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Background: Clinical trials have become larger and more complex. Thus, eSource should be used to enhance efficiency. This study aimed to evaluate the impact of the multisite implementation of eSource direct data capture (DDC), which we define as eCRFs for direct data entry in this study, on efficiency by analyzing data from a single investigator-initiated clinical trial in oncology. Methods: Operational data associated with the targeted study conducted in Japan was used to analyze time from data occurrence to data entry and data finalization, and number of visits to the site and time spent at the site by clinical research associates (CRAs). Additionally, simulations were performed on the change in hours at the clinical sites during the implementation of eSource DDC. Results: No difference in time from data occurrence to data entry was observed between the DDC and the transcribed data fields. However, the DDC fields could be finalized 4 days earlier than the non-DDC fields. Additionally, although no difference was observed in the number of visits for source data verification (SDV) by CRAs, a comparison among sites that introduced eSource DDC and those that did not showed that the time spent at the site for SDV was reduced. Furthermore, the simulation results indicated that even a small amount of data to be collected or a small percentage of DDC-capable items may lead to greater efficiency when the number of subjects per site is significant. Conclusions: The implementation of eSource DDC may enhance efficiency depending on the study framework and type and number of items to be collected. [ABSTRACT FROM AUTHOR]

Background/Aims: Information regarding the use of wearable devices in clinical research, including disease areas, intervention techniques, trends in device types, and sample size targets, remains elusive. Therefore, we conducted a comprehensive review of clinical research trends related to wristband wearable devices in research planning and examined their applications in clinical investigations. Methods: As this study identified trends in the adoption of wearable devices during the planning phase of clinical research, including specific disease areas and targeted number of intervention cases, we searched ClinicalTrials.gov—a prominent platform for registering and disseminating clinical research. Since wrist-worn devices represent a large share of the market, we focused on wrist-worn devices and selected the most representative models among them. The main analysis focused on major wearable devices to facilitate data analysis and interpretation, but other wearables were also surveyed for reference. We searched ClinicalTrials.gov with the keywords "ActiGraph,""Apple Watch,""Empatica,""Fitbit,""Garmin," and "wearable devices" to obtain studies published up to 21 August 2022. This initial search yielded 3214 studies. After excluding duplicate National Clinical Trial studies (the overlap was permissible among different device types except for wearable devices), our analysis focused on 2930 studies, including simple, time-series, and type-specific assessments of various variables. Results: Overall, an increasing number of clinical studies have incorporated wearable devices since 2012. While ActiGraph and Fitbit initially dominated this landscape, the use of other devices has steadily increased, constituting approximately 10% of the total after 2015. Observational studies outnumbered intervention studies, with behavioral and device-based interventions being particularly prevalent. Regarding disease types, cancer and cardiovascular diseases accounted for approximately 20% of the total. Notably, 114 studies adopted multiple devices simultaneously within the context of their clinical investigations. Conclusions: Our findings revealed that the utilization of wearable devices for data collection and behavioral interventions in various disease areas has been increasing over time since 2012. The increase in the number of studies over the past 3 years has been particularly significant, suggesting that this trend will continue to accelerate in the future. Devices and their evaluation methods that have undergone thorough validation, confirmed their accuracy, and adhered to established legal regulations will likely assume a pivotal role in evaluations, allowing for remote clinical trials. Moreover, behavioral intervention therapy utilizing apps is becoming more extensive, and we expect to see more examples that will lead to their approval as programmed medical devices in the future. [ABSTRACT FROM AUTHOR]

Background: Early inclusion of Japan in the global development program could be a key factor in reducing the drug lag, making participation in phase I multiregional clinical trials (Ph. I MRCTs) an important consideration for oncology drug development in Japan. We aimed to investigate the factors associated with the inclusion of Japan in Ph. I MRCTs in oncology. Methods: We compared the trial design, target population, type of primary tested drug, trial conduct profile, and sponsor profile for Ph. I MRCTs with or without Japan conducted by the top 20 companies in more than two countries and started between January 1, 2011, and December 31, 2020. Results: One hundred and ninety-seven Ph. I MRCTs included Japan, and 697 did not. Detailed features of the Ph. I MRCTs in oncology were summarized, and several factors (trial design, target population, trial conduct profile, and sponsor profile) associated with inclusion of Japan in the Ph. I MRCTs were identified. Conclusions: It is important for Japanese subsidiaries within global pharmaceutical companies to closely communicate with the headquarters based on medical practice and unmet needs in Japan to join global development from an early stage. In addition, further efforts to attract emerging biopharmaceutical companies to Japan from the regulatory and/or political perspectives would be needed, thereby preventing drug lag in Japan. [ABSTRACT FROM AUTHOR]

Ivermectin is an antiparasitic drug administered to hundreds of millions of people worldwide. Fundamental research suggests that ivermectin is effective against coronavirus disease 2019 (COVID-19); therefore, we investigated the efficacy and safety of ivermectin as a COVID-19 treatment option. This multi-regional (Japan and Thailand), multicenter, placebo-controlled, randomized, double-blind, parallel-group, Phase III study evaluated the efficacy and safety of ivermectin in patients with mild COVID-19 (IVERMILCO Study). The participants took a specified number of the investigational product (ivermectin or placebo) tablets of, adjusted to a dose of 0.3–0.4 mg/kg, orally on an empty stomach once daily for three days. The primary efficacy endpoint was the time at which clinical symptoms first showed an improving trend by 168 h after investigational product administration. A total of 1030 eligible participants were assigned to receive the investigational product; 502 participants received ivermectin and 527 participants received a placebo. The primary efficacy endpoint was approximately 96 h (approximately four days) for both ivermectin and placebo groups, which did not show statistically significant difference (stratified log-rank test, p = 0.61). The incidence of adverse events and adverse drug reactions did not show statistically significant differences between the ivermectin and placebo groups (chi-square test, p = 0.97, p = 0.59). The results show that ivermectin (0.3–0.4 mg/kg), as a treatment for patients with mild COVID-19, is ineffective; however, its safety has been confirmed for participants, including minor participants of 12 years or older (IVERMILCO Study ClinicalTrials.gov number, NCT05056883.). [ABSTRACT FROM AUTHOR]

Objective: Somapacitan is a long‐acting growth hormone (GH) derivative developed for the treatment of GH deficiency (GHD). This study evaluates the efficacy and tolerability of somapacitan in Japanese children with GHD after 104 weeks of treatment and after switch from daily GH. Design: Subanalysis on Japanese patients from a randomised, open‐labelled, controlled parallel‐group phase 3 trial (REAL4, NCT03811535). Patients and Measurements: Thirty treatment‐naïve patients were randomised 2:1 to somapacitan (0.16 mg/kg/week) or daily GH (0.034 mg/kg/day) up to Week 52, after which all patients received somapacitan. Height velocity (HV; cm/year) at Weeks 52 and 104 were the primary measurements. Additional assessments included HV SD score (SDS), height SDS, bone age, insulin‐like growth factor‐I (IGF‐I) SDS, and observer‐reported outcomes. Results: At Week 52, observed mean HV was similar between treatment groups (10.3 vs. 9.8 cm/year for somapacitan and daily GH, respectively). Similar HVs between groups were also observed at Week 104: 7.4 cm/year after continuous somapacitan treatment (soma/soma) and 7.9 cm/year after 1‐year somapacitan treatment following switch from daily GH (switch). Other height‐related endpoints supported continuous growth. IGF‐I SDS increased in both groups with mean IGF‐I SDS within −2 and +2 during the study. Somapacitan was well tolerated, one mild injection site reaction was reported, with no reports of injection site pain. Patient preference questionnaires showed that most patients and their caregivers (90.9%) who switched treatment at Week 52 preferred once‐weekly somapacitan over daily GH treatment. Conclusions: Somapacitan showed sustained efficacy in Japanese children with GHD over 104 weeks and for 52 weeks after switching from daily GH. Somapacitan was well tolerated and preferred over daily GH. [ABSTRACT FROM AUTHOR]

Background: In Europe, an herbal medicine containing peppermint oil is widely used in patients with irritable bowel syndrome (IBS). In Japan, however, no clinical evidence for peppermint oil in IBS has been established, and it has not been approved as a drug for IBS. Accordingly, we conducted a clinical study to confirm the efficacy and safety of peppermint oil (ZO-Y60) in Japanese patients with IBS. Methods: The study was a multi-center, open-label, single-arm, phase 3 trial in Japanese outpatients with IBS aged 17–60 years and diagnosed according to the Rome III criteria. The subjects were treated with an oral capsule of ZO-Y60 three times a day before meals, for four weeks. The efficacy of ZO-Y60 was evaluated using the patient's global assessment (PtGA), IBS symptom severity score, stool frequency score, stool form score, and physician's global assessment (PGA). The safety of ZO-Y60 was also assessed. Results: Sixty-nine subjects were treated with ZO-Y60. During the four-week administration of ZO-Y60, the improvement rate of the PtGA was 71.6% (48/67) in week 2 and 85.1% (57/67) in week 4. It was also suggested that ZO-Y60 is effective against any type of IBS (IBS with constipation, IBS with diarrhea, and mixed/unsubtyped IBS). The improvement rate of the PGA was 73.1% (49/67) in week 2 and 85.1% (57/67) in week 4, also confirming the efficacy of ZO-Y60. Adverse events were observed in 14 subjects (20.3%), however, none of these adverse events were categorized as serious. Conclusion: The efficacy of treatment was confirmed, subjective symptoms were improved, as was observed in previous clinical studies of ZO-Y60 conducted outside of Japan. All adverse reactions were previously known and were non-serious. These findings suggest that peppermint oil may be effective in the Japanese population and that it has an acceptable safety profile. Trial registration: JAPIC Clinical Trials Information number: JapicCTI-121727 https://jrct.niph.go.jp/en-latest-detail/jRCT1080221685. Registration date: 2012–01-10. [ABSTRACT FROM AUTHOR]

Objectives: RAISE (NCT04115293) was a randomized, multicenter, double‐blind, placebo‐controlled phase III study of zilucoplan, a macrocyclic peptide and complement component 5 inhibitor with a dual mechanism of action, in patients with acetylcholine receptor autoantibody‐positive generalized myasthenia gravis (MG). RAISE showed clinically meaningful and statistically significant improvements in MG‐specific outcomes in the overall population. Here, we assess efficacy and safety of zilucoplan in patients with generalized myasthenia gravis in the Japanese patients enrolled in RAISE. Methods: Adults with acetylcholine receptor autoantibody‐positive generalized MG (MGFA disease class II–IV) were randomized 1:1 to daily self‐administered subcutaneous zilucoplan 0.3 mg/kg or placebo injections for 12 weeks. The primary efficacy endpoint was change from baseline to week 12 in the MG Activities of Daily Living score. Safety was assessed by the incidence of treatment‐emergent adverse events. Efficacy and safety outcomes of a Japanese subgroup were prespecified. Results: Overall, 16 Japanese patients were randomized to zilucoplan 0.3 mg/kg (n = 7) or placebo (n = 9). There was a clinically meaningful improvement in the MG Activities of Daily Living score at week 12 for zilucoplan versus placebo in the Japanese population, with least squares mean difference of −4.26 (95% confidence interval −7.40, −1.12), which was comparable with the overall population. The incidence of treatment‐emergent adverse events was similar in both treatment arms, with 57.1% and 55.6% of patients in the zilucoplan and placebo groups, respectively, experiencing treatment‐emergent adverse events. Conclusions: In a subgroup of Japanese patients, zilucoplan showed clinically meaningful improvement in MG‐specific outcomes with a favorable safety profile, consistent with the overall RAISE population. [ABSTRACT FROM AUTHOR]

Chronic kidney disease-associated pruritus (CKD-aP) is very common and sometimes refractory to treatment in hemodialysis patients. In a trial conducted in Japan, nalfurafine, effectively reduced itching of treatment-resistant CKD-aP. Our present bridging study aimed to evaluate the efficacy and safety of nalfurafine in Chinese cohort with refractory CKD-aP. In this phase III, multicenter bridging study conducted at 22 sites in China, 141 Chinese cases with refractory CKD-aP were randomly (2:2:1) assigned to receive 5 μg, 2.5 μg of nalfurafine or a placebo orally for 14 days in a double-blind manner. The primary end point was the mean decrease in the mean visual analogue scale (VAS) from baseline. A total of 141 patients were included. The primary endpoint analysis based on full analysis set (FAS), the difference of mean VAS decrease between 5 μg nalfurafine and placebo group was 11.37 mm (p =.041); the difference of mean VAS decrease between 2.5 μg and placebo group was 8.81 mm (p =.110). Both differences were greater than 4.13 mm, which met its predefined success criterion of at least 50% efficacy of the key Japanese clinical trial. The per protocol set (PPS) analysis got similar results. The incidence of adverse drug reactions (ADRs) was 49.1% in 5μg, 38.6% in 2.5 μg and 33.3% in placebo group. The most common ADR was insomnia, seen in 21 of the 114 nalfurafine patients. Oral nalfurafine effectively reduced itching with few significant ADRs in Chinese hemodialysis patients with refractory pruritus. [ABSTRACT FROM AUTHOR]

Although five immune‐oncologic‐drug‐based combination therapies, such as ipilimumab plus nivolumab, avelumab plus axitinib, pembrolizumab plus axitinib, nivolumab plus cabozantinib, and pembrolizumab plus lenvatinib, have been approved for advanced renal cell carcinoma (RCC) in Japan, the optimal therapy for advanced RCC has not been determined. Without head‐to‐head comparison, several network meta‐analyses using phase 3 clinical trials presented the highest likelihood of maximal overall survival, progression‐free survival, and objective response rate according to several categories such as the International Metastatic Renal Cell Carcinoma Database Consortium risk group, programmed cell death 1‐ligand 1 expression, sarcomatoid features, or the safety profile of treatment‐related adverse events; however, they did not include the results of additional long‐term follow‐up data in each clinical trial. In the real world, advanced RCC treatment depends on several factors, such as age, comorbidity, tumor burden, or the presence of symptoms that affect daily life. To relieve tumor‐related symptoms, tumor burden reduction is required, which may lead to the use of therapies with high response rates and low risk of disease progression. Moreover, patients with comorbidities, such as uncontrolled diabetes, are required to avoid steroid therapy for adverse events, which may necessitate the use of therapies with a low incidence of adverse events that are needed for high‐dose steroids or permanent steroid replacement therapy. Moreover, novel drugs, such as the hypoxia‐inducible factor 2a inhibitor (belzutifan) or immunostimulatory interleukin‐2 cytokine prodrug (bempegaldesleukin) have been developed, and phase 3 clinical trials of combination therapy using these drugs for treatment‐naïve advanced RCC are ongoing. Further development of systemic therapies for advanced RCC is required. [ABSTRACT FROM AUTHOR]

Resection is the only curative treatment for pancreatic ductal adenocarcinoma (PDAC). Although the outcome of technically resectable PDAC has improved with advances in surgery and adjuvant therapy, the 5-year survival rate remains low at 20% to 40%. More effective therapy is needed. Almost 15 years ago, the National Comprehensive Cancer Network guidelines proposed a resectability classification of PDAC based on preoperative imaging. Since then, treatment strategies for PDAC have been devised based on resectability. The standard of care for resectable PDAC is adjuvant chemotherapy after R0 resection, as shown by the results of pivotal clinical trials. With regard to neoadjuvant treatment, several recent clinical trials comparing neoadjuvant treatment with upfront resection have been conducted on resectable PDAC and borderline resectable PDAC, and the benefits and efficacy of neoadjuvant treatment for pancreatic cancer has become clearer. The significance of neoadjuvant treatment for resectable PDAC remains controversial, but in borderline resectable PDAC the efficacy of neoadjuvant treatment has been further recognised, although the standard of care has not yet been established. Several promising clinical trials for PDAC are ongoing. This review presents previous and ongoing trials of perioperative treatment for resectable and borderline resectable PDAC, focusing on the difference between Asian and Western countries. [ABSTRACT FROM AUTHOR]

The present study aimed to evaluate the efficacy and safety of 1.5% levofloxacin (LVFX) otic solution for the treatment of patients with otitis media. This multicenter, randomized, double-blind, parallel-group, placebo-controlled phase 3 trial was conducted at 34 institutions in Japan. A total of 202 patients with chronic suppurative otitis media (CSOM) or acute otitis media (AOM) were randomized into either the LVFX group or placebo group. A total of 6–10 drops of 1.5% otic solution of LVFX or its matching placebo were administered in the diseased ear twice daily, in the morning and evening for up to 10 days. Images corresponding to three clinical findings—purulent otorrhea, hyperemia (redness), and granulation tissue formation in the middle ear and tympanic membrane—for each diseased ear were evaluated using digital endoscopy by a blinded central independent review committee (BICRC) at each visit after treatment administration. In total, the data of 201 participants (LVFX group, 99; placebo group, 102) were analyzed. The proportion of patients with disappearance (improvement rate) of all three clinical findings at the end of treatment or discontinuation by the BICRC was 46.5% (46/99) in the LVFX group and 23.5% (24/102) in the placebo group, and the difference (95% confidence interval) between the groups was 22.0% (8.7, 34.2), with a significantly higher improvement rate in the LVFX group than in the placebo group (p = 0.001; Cochran–Mantel–Haenszel test), demonstrating the efficacy of LVFX. The bacterial eradication rates were 93.9% (77/82) and 12.5% (11/88) in the LVFX and placebo groups, respectively, and the rate was significantly higher in the LVFX group than in the placebo group (p < 0.001). Treatment-related adverse events (AEs) occurred in 5.1% (5/99) and 7.8% (8/102) of the patients in the LVFX and placebo groups, respectively, and no significant difference was noted in incidence rate between the groups. The clinical efficacy of 1.5% LVFX otic solution for CSOM and AOM was demonstrated by the resolution of inflammation in the middle ear and tympanic membrane as well as through the high bacterial eradication rate observed. No deaths or serious treatment-related AEs were observed. The study provided confirmation that 1.5% LVFX otic solution is a safe, well-tolerated, and effective treatment for CSOM and AOM. [ABSTRACT FROM AUTHOR]

• In healthy Japanese infants/toddlers, V114 given subcutaneously was well tolerated. • The V114 safety profile was comparable to that of PCV13. • V114 elicited immune responses to all 15 serotypes in healthy infants/toddlers. • V114 was non-inferior for the 13 PCV13 serotypes after the three-dose infant series. • V114-elicited immune responses were higher than PCV13 for serotypes 22F and 33F. This phase III study evaluated safety, tolerability, and immunogenicity of V114 (15-valent pneumococcal conjugate vaccine) in Japanese infants. V114 contains all 13 serotypes in PCV13 plus additional serotypes 22F and 33F. Healthy Japanese infants were randomized to receive three primary doses of V114 or PCV13 (dose 1 at 2–6 months of age; doses 2 and 3 ≥ 27 days after prior dose), plus a toddler dose at 12–15 months of age. Adverse events (AEs) were collected on Days 1–14 following each vaccination. Serotype-specific anti-pneumococcal immunoglobulin G (IgG) was measured 30 days post-dose 3, pre-dose 4, and 30 days post-dose 4. Primary objectives included non-inferiority of V114 to PCV13 for the 13 shared serotypes based on serotype-specific IgG response rates (IgG ≥ 0.35 μg/mL) and geometric mean concentration (GMC) ratios, and for serotypes 22F and 33F based on IgG response rates and compared with the lowest response of any serotype in the PCV13 group, at 30 days post-dose 3. Overall, 694 infants were randomized to V114 (n = 347) or PCV13 (n = 347). Proportions of participants with solicited and serious AEs were comparable between vaccination groups. V114 met non-inferiority criteria for all 13 shared serotypes, based on difference in proportion of responders (lower bound of two-sided 95 % confidence interval [CI] > −10.0) and IgG GMC ratios (V114/PCV13, lower bound of two-sided 95 % CI > 0.5) at 30 days post-dose 3. The non-inferiority criterion based on IgG response rates was met for serotype 22F, but narrowly missed for serotype 33F (90.9 %, lower bound of two-sided 95 % CI −10.6). In Japanese infants, a four-dose series of V114 was generally well tolerated. Compared with PCV13, V114 provided non-inferior immune responses to the 13 shared serotypes and higher immune responses to serotype 22F and 33F post-primary series. Trial registration: ClinicalTrials.gov : NCT04384107; EudraCT 2019-003644-68. [ABSTRACT FROM AUTHOR]

Background: Drug lag in Japan has greatly decreased over the past decades; however, new instances of drug lag have appeared along with changes in the circumstances of oncology drug development. We aimed to investigate the factors associated with the approval lag for new oncology drugs between Japan and the United States (US) over the past decade by comparing approval dates and modalities, lead indications, approval types, and phase I strategies for earlier approval in Japan. Method: We descriptively evaluated the characteristics of 117 new oncology drugs approved in either Japan or the US from January 1, 2011, to December 31, 2020. Results: Seventy-one drugs were approved in Japan, 112 in the US, five only in Japan, and 46 only in the US. Interestingly, new oncology drugs were predominantly developed by the top 20 pharmaceutical companies in Japan; however, the opposite was true for drugs that were not yet approved in Japan. However, no clear trend was observed in the relationship between drug lag and the studied factors, except for the phase I strategy. There was a numerical but clear trend in which a higher percentage of phase I multiregional clinical trials (MRCTs) in the drug development strategy was observed for drugs with earlier approval in Japan. Conclusion: Participation in global drug development during the early stages, such as during phase I MRCTs, is one of the keys to successfully minimizing this new instance of drug lag in Japan. [ABSTRACT FROM AUTHOR]

Aim: To assess the safety and efficacy of tirzepatide in people of East Asian descent based on age and body mass index (BMI). Materials and Methods: Data of participants enrolled in East Asian countries in the SURPASS‐1, ‐3, ‐4, ‐5, J‐mono and J‐combo phase 3 clinical trials were included. Participants with type 2 diabetes with a baseline HbA1c of 7.0% up to 11.0% and a BMI of 23 kg/m2 or greater or 25 kg/m2 or greater were included. Participants treated with tirzepatide 5, 10 or 15 mg were evaluated to assess the safety and efficacy of tirzepatide in people of East Asian descent (94% from Japan) based on age (< 65 and ≥ 65 years) and BMI (< 25 and ≥ 25 kg/m2). Key safety and efficacy outcomes were assessed. Results: At baseline, 73% of East Asian participants had a BMI of 25 kg/m2 or greater and 74% were younger than 65 years. At week 52, tirzepatide induced a similar dose‐dependent reduction in HbA1c, waist circumference and BMI across subgroups. Across all BMI and age subgroups, mean absolute HbA1c reductions across the three doses ranged from 2.3% to 3.0%, and mean waist circumference reductions ranged from 4.3 to 9.8 cm. Improvements in absolute insulin sensitivity, assessed by homeostatic model assessment for insulin resistance, were greater in those with a baseline BMI of ≥ 25 kg/m2. Improvements in lipid profiles were similar across subgroups. While the safety profile of tirzepatide was broadly similar across BMI and age subgroups, drug discontinuation because of adverse events was higher in participants with a baseline age of ≥ 65 years. Conclusions: This post hoc analysis showed that once‐weekly tirzepatide had a similar safety and efficacy profile across BMI and age subgroups in East Asian participants. [ABSTRACT FROM AUTHOR]

Background: The shared decision-making model has been proposed as the ideal treatment decision-making process in medical encounters. However, the decision to participate in clinical trials rarely involves shared decision-making. In this study, we investigated the perceptions of Japanese clinical research coordinators who routinely support the informed consent process. Methods: This study aimed to (1) identify clinical research coordinators' perceptions of the current status of shared decision-making implementation and its influencing factors, and (2) obtain suggestions to enhance the shared decision-making process in clinical trials. A cross-sectional survey was conducted using a web questionnaire based on the Theory of Planned behaviour. Invitations were sent to 1087 Japanese medical institutions, and responses from the participants were captured via the web. The shared decision-making process in clinical trials was defined according to the Shared Decision-Making Questionnaire for Doctors. The effect of the attitudes toward shared decision-making, clinical research coordinators' subjective norms towards its implementation, perceived barriers to autonomous decision-making, and the number of difficult steps in the shared decision-making process on the shared decision-making current status as the shared decision-making intention was assessed by multiple regression analysis. Results: In total, 373 clinical research coordinators responded to the questionnaire. Many believed that they were already implementing shared decision-making. Attitudes toward shared decision-making (t = 3.400, p <.001), clinical research coordinators' subjective norms towards its implementation (t = 2.239, p =.026), perceived barriers to autonomous decision-making (t = 3.957, p <.001), and the number of difficult steps in the shared decision-making process (t = 3.317, p =.001) were found to significantly influence current status (Adjusted R2 =.123). However, results on perceived barriers to autonomous decision-making and the number of difficult steps in the shared decision-making process indicate a lack of knowledge of shared decision-making and decision-support skills among clinical research coordinators. Conclusions: Clinical research coordinators might positively perceive shared decision-making based on normative beliefs without sufficient knowledge of it. Therefore, providing appropriate training on shared decision-making to clinical research coordinators and increasing awareness among stakeholders could enable its improvement. Trial registration: Not applicable. [ABSTRACT FROM AUTHOR]

Introduction: Upadacitinib, an oral, selective Janus kinase inhibitor, is approved in Japan for the treatment of moderate-to-severe atopic dermatitis (AD), a chronic inflammatory skin disease characterized by eczematous morphology and intense itch. Methods: Rising Up is an ongoing phase 3, randomized, multicenter study evaluating the long-term safety and efficacy of upadacitinib in Japan. Patients with moderate-to-severe AD were randomized 1:1:1 to topical corticosteroids plus upadacitinib 15 mg (UPA15), upadacitinib 30 mg (UPA30), or placebo at baseline; at week 16, placebo patients were rerandomized 1:1 to UPA15 or UPA30 (plus topical corticosteroids per investigator discretion). This 2-year interim analysis evaluated safety and efficacy through 112 weeks (data cutoff date: 11 August 2021). Adverse events (AEs), AEs of special interest (AESIs), and laboratory data were assessed. Efficacy assessments included ≥ 75% and ≥ 90% improvement from baseline in Eczema Area and Severity Index (EASI 75/90), achievement of clear or almost clear on the validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD 0/1), and ≥ 4-point improvement in the Worst Pruritus Numerical Rating Scale (WP-NRS). Results: A total of 272 patients were enrolled and 242 were ongoing at data cutoff (UPA15, n = 120; UPA30, n = 122). After 112 weeks of treatment, serious AEs, AEs leading to discontinuation, and most AESIs were generally infrequent, and rates were similar between the two upadacitinib groups. One event each of rectal cancer and cerebellar hemorrhage was reported in the UPA15 group; no thrombosis events were observed. The most common AEs included acne, nasopharyngitis, and herpes zoster. EASI 75, EASI 90, vIGA-AD 0/1, and WP-NRS response rates were maintained through week 112. Conclusion: UPA15 and UPA30 were well tolerated through 112 weeks of treatment with similar safety profiles to short-term studies and demonstrated durable long-term efficacy for the treatment of moderate-to-severe AD in adults and adolescents. Trial Registration: ClinicalTrials.gov identifier, NCT03661138. [ABSTRACT FROM AUTHOR]

Regenerative medicine using iPS cell technologies has progressed remarkably in recent years. In this review, we summarize these technologies and their clinical application. First, we discuss progress in the establishment of iPS cells, including the HLA‐homo iPS cell stock project in Japan and the advancement of low antigenic iPS cells using genome‐editing technology. Then, we describe iPS cell‐based therapies in or approaching clinical application, including those for ophthalmological, neurological, cardiac, hematological, cartilage, and metabolic diseases. Next, we introduce disease models generated from patient iPS cells and successfully used to identify therapeutic agents for intractable diseases. Clinical medicine using iPS cells has advanced safely and effectively by making full use of current scientific standards, but tests on cell safety need to be further developed and validated. The next decades will see the further spread of iPS cell technology‐based regenerative medicine. [ABSTRACT FROM AUTHOR]

Stem cell therapy is a current world-wide topic in medical science. Various therapies have been approved based on their effectiveness and put into practical use. In Japan, research and development-related stem cell therapy, generally referred to as regenerative medicine, has been led by the government. The national scheme started in 2002, and support for the transition to clinical trials has been accelerating since 2011. Of the initial 18 projects that were accepted in the budget for preclinical research, 15 projects have begun clinical trials so far. These include the transplantation of retinal, cardiac, and dopamine-producing cells differentiated from human induced pluripotent stem (iPS) cells and hepatocyte-like cells differentiated from human embryonic stem (ES) cells. The distinctive feature of the stem cell research in Japan is the use of iPS cells. A national framework was also been set-up to attain the final goal: health insurance coverage. Now, insurance covers cell transplantation therapies for the repair and recovery of damaged skin, articular cartilage, and stroke as well as therapies introduced from abroad, such as allogeneic mesenchymal stem cells for graft-versus-host disease and chimeric antigen receptor-T (CAR-T) cell therapy. To prepare this review, original information was sought from Japanese authentic websites, which are reliable but a little hard to access due to the fact of multiple less-organized databases and the language barrier. Then, each fact was corroborated by citing its English version or publication in international journals as much as possible. This review provides a summary of progress over the past decade under the national program and a state-of-the-art factual view of research activities, government policy, and regulation in Japan for the realization of stem cell therapy. [ABSTRACT FROM AUTHOR]

Background: The number of patients with non-functional neuroendocrine tumors (NETs) has increased recently, and the rate of liver metastasis of NETs is about 20% in patients at the first diagnosis. Transcatheter arterial embolization (TAE) and everolimus are therapies with reported efficacy, but few reports have described their combined treatment. We therefore aim to evaluate the efficacy and safety of combination therapy with everolimus and TAE in patients with liver metastasis of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in a prospective study. Methods: We design a single-arm, open-label, prospective study to evaluate the efficacy and safety of combination therapy with everolimus and TAE in patients with liver metastases of GEP-NETs. The study started in June 2021 at Okayama University Hospital and is expected to enroll 18 patients over a 2-year period. Discussion: This study is a prospective study investigating a new treatment method for a rare disease called GEP-NETs. We may obtain useful information that contributes to the treatment guidelines in this study. However, NET is a rare disease, and although the number of cases is statistically established, it may not be possible to accurately assess causality. TRIAL REGISTRATION NUMBER: jRCT1061210015. [ABSTRACT FROM AUTHOR]

What is Known and Objective: Sodium‐glucose cotransporter‐2 inhibitors (SGLT‐2is) have been increasingly prescribed for the treatment of type 2 diabetes mellitus (T2DM). We aimed to investigate the impact of clinical trials presenting remarkable results on the prescription of SGLT‐2is and the relationship between the impact and generalisability of the breakthrough trials on SGLT‐2is. Methods: This retrospective cohort study involved 32,949 patients with T2DM who were prescribed at least one antidiabetic agent in the Japan Medical Data Center health insurance database. Prescription rates of SGLT‐2is were calculated monthly from April 2014 to March 2020. We evaluated the impact of the EMPA‐REG OUTCOME study for an Asian subgroup on the prescription rate of empagliflozin and the impact of the CANVAS/CANVAS‐R study on the prescription rate of canagliflozin. Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were estimated using the quasi‐Poisson regression model in the overall population, subgroup with a history of cardiovascular disease (high‐risk group), and subgroup without a history and risk factors of cardiovascular disease (low‐risk group). Results and Discussion: The EMPA‐REG OUTCOME study for the Asian subgroup led to increased prescription rates of empagliflozin 3 months after its publication in the overall population and high‐risk group but not in low‐risk group (IRR [95% CI]: 1.40 [1.17–1.66], 1.39 [1.05–1.84], and 1.00 [0.79–1.27], respectively). The increase in high‐risk group may be appropriate because this study included patients with a history of cardiovascular disease only. The CANVAS/CANVAS‐R study led to increased prescription rates of canagliflozin 3 months after its publication in the overall population, high‐risk group, and low‐risk group (IRR [95% CI]: 1.52 [1.06–2.19], 1.39 [1.06–1.83], and 1.81 [1.20–2.75], respectively). The increase in low‐risk group may not be appropriate because this study did not include patients without a history or risk factors of cardiovascular disease. What is New and Conclusion: The breakthrough trials increased prescription rates not only for patients to whom the trial results could be extrapolated but also for those in whom trial benefits were not certain. Our findings suggest that information about breakthrough trials may need to be provided along with data on trial result generalisability. [ABSTRACT FROM AUTHOR]

Aim: To explore the efficacy and safety of once-weekly insulin icodec (icodec) in Japanese adults (≥20 years old) with type 2 diabetes from the global ONWARDS 1, 2 and 4 trials., Materials and Methods: Insulin-naive (ONWARDS 1) and insulin-experienced (ONWARDS 2 and 4) individuals were randomized to icodec or a once-daily insulin comparator: insulin glargine U100 [ONWARDS 1 (basal insulin only) and 4 (basal-bolus regimen)] or insulin degludec [ONWARDS 2 (basal insulin only)]. The primary outcome was change in glycated haemoglobin from baseline to end of treatment (EOT) (ONWARDS 1: Week 52; ONWARDS 2 and 4: Week 26). Here, we present the Japanese subgroup results., Results: Similar reductions in glycated haemoglobin from baseline to EOT were observed in each trial for icodec and comparators. The proportion of time in range (blood glucose 3.9-10.0 mmol/L) at EOT was also comparable across treatment groups (time in range: 58%-68%), as was time spent with blood glucose below 3.0 mmol/L (<1.0%). Combined clinically significant (blood glucose <3.0 mmol/L) or severe (requiring external assistance for recovery) hypoglycaemia rates were low, with no severe events (ONWARDS 1 and 2) or a single severe event (ONWARDS 4; icodec group) reported. These results generally aligned with findings from the respective global populations. No new safety issues were identified., Conclusions: Icodec improved glycaemic control to a similar degree as once-daily basal insulin comparators while maintaining low levels of clinically significant or severe hypoglycaemia. The findings support icodec use in Japanese individuals with different levels of type 2 diabetes progression., (© 2024 Novo Nordisk and The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Objective: To investigate the efficacy and safety of robot-assisted radical hysterectomy (RARH) as a minimally invasive procedure in patients with cervical cancer that is curable by surgery., Materials and Methods: This study was a multicenter, open-label, single-arm clinical trial. The short-term outcome of open radical hysterectomy was used as the historical control. The primary endpoint was successful surgery with minimal blood loss (300 mL or less) and negative surgical margins. Secondary endpoints included surgical outcomes, recurrence-free survival (RFS), and overall survival (OS) rates., Results: Overall, 101 cases were enrolled in this study at 10 participating medical institutions and 100 underwent RARH. Among these cases, 89 met the primary endpoint, exceeding the threshold of 0.75 set by the lower limit. At 2 years postoperatively, 17 cases had recurrences, 4 were classified as International federation of Obstetrics and Gynecology Stage IB1 or lower, while 13 as IB2 or higher. There were three deaths, including one in Stage IB1 and two in Stage IIB in the second postoperative year, all of which had lymph node metastasis. The oncological outcomes for all cases showed RFS and OS rates of 82.7% and 96.9%, respectively, over a median observation period of 37 months. For cases with Stage IB1, RFS and OS were 94.1% and 98.5%, respectively., Conclusion: RARH demonstrated a significant reduction in blood loss while ensuring radicality, indicating the safety and efficacy of this procedure compared to conventional RH. Although it is conceivable that the results of this oncological analysis could change, as the data collection has not been fully completed, we plan to further evaluate the oncologic outcomes of RARH in future studies., Trial Registration: UMIN-CTR: UMIN000022278, registered on 11th May 2016., (© 2024. The Author(s).)

Tapinarof is a nonsteroidal, topical, aryl hydrocarbon receptor agonist. We evaluated the efficacy and safety of tapinarof cream 1% in Japanese patients aged ≥12 years with atopic dermatitis (AD) in two phase 3 trials, ZBB4-1 and ZBB4-2. ZBB4-1 (N = 216) consisted of an 8-week, double-blind, vehicle-controlled treatment period (period 1) and a 16-week extension treatment period (period 2). Patients were randomized 2:1 to tapinarof or vehicle in period 1; subsequently, all patients who enrolled in period 2 received tapinarof. ZBB4-2 (N = 291) was a 52-week, open-label, uncontrolled trial in which all patients received tapinarof. In period 1 of ZBB4-1, the proportion of patients who achieved an Investigator's Global Assessment (IGA) score of 0 (clear) or 1 (almost clear) with ≥2-grade improvement from baseline at week 8 (IGA treatment success, the primary end point) was 20.24% in the tapinarof group and 2.24% in the vehicle group (p = 0.0007). The proportion of patients with ≥75% improvement from baseline in Eczema Area and Severity Index (EASI) score at week 8 (EASI-75 response, the key secondary end point) was 40.3% in the tapinarof group and 4.3% in the vehicle group (p < 0.0001). In ZBB4-2, IGA treatment success rate was 28.1% at week 16, 32.3% at week 24, and 41.3% at week 52, and EASI-75 response rate was 53.3% at week 16, 63.7% at week 24, and 76.6% at week 52, indicating that efficacy responses improved over time and were maintained over 52 weeks. Across the two trials, most adverse events (AEs) were mild or moderate; common AEs included folliculitis, acne, and headache. In summary, tapinarof cream 1% was effective and generally safe for up to 52 weeks of treatment in Japanese patients with AD., (© 2024 The Author(s). The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

Background: Poor patient accrual can delay reporting of clinical trials and, consequently, the development of new treatments. For reducing the risk of additional resource requirements, a method for setting planned accrual periods with minimal deviation from the actual accrual periods is desirable. Risk factors for poor patient accrual and the appropriate method of estimating the required accrual period for timely completion of clinical trials were evaluated using the data of trials conducted by the Japan Clinical Oncology Group., Methods: The study included 199 trials that started patient accrual between January 1, 1990, and June 30, 2021. The explanatory variables included factors that could be evaluated prior to trial commencement. We also evaluated whether the estimation methods for accrual pace could lead to completion within the planned accrual period., Results: Approximately 23.6% of trials were completed within the planned accrual period. The risk factors for trial extension included planned accrual periods > 3 years (reference group: ≤ 3 years, odds ratio [OR] 0.37, 95% confidence interval [CI]: 0.15-0.92, P = 0.033) and stratified trial design (reference group: nonrandomized phase II trials, nonrandomized phase III trial [OR: 3.28, 95% CI: 0.99-10.9, P = 0.051], randomized phase II trial [OR: 3.91, 95% CI: 0.75-20.30, P = 0.105], and randomized phase III trial [OR: 9.29, 95% CI: 3.39-25.40, P < 0.001]). The method of estimating the accrual pace based on past clinical trials facilitated timely completion of the trial (OR: 3.51; 95% CI: 1.73-7.10, P < 0.001), unlike the estimation method based on survey evaluation of the accrual pace for participating institutions (OR: 1.12, 95% CI: 0.56-2.26, P = 0.751). Furthermore, the discrepancy between planned and actual accrual periods was minimal when using the methods of considering the accrual pace of past clinical trials., Conclusions: Considering the accrual pace of past clinical trials is useful for estimating the required accrual period if data from past trials are available. When conducting a survey, it is necessary to be cautious of overestimating the cases at each facility., (© 2024. The Author(s).)

Introduction: Insurance coverage for oral valganciclovir (VGCV) began in Japan in April 2023 on the basis of results, including our clinical trials for symptomatic congenital cytomegalovirus (CMV) disease. The VGCV treatment is available throughout Japan, so clinicians must consider the likelihood of hearing improvement and the possibility of neutropenia before dosing., Materials and Methods: We performed a substudy of an investigator-initiated, single-arm, prospective, multicenter, clinical trial in which 24 infants with symptomatic congenital CMV disease were orally administered 16 mg/kg VGCV twice daily for 6 months as an intervention. We examined the infants' baseline characteristics associated with improved hearing impairment or a severely reduced neutrophil count., Results: Of the 24 patients, 4 had normal hearing on assessment of their ear with the best hearing. Hearing impairment improved in 14 patients and did not respond to VGCV treatment in 6 patients at the 6-month hearing assessment. CMV DNA levels in plasma at baseline were higher in patients in whom hearing did not respond to treatment. A neutrophil count <500/mm 3 occurred in 5 (21%) patients for the first 6 weeks and in 8 (33%) patients for the first 6 months. A neutrophil count at screening and the lowest neutrophil count over the 6 months showed the highest correlation (r = 0.477, p = 0.019)., Conclusions: Infants with a low plasma viral load at screening tend to have an improvement in hearing impairment. Clinicians should be aware of neutropenia during VGCV treatment particularly in patients with a low neutrophil count during screening., Competing Interests: Declaration of competing interest Mitsubishi Tanabe Pharm Corp. provided Valixa™ dry syrup during the study period for treatment, but this company had no role in this clinical trial. None of the authors have any conflict of interest to declare., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Tapinarof is a non-steroidal, topical, aryl hydrocarbon receptor agonist. We evaluated the efficacy and safety of tapinarof cream (1%) in Japanese patients aged ≥18 years with plaque psoriasis in two phase 3 trials, ZBA4-1 and ZBA4-2. ZBA4-1 (N = 158) consisted of a 12-week, double-blind, vehicle-controlled treatment period (period 1) and a 12-week extension treatment period (period 2). Patients were randomized 2:1 to tapinarof or vehicle in period 1; subsequently, all patients who were enrolled in period 2 received tapinarof. ZBA4-2 (N = 305) was a 52-week, open-label, uncontrolled trial in which all patients received tapinarof. In period 1 of ZBA4-1, the proportion of patients who achieved a Physician Global Assessment (PGA) score of 0 (clear) or 1 (almost clear) with ≥2-grade improvement from baseline at week 12 (PGA treatment success, the primary endpoint) was 20.06% in the tapinarof group and 2.50% in the vehicle group (p = 0.0035). The proportion of patients with ≥75% improvement from baseline in the Psoriasis Area and Severity Index (PASI) score at week 12 (PASI75 response, a key secondary endpoint) was 37.7% in the tapinarof group and 3.8% in the vehicle group (p < 0.0001). In ZBA4-2, PGA treatment success rate was 30.0% at week 12, 51.3% at week 24, and 56.3% at week 52, and PASI75 response rate was 50.4% at week 12, 77.5% at week 24, and 79.9% at week 52, indicating that efficacy responses improved over time and were maintained over 52 weeks. Across the two trials, most adverse events (AEs) were mild or moderate; common AEs included folliculitis and contact dermatitis. In summary, tapinarof cream (1%) was efficacious and generally safe for up to 52 weeks of treatment in Japanese patients with plaque psoriasis., (© 2024 The Author(s). The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

Background:  First-line treatment of nonsquamous non-small cell lung cancer (NSCLC) has undergone a paradigm shift to platinum combination therapy together with immune checkpoint inhibitors (ICIs). However, phase III studies of combinations of cytotoxic chemotherapy and ICIs have included only patients with maintained organ function, not those with renal impairment.Methods: Cytotoxic chemotherapy-naïve advanced nonsquamous NSCLC patients aged 20 years or older with impaired renal function (creatinine clearance of 15 to 45 mL/min) are prospectively registered in this single-arm phase II study and receive combination therapy with carboplatin, nanoparticle albumin-bound (nab-) paclitaxel, and atezolizumab. Individuals with known genetic driver alterations including those affecting EGFR, ALK, ROS1, BRAF, MET, RET, and NTRK are excluded. We plan to enroll 40 patients over 2 years at 32 oncology facilities in Japan. The primary end point is confirmed objective response rate.Discussion: If the study demonstrates efficacy and safety of carboplatin/nab-paclitaxel/atezolizumab, then this combination regimen may become a treatment option even for nonsquamous NSCLC patients with impaired renal function.Trial Registration: Registered with Japan Registry for Clinical Trials on 25 February 2021 (jRCTs071200102). [ABSTRACT FROM AUTHOR]

Non-small cell lung cancer (NSCLC), one of the deadliest types of cancers worldwide, has been the target of immunotherapy due to its high immune antigenicity. With the addition of immune-checkpoint inhibitors (ICIs), including anti-PD-1/PD-L1 antibodies, as an indispensable and powerful regimen for the treatment of this lethal disease, the median survival time for patients with stage IV NSCLC is approximately 2 years. In contrast, the response rate to ICIs remains less than 50%, even if the patients are selected using biomarkers such as PD-L1. Pharmaceutical companies have begun to develop additional anti-PD-1/PD-L1 antibodies to overcome resistance and are devising further immunotherapy combinations. More than 20 anti-PD-1/PDL1antibodies have been approved or are currently in development. Numerous combination therapies are under development, and several combination therapies have provided positive results in randomized controlled trials. This review aimed to examine the current status of approved and investigational anti-PD-1/PD-L1antibodies for NSCLC in Japan, the United States, the European Union, and China. Further, this review discusses the challenges and future perspectives for developing new ICIs in alignment with the global developments in Japan. [ABSTRACT FROM AUTHOR]

Despite recent advance in immunotherapy agents, safe new therapies that enhance the effects of immune checkpoint inhibitors are still required to develop. We previously demonstrated that hemagglutinating virus of Japan-envelope (HVJ-E) induced not only direct tumor cell death but also antitumor immunity through the activation of T and natural killer (NK) cells, thereafter, developed a manufacturing process of HVJ-E (GEN0101) for clinical use. We here performed a phase Ia clinical trial of intratumoral GEN0101 administration in six patients with stage IIIC or IV malignant melanoma. The primary aim was to evaluate the safety and tolerability of GEN0101, and the secondary aim was to examine the objective tumor response. Patients were separated into two groups (n = 3 each) and received a low dose of 30,000 and high dose of 60,000 mNAU of GEN0101. All patients completed a two-week follow-up evaluation without severe adverse events. The overall response rate was 33% (2 of 6), with 2 partial responses in the high-dose group and 2 with stable disease, and 2 with progressive disease in the low-dose group. Local complete or partial responses were observed in 11 of 18 (61%) target lesions. One patient demonstrated shrinkage of lung metastases after the treatment. The activity of NK cells and interferon-γ levels were increased in the circulation, indicating augmentation of antitumor immunity by GEN0101. This trial showed not only the safety and tolerability but also the significant antitumor effect of GEN0101, suggesting that GEN0101 might be a promising new drug for patients with advanced melanoma. [ABSTRACT FROM AUTHOR]

• Third COVID-19 vaccine dose (booster) enhances immune response. • Interim phase 2/3 data for booster ≥6 months after the 2nd dose in Japan are shown. • S-268019-b was noninferior to BNT162b2 in inducing neutralizing antibodies. • Sera boosted with either vaccine neutralized Delta and Omicron virus variants. • S-268019-b was safe, and results support its use as a booster in vaccinated adults. In this randomized, observer-blinded, phase 2/3 study, S-268019-b (n = 101), a recombinant spike protein vaccine, was analyzed for noninferiority versus BNT162b2 (n = 103), when given as a booster ≥6 months after 2-dose BNT162b2 regimen in Japanese adults without prior SARS-CoV-2 infection. Interim results showed noninferiority of S-268019-b versus BNT162b2 in co-primary endpoints for neutralizing antibodies on day 29: geometric mean titer (GMT) (124.97 versus 109.70; adjusted-GMT ratio [95% CI], 1.14 [0.94–1.39]; noninferiority P -value, <0.0001) and seroresponse rate (both 100%; noninferiority P -value, 0.0004). Both vaccines elicited anti-spike-protein immunoglobulin G antibodies, and produced T-cell response (n = 29/group) and neutralizing antibodies against Delta and Omicron pseudovirus and live virus variants (n = 24/group) in subgroups. Most participants reported low-grade reactogenicity on days 1–2, the most frequent being fatigue, fever, myalgia, and injection-site pain. No serious adverse events were reported. In conclusion, S-268019-b was safe and showed robust immunogenicity as a booster, supporting its use as COVID-19 booster vaccine. [ABSTRACT FROM AUTHOR]

Background: Ofatumumab, the first fully human anti-CD20 monoclonal antibody, has been developed as a treatment for relapsing multiple sclerosis (RMS) which can be self-administered at home. Objective: To investigate the efficacy and safety of ofatumumab in RMS patients from Japan and Russia. Methods: APOLITOS included a 24-week, double-blind, placebo-controlled core-part followed by an open-label extension-part. Patients were randomized (2:1) to subcutaneous ofatumumab 20 mg or placebo. Primary outcome was the number of gadolinium-enhancing (Gd+) T1 lesions per scan over 24 weeks. Results: Sixty-four patients were randomized (ofatumumab, n = 43; placebo, n = 21). Primary endpoint was met; ofatumumab reduced Gd + T1 lesions versus placebo by 93.6% (p < 0.001) and the results were consistent across regions (Japan/Russia). Ofatumumab reduced annualized T2 lesion and relapse rate versus placebo by week 24. Both groups showed benefit from ofatumumab in the extension-part. Incidence of adverse events was lower with ofatumumab versus placebo (69.8% vs 81.0%); injection-related reactions were most common. No deaths, opportunistic infections, or malignancies were reported. Conclusion: Ofatumumab demonstrated superior efficacy versus placebo, with sustained effect through 48 weeks in RMS patients from Japan/Russia. Switching to ofatumumab after 24 weeks led to rapid radiological and clinical benefits. Safety findings were consistent with pivotal trials. [ABSTRACT FROM AUTHOR]

Our aims were to determine the clinical impact of oral valganciclovir (VGCV) in infants aged ≤2 months with congenital cytomegalovirus (CMV) disease and evaluate the efficacy of VGCV when initiated beyond the neonatal period. The multicenter, single-arm, open-label clinical trial was conducted in Japan. Twenty-five infants aged ≤2 months with congenital CMV disease involving the central nervous system were enrolled and treated with VGCV for 6 months. The primary endpoint was the change in the whole blood CMV load before and after treatment. The secondary endpoint was the change in the auditory brainstem response (ABR) before and after treatment. Changes in ABR were assessed between the younger and older age groups (≤ and >30 days at treatment initiation). Of the 25 patients, one was excluded owing to epilepsy before VGCV administration. The median change in the CMV DNA level in whole blood was −246.0 IU/mL. The best ear and total ear assessments based on ABR were categorized as (improved + unchanged) after treatment for 100% and 93.8%, respectively. No differences in hearing efficacy were observed between the younger and older age groups. Oral VGCV is a potential therapeutic option for treating infants aged ≤2 months with congenital CMV disease. [ABSTRACT FROM AUTHOR]

Introduction: Dental caries is one of the most common chronic childhood diseases, and many decayed teeth remain untreated in underdeveloped and developing countries. This clinical trial aimed to evaluate the remineralization effect of Moringa oleifera-based nano-silver fluoride (NSF) on deciduous dentin caries Materials and Method: This study was a randomized, single-blinded clinical trial. A total of 138 teeth with carious lesions belonging to 83 children were selected and randomly assigned into three groups. Clinical evaluation was performed at 1 and 3 months after intervention. Results: The percentage of arrested caries within the groups were 86%, 42%, and 37% for NSF, MI varnish (GC, Japan), and FluoroDose varnish groups (Centrix Inc, USA), respectively. Results of 1 and 3 months follow-up period were same. Statistically significant difference was found between study groups (P < 0.001). Conclusion: The present study showed that M. oleifera-based NSF could be used for arresting dental caries when applied directly to the carious lesion. [ABSTRACT FROM AUTHOR]

• Domestic COVID-19 vaccines in Japan are needed. • Interim findings from a phase 1/2 trial in Japan are presented. • S-268019-b vaccine is safe, well tolerated, and induces neutralizing antibodies. • Further evaluation of the vaccine in a large clinical trial is warranted. We initiated a randomized, placebo-controlled, phase 1/2 trial to evaluate the safety and immunogenicity of the S-268019-b recombinant protein vaccine, scheduled as 2 intramuscular injections given 21 days apart, in 60 randomized healthy Japanese adults. We evaluated 2 regimens of the S-910823 antigen (5 μg [n = 24] and 10 μg [n = 24]) with an oil-in-water emulsion formulation and compared against placebo (n = 12). Reactogenicity was mild in most participants. No serious adverse events were noted. For both regimens, vaccination resulted in robust IgG and neutralizing antibody production at days 36 and 50 and predominant T-helper 1-mediated immune reaction, as evident through antigen-specific polyfunctional CD4+ T-cell responses with IFN-γ, IL-2, and IL-4 production on spike protein peptides stimulation. Based on the interim analysis, the S-268019-b vaccine is safe, produces neutralizing antibodies titer comparable with that in convalescent serum from COVID-19-recovered patients. However, further evaluation of the vaccine in a large clinical trial is warranted. [ABSTRACT FROM AUTHOR]

Background In the past decade, several successful clinical trials provided new therapeutic agents approved for advanced gastric cancer (AGC). This study evaluated whether these practice-changing results actually altered the clinical practice. Patients and Methods We retrospectively reviewed medical records of treatment-naive AGC patients who received combination chemotherapy of fluoropyrimidine and platinum between 2007 and 2018 and divided them into three groups: Groups A (2007-10), B (2011-14), and C (2015-2018), respectively. We compared the clinicopathological features, treatment details, and clinical outcomes among the three groups. Results In total, 1004 consecutive patients were enrolled (A; n = 254, B; n = 300, and C; n = 450). The number of patients with poor performance status, older age, esophagogastric junction adenocarcinoma, and primary tumor increased during the study period. All groups had similar median overall survival (OS); ~16 months) without any statistical difference but steady prolongation of survival was observed in the adjusted with imbalance prognostic factors among groups (B/A; hazard ratio, HR 0.82, 95% C.I 0.68-0.98, C/A; HR 0.72, 95% CI 0.60-0.86); OS of HER2-positive AGC patients was clearly improved (HER2-positive vs HER2-negative in Group B, HR 0.80, 95% CI 0.60-1.06; Group C, HR 0.68, 95% CI 0.51-0.90) but that of diffuse-type AGC patients remained dismal. Conclusions The increasing availability of chemotherapy options potentially contributed to improved survival of AGC patients, but expanded chemotherapeutic indications made the survival benefit inconspicuous in the whole population. Future therapeutic development for the AGC subset not adequately receiving benefit from previous clinical trials is warranted. [ABSTRACT FROM AUTHOR]

Avacopan, an orally administered C5a receptor antagonist, has been approved for the treatment of microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) in Japan and the USA. In ADVOCATE Phase III clinical trial, patients with active MPA or GPA received either 30 mg avacopan twice daily or prednisone on a tapering schedule in combination with rituximab or cyclophosphamide (followed by azathioprine). The trial met its two primary endpoints: avacopan showed non-inferiority to prednisone for achieving remission at Week 26 (avacopan, 72.3%; prednisone, 70.1%; p< .001 for non-inferiority and p=.24 for superiority) and superiority for maintaining remission at Week 52 (65.7% for avacopan, 54.9% prednisone, p< .001 for non-inferiority and p=.007 for superiority). Of several key secondary endpoints tested, the glucocorticoid toxicity index (GTI)-cumulative worsening score and GTI-aggregate improvement score were significantly lower in the avacopan group than in the prednisone group at both Weeks 26 and 52. Serious adverse events related and unrelated to the worsening vasculitis were reported at 10.2% and 37.3% in the avacopan group and at 14.0% and 39.0% in the prednisone group, respectively. Avacopan has set the stage for the semi-glucocorticoid-free or glucocorticoid-free treatment of MPA and GPA. [ABSTRACT FROM AUTHOR]

Bayesian methods quantify and interpret the therapeutic effects of investigational drugs based on probability statements of the posterior distribution. However, the basic principle underlying the use of Bayesian methods in registration trials for new drug applications in Japan has not been adequately discussed. Motivated by the two drug approval systems for early approval recently enacted in Japan, we present our perspectives on the application of the Bayesian approach in registration trials in Japan. These are based on discussions among academic, industry, and regulatory experts at invited workshops. Based on the aforementioned early approval systems, we discuss putative common regulatory issues related to the use of the Bayesian approach and introduce instances of clinical trials in which the Bayesian approach is expected to be used. This article provides a well‐defined premise for the discussion between industry and regulatory agencies on the use of Bayesian approaches for early drug approval in Japan. [ABSTRACT FROM AUTHOR]

Introduction: Baricitinib, an oral Janus kinase (JAK)1/JAK2 inhibitor, is indicated in the European Union and Japan for treatment of moderate-to-severe atopic dermatitis (AD) in adults who are candidates for systemic therapy. In the ongoing, placebo-controlled, phase 3 trial BREEZE-AD5, once-daily oral baricitinib 2-mg monotherapy improved disease in moderate-to-severe AD patients who had an inadequate response or intolerance to topical corticosteroids. This post-hoc analysis aimed to identify responders to baricitinib 2 mg, using a proposed clinical tailoring approach based on baseline body surface area (BSA) affected and early clinical improvement, in BREEZE-AD5. Methods: Classification and regression tree method was used to evaluate baseline predictors for the proportion of patients achieving ≥ 75% improvement in Eczema Area and Severity Index (EASI75) at week 16 among baricitinib 2-mg-treated patients. Two-by-two contingency tables evaluated the association between early response, defined as ≥ 50% improvement in BSA or ≥ 3-point improvement in Itch Numeric Rating Scale from baseline at weeks 4 or 8, and response at week 16 for the proportion of patients achieving EASI75, validated Investigator Global Assessment for AD (vIGA-AD) score of 0 or 1, or ≥ 4-point improvement in Itch (Itch ≥ 4), respectively. Missing data were imputed as non-responder. Results: At week 16, EASI75 and vIGA-AD (0,1) were achieved by 37.5% and 31.7% of baricitinib 2-mg-treated patients with baseline BSA 10–50% compared with 9.5% and 4.8% with BSA > 50%. Early response in skin inflammation or itch at week 4 was associated with corresponding EASI75, vIGA-AD (0,1), and Itch ≥ 4 of 55.4%, 48.2%, and 39.3% at week 16, while early response at week 8 was associated with 66.7%, 56.1%, and 42.1% of patients achieving these endpoints. Conclusion: Baseline BSA of 10–50% and early clinical improvement after 4 or 8 weeks of baricitinib 2-mg treatment may identify patients most likely to benefit from long-term baricitinib 2-mg therapy. Clinical Trial Registration: NCT03435081. Plain Language Summary: Baricitinib is a medication that helps a dysregulated immune system readjust. This leads to improvements in the inflammatory disease atopic dermatitis (AD). Baricitinib is approved for adults with moderate-to-severe AD in over 40 countries. In the ongoing study BREEZE-AD5, baricitinib 2 mg improved moderate-to-severe AD in patients who previously did not respond to or could not tolerate topical corticosteroids. Understanding which patients are likely to benefit most from a medication can improve patient experience with treatment. It can also ensure that only patients who are likely to benefit from a medication are exposed to it. This analysis aimed to identify patients who are most likely to benefit from baricitinib 2 mg in BREEZE-AD5, using an approach based on baseline body surface area (BSA) affected and early clinical improvement. We showed that patients with moderate-to-severe AD affecting between 10% and 50% of their BSA account for the majority of patients who respond to baricitinib 2 mg after 16 weeks of treatment. Clinical assessment of skin inflammation or itch in patients after 4–8 weeks of initiation of baricitinib 2-mg treatment further improved the ability to identify patients who are most likely to benefit from long-term therapy. This proposed clinical tailoring approach of baseline BSA of 10–50% and early clinical improvement after 4 or 8 weeks of baricitinib 2-mg treatment may allow for the treatment of patients who are most likely to respond to therapy, and rapid decision on discontinuation of treatment for those who are not likely to benefit from baricitinib 2 mg. [ABSTRACT FROM AUTHOR]

Introduction: Comprehensive genome profiling (CGP) has revolutionized healthcare by offering personalized medicine opportunities. However, its real-world utility and impact remain incompletely understood. This study examined the extent to which CGP leads to genomically matched therapy and its effectiveness., Methods: We analyzed data from advanced solid tumor patients who underwent CGP panel between December 2019 and May 2023 at the Osaka International Cancer Institute. Patient demographics, specimen details, and expert panel assessments were collected. Turnaround time (TAT) and genomically matched therapy outcomes were analyzed. Gene alterations and their co-occurrence patterns were also assessed., Results: Among 1437 patients, 1096 results were available for analysis. The median TAT was 63 [28-182] days. There were 667 (60.9%) cases wherein recommended clinical trials were presented and there were 12 (1.1%) cases that could be enrolled in the trial and 25 (2.3%) cases that could lead to therapies under insurance reimbursement. The median progression free survival of the trial treatment was 1.58 months (95% CI: 0.66-4.37) in clinical trials and 3.66 months (95% CI: 2.14-7.13) in treatment under insurance. Pathologic germline variants were confirmed in 15 patients (1.3%). Co-alteration of CDKN2A, CDKN2B, and MTAP was significantly observed in overall population., Conclusion: The effectiveness of the genomically matched therapy based on the CGP panel was unsatisfactory. Expansion of clinical trials and utilization of remote clinical trials are required to ensure that the results of the CGP panel can be fully returned to patients., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Evidence regarding chemosensitivity to different therapeutic regimens in epithelial ovarian cancer (EOC) remains limited. This study aimed to investigate EOC implementation in daily clinical practice and reveal favorable regimens for EOC among Japanese patients., Methods: We retrospectively collected clinical data of patients newly diagnosed with EOC from 2012 to 2021 at our affiliated institutions. We evaluated overall survival (OS) and progression-free survival (PFS) of conventional paclitaxel plus carboplatin (TC) vs. dose-dense TC (ddTC) according to the eligibility of GOG262 and JGOG3016 and those with bevacizumab (BEV) vs. without BEV based on GOG218. Further, we evaluated OS and PFS of ddTC and ddTC + BEV to TC + BEV among patients with stage III/IV., Results: The ddTC group (n = 402) demonstrated longer PFS and OS than the TC group (n = 165) (adjusted hazard ratios [aHRs] [95% confidential intervals (CIs)]: 0.69 [0.55-0.88] and 0.67 [0.50-0.90], respectively). The group with BEV (n = 158) demonstrated a longer PFS than those without BEV (n = 296) (0.74 [0.57-0.95]), but not for OS (0.84 [0.60-1.17]). The ddTC and ddTC + BEV groups (n = 259 and 117) demonstrated no statistically significant differences in PFS and OS than the TC + BEV group (n = 75) (1.09 [0.79-1.50] and 0.74 [0.52-1.08] for PFS and 0.89 [0.59-1.34] and 0.73 [0.50-1.05] for OS, respectively)., Conclusion: Our study may indicate ddTC, BEV, and their combination regimen as the promising first-line chemotherapy option among Japanese patients with advanced EOC., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Background: The Foods with Function Claim was introduced in Japan in April 2015 to make more products available that are labeled with health functions. A product's functionality of function claims must be explained by the scientific evidence presented in clinical trials (CTs) or systematic reviews, but the quality of recent CTs is unclear. The purpose of this study was to evaluate the risk of bias (RoB) using "a revised tool to assess risk (RoB 2)" published in 2018 for notifications based on all recent CTs published on the Consumer Affairs Agency website., Methods: A total of 38 submitted papers based on CTs that were published on the Consumer Affairs Agency website during the period from 1 January 2023 to 30 June 2024 were eligible. The RoB 2 tool provides a framework for considering the risk of bias in the findings of any type of randomized trial. This tool with five domains was used to evaluate the quality of research methods., Results: Eligible CTs were assessed as "low risk" (11%, n = 4), "medium risk" (13%, n = 5), and "high risk" (76%, n = 29). A number of highly biased papers were published. Bias occurred in all five domains, especially "bias in selection of the reported result (Domain 5)", which was the most serious ("high risk"; 75%). For elements correlated with RoB, there was no significant difference ( p = 0.785) in the RoB 2 score between for-profit and academic research in the author's affiliated organization. There was no significant difference ( p = 0.498) in the RoB score between the published year categories of 2000-2019 and 2020-2024, and no significant difference ( p = 0.643) in the RoB score between English and Japanese language publications., Conclusion: Overall, the quality of the latest CTs submitted after 2023 was very low, occurring in all five domains, and was most serious for "bias in selection of the reported result (Domain 5)".

Breast cancer is the most common type of cancer among women worldwide and in Japan. The majority of breast cancers are hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2‒), and endocrine therapy is an effective therapy for this type of breast cancer. However, recent substantial advances have been made in the management of HR+/HER2‒ advanced breast cancer (ABC) with the advent of targeted therapies, such as cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, resulting in significant improvements in survival outcomes versus endocrine therapy alone. To evaluate the optimal use of palbociclib, a CDK4/6 inhibitor, in HR+/HER2– ABC, this review summarizes clinical trial and real-world data for palbociclib. In addition, current biomarker studies in palbociclib clinical research are reviewed. In Japanese patients, palbociclib was shown to be effective with a manageable safety profile, although differences were observed in the frequency of adverse event and dosing parameters. Current evidence supporting palbociclib as a first-line treatment strategy for patients with HR+/HER2‒ ABC in Asia, and specifically japan, is also discussed. [ABSTRACT FROM AUTHOR]

What is known and objective: Drug development is generally a long and expensive process. Regulatory authorities have established several expedited regulatory pathways, such as accelerated approval designation in the United States (1992) and conditional approval regulation in Japan (2017). In Japan, prior to 2017, the Pharmaceutical and Medical Device Agency (PMDA) granted marketing approval without requesting the results of confirmatory clinical trials case by case basis, and even after 2018, only three drugs have been approved via the conditional approval pathway, although many drugs without confirmatory clinical trials have been approved without this pathway; therefore, it is difficult to predict the circumstances under which confirmatory clinical trials may be waived. The aim of this study was to investigate the characteristics of drugs for which the requirement of confirmatory clinical trials for approval was waived in Japan. We also aimed to identify factors and formulae to predict a waiver of confirmatory clinical trials. Methods: Data on approved drugs and their characteristics were mainly extracted from the Japan Pharmaceuticals and Medical Device Agency database. The seriousness of the disease, existence of available treatments and number of patients were considered as candidate factors. The influence of each factor on receiving a waiver was determined using logistic regression analysis comparing drugs approved with and without confirmatory clinical trials as the binary response variable. The predictive formula was derived from the results of the logistic regression analysis. A receiver operating characteristic curve was used to evaluate the accuracy of the prediction. Results and discussion: Categorization of drugs as antineoplastic agents, use of the cost accounting method in the drug pricing system, "orphan" designation and accelerated approval designation in the United States emerged as significant factors in the logistic regression analysis, predicting a waiver for confirmatory clinical trials (p ≤ 0.05). These factors were then used to establish a predictive model to ascertain whether confirmatory clinical trials would be necessary for a new drug, exhibiting good sensitivity (0.8) and specificity (0.8) and high accuracy for newly approved drugs. What is new and conclusion: The identification of key factors that can predict waivers of confirmatory clinical trials may accelerate the development of clinically important drugs and improve patient access globally. This study investigated the characteristics of drugs that confirmatory clinical trials were waived for approval in Japan, and identified key factors and formulae to predict the waiver of confirmatory clinical trials. [ABSTRACT FROM AUTHOR]

Aims: In this study, the effects of licorice flavonoid oil (LFO) supplementation on mobility functions were evaluated in middle-aged and older women who underwent daily physical exercise. Methods: The 73 women aged 59–85 years (71.2 ± 5.2 years) were randomly assigned to the LFO group (n = 37) or the placebo group (n = 36). For 16 weeks, the LFO group consumed a daily capsule containing 300 mg of LFO, while the placebo group consumed a placebo capsule. All participants were instructed to complete a strength training program during the 16 weeks and to increase their daily step count by 1000. 10-m walking speed (with/no obstruction), one-leg standing time with eyes open, handgrip strength, isometric knee extension strength, and body composition were evaluated at baseline and every eight weeks. Results: In the 10-m walking speeds (with/no obstruction), LFO supplementation did not show significant improvements. One-leg standing time was significantly prolonged with LFO intake (LFO: baseline 73.9 s vs 16 weeks 93.5, placebo: baseline 82.8 vs 16 weeks 87.1, p = 0.03). In addition, a significant decrease in BMI and body fat percentage with LFO was found (p = 0.01, p = 0.03, respectively). Discussion: Since a lower BMI corresponds to a lighter physical load on the lower limb, in addition, since LFO might improve skeletal muscle function by antioxidant activity, participants could stand longer and body balance control was improved. Conclusion: LFO supplementation improved body balance control and may contribute to fall prevention in healthy middle-aged and older women having daily physical exercise. Trial Registration: UMIN Clinical Trial Registry No. 000029712. [ABSTRACT FROM AUTHOR]

The standard of care for advanced non-small cell lung cancer (NSCLC) without known driver oncogenes is immune checkpoint inhibitor (ICI) therapy combined with platinum-based chemotherapy. About 20% of patients with advanced NSCLC have brain metastases, which are related to poor prognosis. However, the effect of ICI therapy combined with platinum-based chemotherapy on untreated brain metastases derived from NSCLC remains unclear. The primary endpoint of this study is intracranial response rate as determined by modified Response Evaluation Criteria in Solid Tumors (RECIST) for brain metastases of ≥ 5 mm as target lesions. Eligible patients are 20 years of age or older with chemotherapy-naïve advanced NSCLC and at least one brain metastasis ≥ 5 mm in size that has not been previously treated. Patients receive nivolumab plus ipilimumab intravenously combined with histology-based platinum doublet chemotherapy (two cycles). Individuals with known genetic driver alterations such as those affecting EGFR or ALK are excluded. Planned enrollment is 30 patients over 2.5 years at 27 oncology facilities in Japan. This is the first prospective study to focus on the intracranial response to ICI therapy combined with platinum-based chemotherapy in patients with untreated brain metastases derived from NSCLC. If the study demonstrates intracranial efficacy for this patient population, then this regimen has the potential to become a new treatment option for such individuals. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to evaluate the efficacy of lurasidone in acute schizophrenia in Japan and other countries. Methods: Subjects (aged 18–74 years) diagnosed with schizophrenia were randomized to lurasidone 40 mg/day or placebo. The primary efficacy endpoint was change from baseline on the Positive and Negative Syndrome Scale (PANSS) total score at Week 6. Secondary efficacy assessments included the Clinical Global Impression‐Severity Scale (CGI‐S). Safety endpoints included adverse events, and laboratory and electrocardiogram parameters. Results: A total of 483 subjects were randomized to lurasidone or placebo; 107 subjects were from Japan. Mean changes from baseline at Week 6 endpoint in PANSS total scores were −19.3 in the lurasidone group and −12.7 in the placebo group (treatment difference: P < 0.001, effect size = 0.41). Changes from baseline for Week 6 CGI‐S scores were −1.0 for lurasidone and −0.7 for placebo (treatment difference: P < 0.001, effect size = 0.41). All‐cause discontinuation during the 6‐week, double‐blind period was 19.4% for lurasidone and 25.4% for placebo, and discontinuation rates due to adverse event were 5.7% for lurasidone and 6.4% for placebo. The following common treatment‐emergent adverse events occurred in more than 2% on lurasidone and at a rate at least twice that of the placebo group: akathisia (4.0%), dizziness (2.8%), somnolence (2.8%), abdominal discomfort (2.0%) and asthenia (2.0%). No significant changes in bodyweight or metabolic parameters were observed. Conclusion: Lurasidone 40 mg once daily dosing demonstrated efficacy in a patient population with acute schizophrenia, including subjects from Japan, and was generally safe and well‐tolerated. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the effects of an intensified multifactorial intervention and patient characteristics on the incidence of fractures comorbid with type 2 diabetes.Methods: Fracture events were identified and analyzed among adverse events reported in the J-DOIT3 study, a multicenter, open-label, randomized, parallel-group trial that was conducted in Japan, in which patients with type 2 diabetes were randomly assigned to receive conventional therapy for glucose, blood pressure, and lipids (targets: HbA1c < 6.9%, blood pressure <130/80 mm Hg, LDL-cholesterol <120mg/dL) or intensive therapy (HbA1c < 6.2%, blood pressure <120/75 mm Hg, LDL-cholesterol <80mg/dL) (ClinicalTrials.gov registration no. NCT00300976).Results: The cumulative incidence of fractures did not differ between those receiving conventional therapy and those receiving intensive therapy (hazard ratio (HR) 1.15; 95% CI, 0.91-1.47; P = 0.241). Among the potential risk factors, only history of smoking at baseline was significantly associated with the incidence of fractures in men (HR 1.96; 95% CI, 1.04-3.07; P = 0.038). In contrast, the incidence of fractures in women was associated with the FRAX score [%/10 years] at baseline (HR 1.04; 95% CI, 1.02-1.07; P < 0.001) and administration of pioglitazone at 1 year after randomization (HR 1.59; 95% CI, 1.06-2.38; P = 0.025).Conclusions: Intensified multifactorial intervention may be implemented without increasing the fracture risk in patients with type 2 diabetes. The fracture risk is elevated in those with a history of smoking in men, whereas it is predicted by the FRAX score and is independently elevated with administration of pioglitazone in women. [ABSTRACT FROM AUTHOR]

Telisotuzumab vedotin (formerly ABBV‐399) is an antibody‐drug conjugate targeting c‐Met–overexpressing tumor cells, irrespective of MET gene amplification status. Safety, pharmacokinetics, and preliminary efficacy of telisotuzumab vedotin were evaluated outside of Japan. This phase 1 open‐label study evaluated the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of telisotuzumab vedotin in Japanese patients with advanced solid tumors. Telisotuzumab vedotin was administered intravenously at either 2.4 mg/kg (n = 3) or 2.7 mg/kg (n = 6) every 3 weeks, following a 3 + 3 design. Maximum tolerated dose was not reached on the basis of the study design; no dose‐limiting toxicity events were observed. The most common treatment‐emergent adverse events related to telisotuzumab vedotin were peripheral sensory neuropathy (44%), and nausea, decreased appetite, and decreased white blood cell count (33% each). Most frequent grade ≥3 treatment‐emergent adverse events, irrespective of relationship to telisotuzumab vedotin, were decreased neutrophil count and hypoalbuminemia, reported in two patients (22%) each. Systemic exposure of telisotuzumab vedotin at both dose levels was approximately dose proportional. Pharmacokinetic profile in Japanese patients was similar to that previously reported in non‐Japanese patients. Two (22%) patients achieved a partial response, six (67%) had stable disease, one (11%) had progressive disease. Overall disease control rate was 89% (eight of nine patients; 95% confidence interval: 51.8%–99.7%]). Median progression‐free survival was 7.1 months (95% confidence interval: 1.2–10.4). In conclusion, telisotuzumab vedotin demonstrated a manageable safety profile, with antitumor activity in Japanese patients with advanced solid tumors; the recommended phase 2 dose was confirmed as 2.7 mg/kg every 3 weeks. ClinicalTrials.gov registration number: NCT03311477. [ABSTRACT FROM AUTHOR]

Objectives: To compare the radiographic and clinical effects of 25 versus 10 mg twice-weekly (BIW) etanercept over 52 weeks in Japanese patients with active rheumatoid arthritis (RA). Methods: This was a post-hoc analysis of a Phase 3 study where Japanese patients with active RA were randomized to receive BIW etanercept 25 mg (n = 182), etanercept 10 mg (n = 192), or methotrexate (n = 176) for 52 weeks (NCT00445770). This analysis included assessments of week-24 and week-52 disease activity, week-52 radiographic progression, and the relationship between baseline characteristics and week 52 clinical outcomes with clinically relevant radiographic progression (CRRP) at week 52. Results: At week 52, there were no significant differences between 25 and 10 mg etanercept in terms of achieving low disease activity or remission. CRRP was observed in 36% and 32% of patients in the 10 and 25 mg groups, respectively. Predictor analysis suggested that worse background disease status, treatment with methotrexate rather than etanercept, and poorer clinical outcomes at week 52 were associated with CRRP. Conclusions: The 25 mg BIW etanercept dosage does not appear to be significantly more efficacious than 10 mg in Japanese patients with RA. Further studies evaluating the optimal etanercept dosing regimen in this patient population may be merited. [ABSTRACT FROM AUTHOR]

Introduction: In the randomized Peptide InnOvatioN for Early diabEtes tReatment (PIONEER) 10 trial, once-daily orally administered semaglutide—the first oral glucagon-like peptide 1 receptor agonist (GLP-1RA)—was similarly tolerated with comparable (at 7 mg) or better (at 14 mg) efficacy versus the injectable GLP-1RA dulaglutide 0.75 mg. Health-related quality of life (HRQoL) in PIONEER 10 was assessed using the Japanese-specific Diabetes Therapy-Related Quality of Life (DTR-QoL) questionnaire. Methods: The DTR-QoL comprises 29 questions, providing four domain and total scores. Answers were converted to a score between 0 and 100, with higher scores indicating greater HRQoL. Two estimands were prespecified: treatment policy (regardless of treatment discontinuation or rescue medication use) and trial product (assuming on treatment without rescue medication) in all randomized patients. Outcomes were assessed at weeks 26 and 52. Results: Mean baseline DTR-QoL domain scores were similar between treatment arms and were generally lower (giving more scope for improvement) for "anxiety and dissatisfaction with treatment" (62.1–65.3) and "satisfaction with treatment" (53.9–57.9) than "burden on social activities and daily activities" (76.5–77.7) and "hypoglycemia" (83.5–88.2). Using the treatment policy estimand, orally administered semaglutide 7 and 14 mg improved HRQoL versus dulaglutide 0.75 mg for the total score (estimated mean change from baseline [CfB] 7.3 and 8.1 vs 3.3; estimated treatment difference [ETD] 3.9 and 4.8) and the "anxiety and dissatisfaction with treatment" domain (CfB 9.7 and 10.9 vs 3.7; ETD 6.0 and 7.2) at week 52. Orally administered semaglutide 14 mg improved the "satisfaction with treatment" domain versus dulaglutide 0.75 mg (CFB 13.8 vs 5.7; ETD 8.1). DTR-QoL scores for orally administered semaglutide tended to be more durable (sustained over time) than for dulaglutide. Outcomes for the trial product estimand were similar. Conclusion: Orally administered semaglutide 7 and 14 mg improved the patients' HRQoL measured by the Japanese-specific DTR-QoL instrument versus dulaglutide 0.75 mg at week 52. Trial registration: ClinicalTrials.gov NCT03015220. [ABSTRACT FROM AUTHOR]