Clinical Trials In Japan Research Articles

Advanced Nanotechnology-Based Nucleic Acid Medicines

Nucleic acid medicines are a highly attractive modality that act in a sequence-specific manner on target molecules. To date, 21 such products have been approved by the Food and Drug Administration. However, the development of nucleic acid medicines continues to face various challenges, including tissue and cell targeting as well as intracellular delivery. Numerous research groups are addressing these issues by advancing the development of nucleic acid medicines through nanotechnology. In countries other than Japan (including Europe and the USA), >40 nanotechnology-based nucleic acid medicines have been tested in clinical trials, and 15 clinical trials are ongoing. In Japan, three phase I trials are ongoing, and future results are awaited. The review summarizes the latest research in the nanotechnology of nucleic acid medicines and statuses of clinical trials in Japan, with expectations of further evolutions.

Case report of QT interval prolongation induced by anamorelin in an obese patient with non-small cell lung cancer

BackgroundAnamorelin, a drug to treat cancer cachexia, binds to ghrelin receptors and improves body weight and appetite. In clinical trials in Japan, patients experienced a 10.7% frequency of stimulant conduction system depression as a severe side effect. Although rare, anamorelin sometimes causes fatal arrhythmias. Because patients with cancer cachexia are often underweight, data on the safety of anamorelin in obese patients are lacking. We report a case of QT interval prolongation after anamorelin administration to an obese patient with non-small cell lung cancer.Case presentationA female patient with a body mass index of 30 kg/m2 underwent immunotherapy for lung adenocarcinoma. She presented with severe weight loss, anorexia, and fatigue. She had no history of heart disease. On day 12, after administration of anamorelin 100 mg once daily, the patient developed nausea, diarrhea, and anorexia, which were considered cancer immunotherapy-induced immune-related adverse events, and she was admitted to the hospital. An electrocardiogram (ECG) on admission showed a QTc interval of 502 ms. On admission, her hepatic function was Child–Pugh class B, and anamorelin was discontinued the next day. On day 3 after anamorelin discontinuation, the QTc interval was prolonged by up to 557 ms, then decreased to 490 ms on day 6, and improved to 450 ms on day 16. Re-administration of anamorelin was avoided.ConclusionsWhen administering anamorelin to obese patients, we should be aware of the potential for stimulatory conduction system depression, as in underweight patients. Therefore, we should monitor patients by ECG from the early stages of anamorelin administration. Anamorelin is lipophilic, and its volume of distribution is increased in obese patients. Consequently, obese patients may continue to have QT interval prolongation after discontinuation of anamorelin, requiring long-term side-effect monitoring.

Risk Factors for Thromboembolic Events in Patients With Dialysis-Dependent CKD: Pooled Analysis of Phase3 Roxadustat Trials in Japan.

Thromboembolic events have occurred in clinical trials of roxadustat. This post hoc analysis explored potential factors related to thromboembolic events in dialysis-dependent patients treated with roxadustat in four phase3 clinical trials in Japan. Thromboembolic events with onset before and after week12 were evaluated. Baseline risk factors for thromboembolic events were investigated by Cox regression analyses. Nested case-control analyses using conditional logistic models with matched pairs of case-control data explored relationships between thromboembolic events and laboratory parameters. Of the 444 patients, 56 thromboembolic events were observed in 44 patients during ≤ 52weeks of treatment. The proportion of venous and arterial thromboembolic events gradually increased after week12. Baseline risk factors included hemodialysis (vs peritoneal dialysis), advanced age (≥ 65years), shorter dialysis vintage (< 4 months), and history of thromboembolism. The absence of concomitant intravenous or oral iron therapy (including ferric citrate) was associated with thromboembolic events before week12 (hazard ratio 11.25; 95% confidence interval [CI] 3.36-37.71; vs presence). Case-control analysis revealed that low average transferrin saturation (< 10%; unadjusted odds ratio [OR] 6.25; 95%CI 1.52-25.62; vs ≥ 20%), high average transferrin level (≥ 2.5 g/L; unadjusted OR 4.36; 95%CI 1.23-15.39; vs < 2.0 g/L), and high average roxadustat dose (≥ 150mg; unadjusted OR 5.95; 95%CI 1.07-33.16; vs < 50mg) over the previous 8weeks before the event onset were associated with thromboembolic events after week12. However, adjustment for iron status extinguished the significant relationship between roxadustat dose and events. Multivariate case-control analysis showed that increased transferrin from baseline (≥ 1.0 g/L; adjusted OR 7.85; 95%CI 1.82-33.90; vs < 0.5 g/dL) and decreased mean corpuscular volume (< - 2fL; adjusted OR 5.55; 95%CI 1.73-17.83; vs ≥ 0fL) were associated with increased risk of thromboembolic events. In addition to established risk factors, iron deficiency may be related to thromboembolic events. Graphical Abstract available for this article. NCT02780726, NCT02952092, NCT02780141, NCT02779764.

Comparison of the Quality of Phase Ⅲ Non-commercial Clinical Trials in Japan, the United States, and the United Kingdom before the Implementation of the New Japanese Clinical Trials Act

Recent research misconduct, represented by the valsartan scandal, has raised questions about the quality of non-commercial trials not for regulatory approval in Japan. Unlike in the US and Europe, non-commercial clinical trials are not regulated by law in Japan, which was believed to be a reason why quality could not be guaranteed. However, until now, few studies have compared the quality of clinical studies among countries. In this study, the quality of Japanese non-commercial phase Ⅲ trials before the implementation of the Clinical Trials Act (CTA) in 2018 was compared with Western non-commercial trials registered in the database using study design as quality indicators. The study found a lower proportion of randomized, controlled trials (RCTs) (70％ in Japan, 89％ in the US, and 88％ in the UK) and fewer blinded designs (46％ in Japan, 59％ in the US, and 52％ in the UK) in non-commercial trials in Japan. Single-arm trials not for either cancer or rare diseases, which are usually considered low quality because of a lack of fair comparison, were more common in Japan (82％) than in the US (76％) and the UK (50％). In terms of endpoint setting, most non-commercial trials in Japan had surrogate endpoints, with only a few trials using true endpoints (5％) compared to the US (24％) and the UK (40％). A comparison of these quality indicators in Japanese non-commercial trials before and after the CTA implementation showed no increases in the proportion of RCT and blinded designs, but an increase in the proportion of trials using true endpoints and appropriate use of single-arm design. In conclusion, the lack of legal regulation in Japan may have indirectly affected the quality of non-commercial phase Ⅲ trials in Japan at the time. Implementation of the CTA has contributed to some quality improvements, but the effect is limited at present.

Correlation of Anticancer Drug Prices with Outcomes of Overall Survival and Progression-Free Survival in Clinical Trials in Japan.

Drug pricing methods vary extensively across countries. Japan calculates drug prices using cost accounting and based on the efficacy of similar drugs. This study investigated the relationship between drug prices and their clinical efficacy and usefulness using public information on anticancer drugs reimbursed by the National Health Insurance price listing between January 2009 and March 2020. We investigated drug characteristics, prices, and clinical benefits based on overall survival (OS) and progression-free survival (PFS). Eighty anticancer drugs were approved in Japan during the study period. The largest number (28 drugs, 35.0%) was approved based on PFS, 18 (22.5%) were approved based on OS, and 13 (16.3%) based on the response rate. The mean (±SD) drug price was JPY 88,416.2 (±148,974.7), while the median drug price (with quartiles) was JPY 21,694 (JPY 4855.0-JPY 93,396.8). Drug prices were significantly higher for PFS than for OS, while cost index-the drug price to extend PFS or OS by one day-did not differ significantly between PFS and OS. The relationship between the 46 drugs approved based on OS or PFS and their prices was examined. A correlation was found between drug prices and their clinical usefulness in terms of OS but not PFS.

Japanese Pharmaceutical Regulations of Engineered Viral Vectors for Medical Use Compared With Those in the United States and the European Union.

Japanese Pharmaceutical Regulations of Engineered Viral Vectors for Medical Use Compared With Those in the United States and the European Union.

Association of change in health-related quality of life and treatment discontinuation in metastatic breast cancer: a post hoc, exploratory analysis of two randomized clinical trials.

PurposeIdentifying factors associated with treatment alteration (treatment discontinuation and dose reduction) may help to attain the treatment goals for metastatic breast cancer. The value of changes in the quality of life (QOL) in predicting treatment alteration remained unclear. This study aimed to examine the relationship between changes in the QOL and treatment alteration of first-line chemotherapy for metastatic breast cancer.MethodsWe merged data from two randomized clinical trials in Japan, conducted from 2006 to 2017, that included patients who were diagnosed with human epidermal growth factor receptor 2-negative and endocrine treatment-resistant breast cancer, with metastatic disease at presentation or recurrence after surgery. The European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 was used to assess QOL. The association between change in time-dependent QOL (worsening by 10-point or not) and time to treatment alteration was assessed using the Cox regression models controlling for patient characteristics (age, liver metastasis, hormone status, and treatment regimen) and baseline QOL.ResultsWorsening physical functioning, global health status, and dyspnea were significantly associated with treatment discontinuation. Worsening role functioning, global health status, and fatigue were significantly associated with dose reduction. The threshold for defining worsening did not have a significant impact on the relationship.ConclusionChanges in QOL are associated with the probability of treatment alteration among metastatic breast cancer patients. Physical functioning, role functioning, global health status, dyspnea, and fatigue should be prioritized for symptom management in patients with metastatic breast cancer.Supplementary informationThe online version contains supplementary material available at 10.1007/s00520-022-07283-0.

APJS-3 Current status and future perspectives of ATLAS project

Most of the international clinical trials in Japan have been sponsored by pharmaceutical companies. There are only a few academic international trials, and if any, most were led by Western countries. Since 2018, National Cancer Center Hospital (NCCH) has been conducting Japan-led investigator-initiated clinical trials aimed at obtaining regulatory approval for off-label drugs with the participation of South Korea, Taiwan, and Singapore (PATHWAY trial). Since 2020, we have launched the ATLAS project with a support from AMED to provide infrastructure and capacity building programs and education and to conduct international clinical trials involving not only the existing collaborators but also some ASEAN countries, Thailand, Malaysia, Vietnam, Philippines, and Indonesia.

Long term efficacy and safety of pabinafusp-alfa (JR-141) in Hunter syndrome (MPS-II): 104-week data from the clinical trials in Japan and Brazil

Long term efficacy and safety of pabinafusp-alfa (JR-141) in Hunter syndrome (MPS-II): 104-week data from the clinical trials in Japan and Brazil

Effects of rasagiline on Parkinson's Disease Questionnaire (PDQ-39) emotional well-being domain in patients with Parkinson's disease: A post-hoc analysis of clinical trials in Japan.

BackgroundIdentifying the factors that influence health-related quality of life (HRQoL) is of great scientific interest, but a potential causal relationship between treatment and HRQoL has yet to be fully elucidated. Japanese patients reported better HRQoL outcomes on the Parkinson’s Disease Questionnaire (PDQ-39) emotional well-being domain, a 6-question subset of the PDQ-39 which is considered to reflect the emotional aspects of the disease-specific HRQoL, when treated with rasagiline, than placebo, in both a monotherapy clinical trial (NCT02337725) and an adjunctive therapy clinical trial in patients with wearing-off phenomena (NCT02337738).ObjectiveTo investigate how rasagiline exerts its effect on the PDQ-39 emotional well-being domain in Japanese patients with Parkinson’s disease.MethodsA path analysis was performed to assess the direct treatment effects of rasagiline on the PDQ-39 emotional well-being domain and the effects mediated indirectly through the influence on items related to motor symptoms by a post-hoc analysis of two clinical trials in Japan.ResultsIn the monotherapy trial, the PDQ-39 emotional well-being domain was mainly affected indirectly through items related to motor symptoms (80.7%) composed of the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part II (67.2%) and Part III (13.5%). In the adjunctive therapy trial, the PDQ-39 emotional well-being domain was also mainly influenced indirectly through effects on items related to motor symptoms (1 mg/day: 54.7%, 0.5 mg/day: 57.6%) composed of MDS-UPDRS Part II (1 mg/day: 35.6%, 0.5 mg/day: 40.9%), Part III (1 mg/day: 8.0%, 0.5 mg/day: 8.3%) and mean daily OFF-time (1 mg/day: 11.1%, 0.5 mg/day: 8.4%).ConclusionsThe effects of rasagiline on the PDQ-39 emotional well-being domain were mediated primarily by influence on the subjective aspects of motor experiences of daily living.

Towards Realization of Decentralized Clinical Trials in Japan ―From Perspective of Pharmaceutical Industries―

Towards Realization of Decentralized Clinical Trials in Japan ―From Perspective of Pharmaceutical Industries―

Scientific misconduct in sponsored clinical trials in Japan: published cases are the “tip of the iceberg”

Scientific misconduct in sponsored clinical trials in Japan: published cases are the “tip of the iceberg”

Zonisamide improves wearing off in Parkinson's disease without exacerbating dyskinesia: Post hoc analysis of phase 2 and phase 3 clinical trials

IntroductionAlthough phase 2 and 3 clinical trials in Japan showed that zonisamide improved wearing off in patients with Parkinson's disease (PD), no studies to date have evaluated whether zonisamide improves wearing off in patients with PD without exacerbating dyskinesia. Therefore, we examined this hypothesis in a post hoc analysis of pooled data from the previous phase 2 and 3 trials. MethodsBoth trials evaluated zonisamide 25 mg and 50 mg versus placebo during a 12-week treatment period. In our analysis, primary efficacy variables were adjusted mean change in wearing off (evaluated as change in “off” time) and dyskinesia from baseline to 12 weeks. Dyskinesia was evaluated using Unified Parkinson's Disease Rating Scale (UPDRS) part 4 items 32 (4-32; duration of dyskinesia) and 33 (4-33; disability of dyskinesia) score. Criteria outcomes included rates of patients meeting specific criteria based on off time plus UPDRS part 4-32 or 4-33. ResultsA total of 212 patients were included in this analysis. Zonisamide 50 mg significantly reduced off time and UPDRS part 4-33 score at week 12 versus placebo without increasing UPDRS part 4-32 score. The proportion of patients receiving zonisamide 50 mg who met the criterion “Off time decreased and UPDRS part 4-33 score did not increase” was significantly higher than that of patients receiving placebo. ConclusionZonisamide improves wearing off without exacerbating dyskinesia in Japanese patients with PD. Moreover, zonisamide 50 mg may improve dyskinesia. Further studies are needed to prospectively determine the benefits and clinical relevance of zonisamide on dyskinesia.

Medical Affairs in Pharmaceutical Companies and Related Pharmaceutical Regulations in Japan.

Medical affairs has received a lot of attention in recent years in Japan, but it is also often misunderstood or poorly understood in the healthcare industry in Japan. In the United States, the function of medical affairs has been established for a long time, whereas its history in Japan is relatively short. Many scandals in clinical trials occurred with inappropriate relationship between medical doctors and the sales departments of pharmaceutical companies from 2012. These incidents undermined confidence in clinical trials in Japan and triggered the enforced separation of sales departments from the conduct of post-marketing clinical trials and evidence generation. There have been growing compliance issues identified in marketing and sales practices, and off-label promotion is also becoming an issue in Japan. These issues resulted in the establishment of independent medical affairs departments from sales departments in pharmaceutical companies operating in Japan. Due to the short history of medical affairs in Japan, the roles and responsibilities vary between companies in Japan. Medical affairs departments aim to fulfill unmet medical needs through the generation of scientific evidence and to deliver scientific value to key stakeholders and patients. People working in medical affairs need to engage in scientific exchange activities with key opinion leaders independent of sales departments. Through these activities, medical affairs ensures that patients receive optimal medical care. Medical affairs in Japan is still developing, and its roles, responsibilities, and functions are improving. This article covers the history of medical affairs in Japan and the current status and future perspectives of medical affairs in Japan.

Efficacy and Cost-effectiveness of Promotion Methods to Recruit Participants to an Online Screening Registry for Alzheimer Disease Prevention Trials: Observational Study.

BackgroundWeb-based screening may be suitable for identifying individuals with presymptomatic latent diseases for recruitment to clinical studies, as such people do not often visit hospitals in the presymptomatic stage. The promotion of such online screening studies is critical to their success, although it remains uncertain how the effectiveness of such promotion can differ, depending on the different promotion methods, domains of interest, or countries of implementation.ObjectiveThe Japanese Trial-Ready Cohort (J-TRC) web study is our ongoing online screening registry to identify individuals with presymptomatic Alzheimer disease (AD), aimed at facilitating the clinical trials for AD prevention. Within the first 9 months of its 2019 launch, the J-TRC web study recruited thousands of online participants via multiple methods of promotion, including press releases, newspaper advertisements, web advertisements, or direct email invitations. Here, we aimed to quantitatively evaluate efficacy and cost-effectiveness of each of these multimodal promotion methods.MethodsWe applied the vector-autoregression model to assess the degree of contribution of each type of promotion to the following target metrics: number of daily visitors to the J-TRC website, number of daily registrants to the J-TRC web study, daily rate of registration among visitors, daily rate of eligible participants among registrants, and median age of daily registrants. The average cost-effectiveness for each promotion method was also calculated using the total cost and the coefficients in the vector-autoregression model.ResultsDuring the first 9 months of the reviewed period from October 31, 2019 to June 17, 2020, there were 48,334 website visitors and 4429 registrations (9.16% of 48,334 visitors), of which 3081 (69.56%) were eligible registrations. Initial press release reports and newspaper advertisements had a marked effect on increasing the number of daily visitors and daily registrants. Web advertisements significantly contributed to the increase in daily visitors (P<.001) but not to the daily registrants, and it also lowered the rate of registrations and the median age of daily registrants. Website visitors from the direct email invitation sent to other cognitive registries seem to have registered with the highest reliability. The calculated average cost-effectiveness for the initial press release was US $24.60 per visitor and US $96.10 per registrant, while the calculated average cost-effectiveness for the newspaper advertisements was US $28.60 per visitor and US $227.90 per registrant.ConclusionsOur multivariate time-series analysis showed that each promotion method had different features in their effect of recruiting participants to the J-TRC web study. Under the advertisement condition settings thus far, newspaper advertisements and initial press releases were the most effective promotion methods, with fair cost-effectiveness that was equivalent to earlier online studies. These results can provide important suggestions for future promotions for the recruitment of presymptomatic participants to AD clinical trials in Japan.

PSY6-5 Challenges of gynecologic cancer research with Asian countries

With growing and aging populations and the economic development, the need for cancer treatment development is increasing in Asian countries. There are some cancer types and histological types that are rare in the West but common in Asia. However, these cancers may fall outside the main scope of Western-led therapy development. Among gynecologic cancers, cervical cancer and ovarian clear cell carcinoma are common in Asian countries but rare in the west. For the development of cancer treatment in these Asian countries, it is necessary to develop not only the cancer treatment in Asia, but also to develop the infrastructure for advanced medicine such as genomic medicine. National Cancer Center Hospital, Tokyo is launching ATLAS (Asian clinical TriaLs network for cAncerS) project to establish a clinical research network across Asia. With partners in Malaysia, Viet Nam, Thailand, the Philippines and Indonesia, a framework for international clinical trials will be created. This project is aiming advance cancer genomic medicine and both investigators-initiated and industry-sponsored trials to achieve regulatory approval. The project will improve oncology drug access in Asia, where available drugs are limited, with establishment of cancer genomic medicine, and drug development. As a part of the ATLAS project, we are preparing following project: TEAL trial, A-TRAIN, MASTER KEY Asia. TEAL trial is an international investigator-initiated clinical trial for cervical cancer in Asian countries. A-TRAIN is a study comprehensively investigating circulating tumor DNA for metastatic / recurrent solid tumors including gynecologic cancers. MASTER KEY is a platform study to promote treatment development for rare cancers including a registry study, and multiple clinical trials in Japan. In MASTER KEY Asia, registration from Asian partner sites are planned in Asian counties. Of these projects, this presentation will focus on efforts against gynecologic cancer.

The Right Treatment of the Right Patient: Integrating Genetic Profiling Into Clinical Decision Making in Advanced Gastric Cancer in Asia.

Gastric cancer is a major global health burden, especially when patients are diagnosed with recurrent or metastatic gastric cancer. Despite recent advances in treatment options with palliative chemotherapy, the median overall survival of patients with gastric cancer remains within 1 or 2 years after the diagnosis of metastatic disease. Gastric cancer is significantly more prevalent in eastern Asia (e.g., Japan and Korea). Next-generation sequencing (NGS) is rapidly being adopted as part of clinical practice in Korea and Japan, especially in patients with gastric cancer. Approximately 10% to 15% of the patients with gastric cancer who undergo NGS of their tumor specimen are allocated to target-matched clinical trials in Japan and Korea. In Japan and Korea, a cell-free DNA NGS panel is also actively being investigated as an alternative NGS test for patients with gastric cancer, which may reflect the tumor heterogeneity of gastric cancer. In Japan and Korea, multiple biomarkers, such as HER2, mismatch repair, Epstein-Barr virus, PD-L1 (combined positive score), EGFR, FGFR2, and CLDN18.2, are routinely assessed through immunohistochemistry or in situ hybridization before initiation of the first-line treatment in all patients with gastric cancer. Most tertiary cancer centers in Korea routinely perform HER2, mismatch repair, Epstein-Barr virus, and PD-L1 NGS before palliative chemotherapy in patients with gastric cancer. Biomarker evaluation for all patients with metastatic gastric cancer enables clinicians to identify available biomarker-based clinical trials early during the course of treatment, which expands treatment opportunities while patients are medically fit for clinical trials, if available. Comprehensive genomic profiling using a tissue or circulating tumor DNA NGS panel is considered necessary during second-line or subsequent treatment. It is hoped that a comprehensive molecular profiling strategy will facilitate greater use of precision medicine through molecularly targeted therapies for patients with gastric cancer in the near future.

Exploration of the efficacy of pabinafusp-alfa (JR-141) on neurocognitive development in Hunter syndrome (MPS II): 52-week data from clinical trials in Japan and Brazil

Exploration of the efficacy of pabinafusp-alfa (JR-141) on neurocognitive development in Hunter syndrome (MPS II): 52-week data from clinical trials in Japan and Brazil

Points to Consider for Implementation of the ICH E17 Guideline: Learning from Past Multiregional Clinical Trials in Japan.

We identified the major points that are described in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E17 guideline but have not been considered in the past multiregional clinical trials (MRCTs) used for drug approval in Japan to elucidate potential challenges in the implementation of the ICH E17 guideline in Japan. Based on the analysis of 167 MRCTs of 130 drugs, several points, such as the same dose setting and consistency between the overall and Japanese populations, in addition to good clinical practice compliance, have been well considered in ≥ 75% of MRCTs. In contrast, the use of relevant guidelines for disease and primary end point definitions, standardization of efficacy/safety information, sample size allocation, as well as training/validation on subject selection and primary end point, have been addressed less adequately and may need to be considered when planning future MRCTs. This study provides useful information for the implementation of the ICH E17 guideline in Japan.

Combined Analysis of Clinical Data on HGF Gene Therapy to Treat Critical Limb Ischemia in Japan.

The objective of this combined analysis of data from clinical trials in Japan, using naked plasmid DNA encoding hepatocyte growth factor (HGF), was to document the safety and efficacy of intramuscular HGF gene therapy in patients with critical limb ischemia (CLI). HGF gene transfer was performed in 22 patients with CLI in a single-center open trial at Osaka University; 39 patients in a randomized, placebo-controlled, multi-center phase III trial, 10 patients with Buerger's disease in a multi-center open trial; and 6 patients with CLI in a multi-center open trial using 2 or 3 intramuscular injections of naked HGF plasmid at 2 or 4 mg. Resting pain on a visual analogue scale (VAS) and wound healing as primary endpoints were evaluated at 12 weeks after the initial injection. Serious adverse events caused by gene transfer were detected in 7 out of 77 patients (9.09%). Only one patient experienced peripheral edema (1.30%), in contrast to those who had undergone treatment with VEGF. At 12 weeks after gene transfer, combined evaluation of VAS and ischemic ulcer size demonstrated a significant improvement in HGF gene therapy group as compared to the placebo group (P=0.020). The long-term analysis revealed a sustained decrease in the size of ischemic ulcer in HGF gene therapy group. In addition, VAS score over 50 mm at baseline (total 27 patients) demonstrated a tendency (P=0.059), but not significant enough, to improve VAS score in HGF gene therapy as compared to the placebo group. The findings indicated that intramuscular injection of naked HGF plasmid tended to improve the resting pain and significantly decreased the size of the ischemic ulcer in the patients with CLI who did not have any alternative therapy, such as endovascular treatment (EVT) or bypass graft surgery. An HGF gene therapy product, CollategeneTM, was recently launched with conditional and time-limited approval in Japan to treat ischemic ulcer in patients with CLI. Further clinical trials would provide new therapeutic options for patients with CLI.