm, infection, mental, and circulatory disorders. Such a lag may arise not only between Japan and the US/EU, but also between Japan and other countries in the East Asian region.

IntroductionSecondary lower extremity lymphoedema is a chronic progressive condition that frequently develops after cancer treatment and results in persistent swelling, recurrent cellulitis and impaired quality of life. Lymphaticovenous anastomosis (LVA) is an established physiological microsurgical treatment; however, postoperative outcomes vary and evidence-based adjunctive postoperative management remains limited. A novel pneumatic lymphatic drainage (PLD) system has been developed to deliver anatomically directed, pathway-aligned mechanical stimulation that mimics manual lymphatic drainage. Its clinical efficacy following LVA has not yet been evaluated in a randomised controlled trial.Methods and analysisThis multicentre, open-label, parallel-group randomised controlled trial will enrol adults (≥18 years) with unilateral secondary lower extremity lymphoedema (International Society of Lymphology stage I–II) undergoing LVA. Participants will be randomised 1:1 to receive PLD plus standard postoperative care or standard postoperative care alone. PLD will be initiated on the day of surgery and continue for 6 months (Day 183). The primary outcome is the rate of improvement in excess limb volume (EV) at Day 183 relative to baseline, calculated from circumferential measurements taken at 4 cm intervals using the truncated cone method, with the contralateral limb serving as an internal control. Secondary outcomes include longitudinal trajectories of EV, improvement in excess limb fluid volume assessed by bioimpedance, the Lymphedema Quality of Life Questionnaire, cellulitis incidence and safety outcomes. A total of 64 participants (32 per group) will provide 80% power (two-sided α=0.05) to detect a 15-percentage-point between-group difference in the rate of improvement in EV at 6 months, assuming a common SD of 20 percentage points and allowing for attrition. Primary analyses will follow the ITT principle using mixed-effects models for repeated measures.Ethics and disseminationThe study was approved by the Chiba University Certified Review Board (approval number: CRB0119-25; approval date: 15 December 2025) and was conducted in accordance with the Declaration of Helsinki and the Japanese Clinical Trials Act. Results will be disseminated through peer-reviewed publications and presentations at national and international scientific conferences, irrespective of study outcomes.Trial registrationjRCTs032250600.

IntroductionHeart failure occasionally develops after transcatheter aortic valve implantation (TAVI) for severe aortic stenosis (AS), despite procedural success. Most cases present with mildly reduced or preserved left ventricular ejection fraction (LVEF), underscoring the role of diastolic dysfunction. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown benefits across the heart failure spectrum, independent of LVEF. The purpose of this randomised controlled trial is to determine whether adding a SGLT2 inhibitor to conventional medications improves LV diastolic function in patients with preserved LVEF after TAVI.Methods and analysisThis study is a prospective, single-centre, open-label, randomised, parallel-group, two-arm trial enrolling patients with mildly reduced or preserved LVEF (≥40%) undergoing TAVI for severe AS. Participants will be randomised in a 1:1 ratio to receive either conventional medications plus empagliflozin or conventional medications alone. In the empagliflozin group, participants will receive conventional medical therapy plus empagliflozin 10 mg orally once daily, initiated 4 weeks after TAVI. Empagliflozin treatment will continue throughout the study period. Participants in the control group will receive conventional medications without empagliflozin. The primary endpoint is the change in E/e’, assessed by echocardiography from treatment initiation at 4 weeks post TAVI (day 1) to day 168 (week 24). Each group will include 50 patients, totalling 100 patients.Ethics and disseminationEthical approval for this study has been obtained from the Chiba University Hospital Certified Clinical Research Review Board (CRB0111-25).Trial registration numberjRCT1031250190.

IntroductionThe effect of prophylactic clipping for colorectal cold snare polypectomy (CSP) on delayed bleeding (DB) in patients with antithrombotic drugs remains unverified. The aim of the PERCOLD study is to demonstrate the non-inferiority of DB rates in cases without prophylactic clips compared with cases with prophylactic clips in patients taking antithrombotic drugs for colorectal CSP through randomised controlled trial (RCT).Methods and analysisThis study is a multicentre prospective parallel-group RCT phase 3 trial that is being conducted at 14 institutions in Japan at the time of writing this manuscript. After providing consent, patients will undergo screening and assessment for study enrolment eligibility. Patients taking antithrombotic drugs (aged 20 years or older at the time of consent and who have agreed to participate in this study) will be selected if they have a preoperative suspected adenoma (including sessile serrated lesion) with an endoscopic diameter of <10 mm and an indication for CSP, provided they do not meet the exclusion criteria. The primary endpoint is the percentage of DB within 2 weeks after CSP per patient. DB is defined as haematochezia requiring endoscopic haemostasis. Secondary endpoints are rate of haematochesia within 2 weeks after CSP (per patient), rate of DB within 2 weeks after CSP (per polyp), percentage of performing endoscopy for haematochesia within 2 weeks after CSP (by patient and polyp), treatment time (from magnification of the first polyp to clip closure of the last polyp in the clip closure group and to observation after last polyp resection in the non-clip closure group) and complication rates (immediate bleeding, intraoperative perforation, delayed perforation and post polypectomy syndrome). The selected patients will be randomised 1:1 into the clip closure group and the non-clip closure group after registration, with 287 patients in each group.Ethics and disseminationThe trial protocol has been approved by the Chiba University Certified Clinical Research Reviewer Board (CRB3180015), which serves as the central ethics committee, and registered with Japan Registry of Clinical Trials. The current protocol V.1.7, dated 4 October 2024. Written informed consent for participation in the study will be obtained from all participating patients. All participating institutions have formally agreed to conduct the study in accordance with this central approval, and local site permissions were obtained as required by each institution. The results of this study will be submitted for publication in international peer-reviewed journals and the key findings will be presented at international scientific conferences.Trial registration numberJapan Registry of Clinical Trials (jRCT1032230086).

A risk management plan (RMP) has an important role in assuring the optimal benefit–risk balance of a drug throughout its life cycle. However, no clear standards have been established for differentiating risk classification between “important identified risks” and “important potential risks”. This study was a review and descriptive analysis for Japanese RMPs with a focus on antineoplastic agents to identify effective factors to discriminate an important identified risk from an important potential risk. Analysis based on 51 RMPs, reporting 310 important identified risks and 72 important potential risks, revealed significant associations between selection of the risk classification and several factors, including severe cases, actual cases in the Japanese population, availability of confirmatory trial data, and incidence of adverse events. Trend of the association was also found for discontinuation cases and immune-oncology agents [IO (drug type)]. These results suggest that consideration of these factors may be useful for coherent risk classification in creating a RMP.

IntroductionConcurrent chemoradiotherapy is considered the standard treatment strategy for locally advanced cervical cancer. Most recent reports indicate that patients with bulky tumours or adenocarcinoma subtypes have poorer local control. Carbon-ion radiotherapy (CIRT) with the concurrent use of chemotherapy has shown promising results in such cases of difficult-to-treat uterine cervical cancer. Programmed death-ligand 1 (PD-L1) upregulation was observed in tumour tissue samples from patients who had undergone CIRT. Thus, a combination of CIRT and anti-PD-L1 antibody may suppress metastasis by activating antitumour immune response, in addition to exhibiting strong local effects.ObjectiveWe will assess the safety and tolerability (primary endpoint) of the concomitant use of durvalumab, an anti-PD-L1 antibody, with CIRT and weekly cisplatin for locally advanced cervical cancer.Methods and analysisThis study is a non-randomised, open-label, prospective phase 1b study. Up to 10 patients with histologically proven uterine cervical cancer at stage IIB, IIIA, IIIB, IIIC1 or IVA as per International Federation of Gynecology and Obstetrics (2018) staging will be enrolled. All patients will receive CIRT of 74.4 Gy relative biological effectiveness in 20 fractions over 5 weeks (four fractions per week). Weekly cisplatin at a dose of 40 mg/m2 will be administrated up to five times. Durvalumab at a dose of 1500 mg/body will be administrated at weeks 2 and 6. Safety and tolerability will be evaluated based on the frequency of dose-limiting toxicities until 92 days after CIRT starts. Patients will be followed-up strictly as per the scheduled protocol for 1 year after CIRT initiation.Ethics and disseminationThe Human Research Ethics Committees of QST Hospital (#C21-002) and Chiba University (#2021006) have approved this study protocol. The findings will be published in peer-reviewed journals and presented at scientific conferences.Trial registration numberJapan Registry of Clinical Trials (jRCT2031210083), registered on 12 May 2021.

Nicorandil has vasodilatory effects on both the epicardial coronary arteries and the coronary microvasculature, thereby increasing coronary blood flow. The objective of the present study was to investigate the effectiveness of intravenous (IV) nicorandil infusion for fractional flow reserve (FFR) measurement. In this crossover randomized study, 49 patients underwent FFR measurement with a consecutive randomized order of patient-blind infusions of continuous IV adenosine administration and a single bolus IV administration of nicorandil. The primary endpoint was the difference between the FFR by nicorandil and the FFR by adenosine, as assessed by the Bland–Altman method. The mean FFR value measured by nicorandil was not significantly different from that measured by adenosine [0.8125 ± 0.1349 vs. 0.7978 ± 0.124; mean difference, 0.0147 (95% confidence interval − 0.0373, 0.0667); P  = 0.58]. There was no clinically significant diagnostic discordance, with the FFR by nicorandil > 0.80 and that by adenosine < 0.75. Hyperemia was achieved earlier using nicorandil than adenosine (34 ± 13 vs. 58 ± 15, P  < 0.001). The duration of hyperemia after IV nicorandil was variable (6–570 s, mean 89 ± 98 s). IV nicorandil decreased systolic blood pressure by 32 ± 16 mm Hg (24 ± 10%) from baseline. Linear regression analysis showed that the average FFR value and the difference in systolic blood pressure were significantly associated with the bias in the FFR value between the two drugs. In conclusions, the results of the present study suggest that IV nicorandil can achieve maximal hyperemia easily and rapidly, providing an acceptable diagnostic performance for FFR assessment. However, a wide range of variation in hyperemic plateau and a decrease in blood pressure are the major limitations of this method.

In terms of medical policy for cervical cancer prevention, Japan lags far behind other industrialized countries. We initiated a randomized controlled trial to evaluate the self-sampling human papillomavirus (HPV) test as a tool to raise screening uptake and detection of pre-cancer. This study was conducted to explore the acceptability and preference of self-sampling using a subset of the data from this trial. A pre-invitation letter was sent to eligible women, aged 30-59 years who had not undergone cervical cancer screening for three or more years. After excluding those who declined to participate in this trial, the remaining women were assigned to the self-sampling and control groups. A second invitation letter was sent to the former group, and those wanting to undergo the self-sampling test ordered the kit. A self-sampling HPV kit, consent form, and a self-administered questionnaire were sent to participants who ordered the test. Of the 7,340 participants in the self-sampling group, 1,196 (16.3%) administered the test, and 1,192 (99.7%) answered the questionnaire. Acceptability of the test was favorable; 75.3-81.3% of participants agreed with positive impressions (easy, convenient, and clarity of instruction), and 65.1-77.8% disagreed with negative impressions (painful, uncomfortable, and embarrassing). However, only 21.2% were confident in their sampling procedure. Willingness to undergo screening with a self-collected sample was significantly higher than that with a doctor-collected sample (89.3% vs. 49.1%; p<0.001). Willingness to undergo screening with a doctor-collected sample was inversely associated with age and duration without screening (both p<0.001), but that with a self-collected sample was not associated. Among women who used the self-sampling HPV test, high acceptability was confirmed, while concerns about self-sampling procedures remained. Screening with a self-collected sample was preferred over a doctor-collected sample and the former might alleviate disparities in screening rates.

ObjectivesThe LoVAS trial reported non-inferiority in remission induction rates between the reduced-dose and conventional high-dose glucocorticoid regimens plus rituximab for antineutrophil cytoplasm antibody (ANCA)-associated vasculitis at 6 months; however, maintenance glucocorticoid requirements and long-term outcomes are unknown.MethodsA total of 140 patients with new-onset ANCA-associated vasculitis without severe glomerulonephritis or alveolar haemorrhage were randomised to receive reduced-dose prednisolone (0.5 mg/kg/day) plus rituximab (375 mg/m2/week×4) or high-dose prednisolone (1 mg/kg/day) plus rituximab. After achieving remission, patients received the rituximab maintenance therapy (1 g/6 months).ResultsA total of 134 patients were analysed. Among patients who achieved remission with the protocolised treatments, the majority of patients in the reduced-dose group (89.7%) and 15.5% in the high-dose group discontinued prednisolone (median time to withdrawal, 150 and 375 days, respectively). During 24-month trial period, two patients in the reduced-dose group (2.8%) died, while five patients in the high-dose group (7.6%) died (p=0.225). Relapse occurred in nine patients in the reduced-dose group (13.0%) (two major and seven minor) and five in the high-dose group (7.6%) (two major and three minor) (p=0.311). Serious adverse events (SAEs) were less frequent in the reduced-dose group (36 events in 19 patients, 27.5%) than in the high-dose group (54 events in 30 patients, 46.2%) (p=0.025).ConclusionAt 24 months, frequencies of relapse did not differ between the groups, and SAEs were less frequent in the reduced-dose group due to the lower event rate in the 6-month induction phase. The bias to myeloperoxidase-ANCA positivity (85.8%) in the trial population should be noted.Trial registration number NCT02198248.

Natural killer T (NKT) cells show intense tumor-killing activity through direct and indirect pathways. However, humans have less than 0.01% of NKT cells in the peripheral blood, making it difficult to apply NKT cells for cancer treatment. We have successfully produced invariant NKT cells derived from induced pluripotent stem cells (iPSC-iNKT cells) and demonstrated the tolerability of this product in a previous phase 1 clinical trial. Although the iPSC-iNKT cells showed substantial anti-tumor activity against various tumor cell types when combined with α-Galactosylceramide-pulsed autologous dendritic cells (DC/Gal) in non-clinical experiments, the tolerability of this combination therapy for humans has not demonstrated yet. Thus, we planned this first-in-human phase 1 open-label clinical trial to demonstrate data on tolerability and safety, as well as explore the immunological changes that occur following this combination treatment. We hypothesize that the sequential induction of nasal submucosal DC/Gal injection and intra-arterial administration of the iPSC-iNKT cells is tolerable and has a favorable safety profile for cancer patients. This trial provides vital and fundamental information for next-phase clinical trials and future applications of iPSC-iNKT cells for various cancer patients (jRCTa030220741; URL: https://jrct.mhlw.go.jp/en-latest-detail/jRCTa030220741 ).