Clinical Trials In Japan Research Articles

New Arrival of Disease Modifying Drugs Initiates New Era in Multiple Sclerosis Treatment in Japan

Multiple sclerosis disease modifying drugs (MS-DMD) currently used in Japan are interferon β-1a, interferon β-1b and gratiramer acetate, fingolimod, dimethyl furmarate, and natalizumab. Ofatumumab and siponimod will be approved probably in 2021. Ofatumumab is an ant-CD20 human monoclonal antibody. A clinical trial revealed that the efficacy of ofatumumab is clearly superior to teriflunomide that has comparable efficacy to dimethyl fumarate. Siponimod, a selective sphingosine-1-phosphate receptor modulator, exhibited mild, but significant efficacy for secondary progressive form of MS. OCH, a synthetic glycolipid agent, is being tested in phase II clinical trials in Japan. What DMD is to select is challenging since MS prognosis varies and is unexpected. Only very few have truly benign course without treatment. Silent progression should be considered especially in cases with those with interferon β-1a, interferon β-1b and gratiramer acetate. Escalation therapy is more widely accepted than initiation of high efficacy therapy in Japan because emphasizing safety. In such strategy three injectables and dimethyl fumarate are regarded as first line therapies. On the other hand, initiation of high efficacy drugs may be reasonable to prevent from disease progression. Even if either is acceptable, early induction of DMD with sufficient efficacy is mandatory for MS treatment.

Regulatory changes after the enforcement of the new Clinical Trials Act in Japan.

ObjectiveTo describe changes in Japanese clinical trial regulations after the implementation of the Clinical Trials Act in April 2018.MethodsFirst, how to apply multiple regulations after the enforcement of Clinical Trials Act was described. Second, the changes in the number of clinical trials in the National Cancer Center Hospital under each regulation were compared before and after the implementation of Clinical Trials Act. Third, new requirements imposed by Clinical Trials Act and their influences were discussed.ResultsIn April 2018, Clinical Trials Act was enacted and academic clinical trials were classified into the following three categories: (i) investigator-initiated registration-directed trial under the Pharmaceuticals and Medical Devices Act; (ii) clinical trial under Clinical Trials Act; and (iii) clinical trial under the Ethical Guidelines. While 90% (205/227) of interventional studies were conducted under the Ethical Guidelines before the implementation of Clinical Trials Act in 2018, 46% (94/204) were subject to Clinical Trials Act in 2019 at the National Cancer Center Hospital. Under the Clinical Trials Act, investigators receive a scientific/ethical review by a certified review board (CRB). The identification of investigators in charge is mandated and they are required to submit the conflict of interest management plan to CRB. After the CRB review, the principal investigator must submit the trial plan to the government, and the content is uploaded to the newly established clinical trial registry site, the Japan Registry of Clinical Trials.ConclusionsThe enforcement of the new Clinical Trials Act was supposed to improve the reliability of academic clinical trials in Japan; however, the financial and administrative burden may reduce clinical trial activity in the years to come.

わが国の治験・臨床試験の規制：GCPの歴史とその結果得られたもの

わが国の治験・臨床試験の規制：GCPの歴史とその結果得られたもの

Pediatric drug development in Japan: Current issues and perspectives.

.The number of clinical trials in Japan that aim to obtain regulatory approval for new drugs and devices has increased for adults, but not children. The following reasons have been proposed for this discrepancy: the wide range of ages from newborns to adolescents, requirements for many drug formulations, the difficulties associated with obtaining consent, and less profit for companies. The processes required to obtain regulatory approval for drugs and devices, particularly in the pediatric field, differ among Japan, Europe, and the United States (US). While clinical trials are not necessarily required for the development of new drugs or obtaining additional indications in Japan, laws in Europe and the US require clinical trials on children for newly developed drugs; however, pharmaceutical companies are entitled to a 6-mo extension for a patent when pediatric data are added to the attached documents for clinical trials. We herein discuss the current status of and issues associated with pediatric drug development, including clinical trials, in Japan as well as future perspectives.

Prospects for Treatment of Neuromyelitis Optica Spectrum Disorder

Neuromyelitis optica spectrum disorder (NMOSD) is a disease related to anti-aquaporin-4 antibody. Since NMOSD was once considered a phenotype of multiple sclerosis, no approved drugs are available for its treatment. In Japan, the current standard treatment for preventing relapses in patients with NMOSD is low-dose prednisolone and/or oral immuno-suppressants. There is a critical unmet need for non-steroid treatments for patients with NMOSD. Four monoclonal antibodies have completed their clinical trials in Japan and are pending approval. In this review, we summarize the results of each of these clinical trials.

PRS9 HOW CLINICAL TRIALS INCORPORATED OUTCOMES RELEVANT FOR HEALTH ECONOMIC EVALUATION: AN EVIDENCE GAP ANALYSIS BASED ON SYSTEMATIC REVIEW OF CLINICAL TRIALS FOR MODERATE-TO-SEVERE ASTHMA IN JAPAN

To conduct a systematic review of clinical trials for moderate-to-severe asthma (MSA) in Japan and assess how they incorporated economic relevant outcomes recommended by National Institute of Health (NIH), identifying evidence gaps for future economic evaluations in this field. A systematic search using four databases (Medline, Embase, Cochrane CENTRAL, Ichushi) was conducted to identify randomized controlled trials of MSA in Japan (or global trials including Japan) published between 1980-2017. The outcome measures in these trials were compared with NIH recommendations and also another published systematic review (Makoka 2019). For outcome data not available from clinical trials, a target literature review of other Japanese studies was further conducted to identify evidence gaps for future economic evaluations. In total, 12 published trials were identified from the systematic literature review. Eight trials were conducted entirely in Japan, while the other four were global trials that included Japan. While pulmonary function outcomes were reported by all these trials, asthma exacerbation and rescue medication use, which are listed as core outcomes in NIH recommendation, were reported much less often, especially in the Japanese-only trials (2 of 8 trials). Nine trials incorporated patient-reported outcomes, while six trials reported study discontinuation data. Other core/supplemental outcomes in NIH recommendation, such as healthcare resource uses and school/work absences, were not reported in these trials. Although a target literature review of studies other than clinical trials could help solve the evidence gaps, it subjects to the issues of evidence quality and heterogeneity of data sources. Clinical trials in Japan are expected to consider and incorporate more economic relevant outcomes to expedite the good value assessment of different therapies for MSA in future.

Chemotherapy for Soft Tissue Sarcoma: Development of New Standard Treatments and Clinical Trials in Japan

Abstract Recently, pembrolizumab has been approved for microsatellite instability-high cancers, and genome profiling panel has also been approved for advanced refractory cancers including soft tissue sarcomas (STS) in Japan. However, efficacy and cost-benefit balance of these new strategies for STS should be confirmed by the future clinical trials. For localized STS, efficacy of perioperative chemotherapy has remained controversial. Meta-analysis of randomized controlled trials (RCT) comparing chemotherapy with surgery showed significant survival benefit of the chemotherapy for localized STS. Subsequently, recent RCT have compared chemotherapy regimens with each other especially in neoadjuvant setting, not with surgery. The Italian Sarcoma Group study ISG-STS1001 demonstrated significantly better survival by neoadjuvant epirubicin plus ifosfamide than histology-tailored regimens for high-risk STS. The 10-year follow-up of our trial, JCOG0304, also showed good stable results of neoadjuvant chemotherapy using adriamycin and ifosfamide (AI) for high-risk STS. These observations suggest that neoadjuvant AI could be recommended for localized high-risk STS. Besides high efficacy of AI, significant toxicities of the regimen should also be noted. We are now conducting a randomized phase II/III study, JCOG1306, to confirm the non-inferiority of neoadjuvant gemcitabine plus docetaxel (GD) to AI for high-risk STS. For advanced STS, adriamycin-based chemotherapy remains standard first-line treatment since phase III study of olaratumab resulted in negative. On the other hand, the standard second-line regimen for advanced STS has not been established yet. There are several options including GD, pazopanib, trabectedin and eribulin, however, no evidence has been shown which regimen is the best as second-line therapy. To establish the standard therapy of second-line treatment for advanced STS, we are currently conducting randomized phase II study comparing pazopanib, trabectedin and eribulin.

Real-world data on initial treatment strategies for older adult patients with endometrial cancer in Japan.

Current strategies for the treatment of endometrial cancer in older adult patients require re-evaluation given the global trend in population aging, especially in Japan. We sought to evaluate initial treatment offered to older adult patients with endometrial cancer in Japan. We retrospectively analyzed data on the standard treatment by age group in patients with endometrial cancer who underwent surgery between January 2005 and December 2013 at the National Cancer Center Hospital (Tokyo, Japan). Patients were stratified into four groups according to age: a younger group, aged 64years or younger; older adult group 1, aged 65-69years; older adult group 2, aged 70-74years; and older adult group 3, aged ≥75years. Among 551 patients with endometrial cancer diagnosed and treated at our hospital, data from 531 eligible patients were analyzed. The proportion of patients in the older adult groups 1 or 2 who received standard treatment was the same as in the younger group. However, significantly fewer patients in older adult group 3 received standard treatment compared with the younger group (26% vs. 71%, p = 0.0001). Furthermore, the proportion of patients in older adult group 3 who underwent standard surgery was significantly lower than that in the younger group (26% vs. 72%, p = 0.0001). The results indicate that age 75years and older might represent a cutoff for the development of age-based treatment strategies for endometrial cancer. This information could be used to determine the upper age limit for participation in clinical trials in Japan.

A comparative study of curated contents by knowledge-based curation system in cancer clinical sequencing

Medical oncologists are challenged to personalize medicine with scientific evidence, drug approvals, and treatment guidelines based on sequencing of clinical samples using next generation sequencer (NGS). Knowledge-based curation systems have the potential to help address this challenge. We report here the results of examining the level of evidence regarding treatment approval and clinical trials between recommendations made by Watson for Genomics (WfG), QIAGEN Clinical Insight Interpret (QCII), and Oncomine knowledge-based reporter (OKR). The tumor samples obtained from the solid cancer patients between May to June 2018 at Kindai University Hospital. The formalin-fixed paraffin-embedded tumor samples (n = 31) were sequenced using Oncomine Comprehensive Assay v3. Variants including copy number alteration and gene fusions identified by the Ion reporter software were used commonly on three curation systems. Curation process of data were provided for 25 solid cancers using three curation systems independently. Concordance and distribution of curated evidence levels of variants were analyzed. As a result of sequencing analysis, nonsynonymous mutation (n = 58), gene fusion (n = 2) or copy number variants (n = 12) were detected in 25 cases, and subsequently subjected to knowledge-based curation systems (WfG, OKR, and QCII). The number of curated information in any systems was 51/72 variants. Concordance of evidence levels was 65.3% between WfG and OKR, 56.9% between WfG and QCII, and 66.7% between OKR and QCII. WfG provided great number of clinical trials for the variants. The annotation of resistance information was also observed. Larger differences were observed in clinical trial matching which could be due to differences in the filtering process among three curation systems. This study demonstrates knowledge-based curation systems (WfG, OKR, and QCII) could be helpful tool for solid cancer treatment decision making. Difference in non-concordant evidence levels was observed between three curation systems, especially in the information of clinical trials. This point will be improved by standardized filtering procedure and enriched database of clinical trials in Japan.

Application of Adaptive Designs in Clinical Trials in Japan and the United States

Application of Adaptive Designs in Clinical Trials in Japan and the United States

Abstract 1668: A comparative study of curated contents by knowledge-based curation system in cancer clinical sequencing

Abstract Background: Medical oncologists are challenged to personalize medicine with scientific evidence, drug approvals, and treatment guidelines based on sequencing of clinical samples using next generation sequencer (NGS). Knowledge-based curation systems have the potential to help address this challenge. We report here the results of examining the level of evidence regarding treatment approval and clinical trials between recommendations made by Watson for Genomics (WfG), QIAGEN Clinical Insight Interpret (QCII), and Oncomine knowledge-based reporter (OKR). Patients and methods: The tumor samples obtained from the solid cancer patients between May to June 2018 at Kindai University Hospital. The formalin-fixed paraffin-embedded tumor samples (n=31) were sequenced using Oncomine Comprehensive Assay v3. Variants including copy number alteration and gene fusions identified by the Ion reporter software were used commonly on three curation systems. Curation process of data were provided for 25 solid cancers using three curation systems independently. Concordance and distribution of curated evidence levels of variants were analyzed. Results: As a result of sequencing analysis, nonsynonymous mutation (n=58), gene fusion (n=2) or copy number variants (n=12) were detected in 25 cases, and subsequently subjected to knowledge-based curation systems (WfG, OKR, and QCII). The number of curated information in any systems was 51/72 variants. Concordance of evidence levels was 65.3% between WfG and OKR, 56.9% between WFG and QCII, and 66.7% between OKR and QCII. WfG provided great number of clinical trials for the variants. The annotation of resistance information was also observed. The larger difference was observed in the clinical trials information. It was due to the different filtering process among three curation systems possibly. Conclusion: This study demonstrates knowledge-based curation systems (WfG, OKR, and QCII) could be helpful tool for solid cancer treatment decision making. Difference in non-concordant evidence levels was observed between three curation systems, especially in the information of clinical trials. This point will be improved by standardized filtering procedure and enriched database of clinical trials in Japan. Citation Format: Masayuki Takeda, Kazuko Sakai, Shigeki Shimizu, Takayuki Takahama, Takeshi Yoshida, Satomi Watanabe, Tsutomu Iwasa, Kimio Yonesaka, Shinichiro Suzuki, Hidetoshi Hayashi, Hisato Kawakami, Yoshikane Nonagase, Kaoru Tanaka, Junji Tsurutani, Kazumasa Saigo, Akihiko Ito, Tetsuya Mitsudomi, Kazuhiko Nakagawa, Kazuto Nishio. A comparative study of curated contents by knowledge-based curation system in cancer clinical sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1668.

Efficacy and safety of leuprorelin acetate for subjects with spinal and bulbar muscular atrophy: pooled analyses of two randomized-controlled trials.

Spinal and bulbar muscular atrophy (SBMA) is an adult-onset, hereditary neuromuscular disease characterized by muscle atrophy, weakness, contraction fasciculation, and bulbar involvement. Although the causative gene, androgen receptor, has been identified, the development of novel therapeutics for SBMA is incomplete. In this study, the efficacy and safety of leuprorelin acetate administration for patients with SBMA, using the pooled data of two randomized-controlled trials, was studied. Two randomized double-blinded studies (JASMITT-06DB and JASMITT-11DB) were done as multicentric, investigator-initiated clinical trials in Japan. In both studies, eligible patients were randomly assigned 1:1 to receive leuprorelin acetate administration once per 12 weeks for 48 weeks. The primary endpoint was the longitudinal change of pharyngeal barium residues from the baseline data measured with videofluorographic swallowing analyses. The pooled analysis plan was decided upon after the 06B study was finished and before the 11DB study began. The primary endpoint difference between the leuprorelin group and the placebo group was pharyngeal barium residue after initial swallowing, - 4.12% (95% CI, - 8.40-0.15; p = 0.058). The primary endpoint of this study does not reach significant results, although inter-group differences of pharyngeal barium residues after the initial swallowing indicated that leuprorelin acetate may be effective at each assessment point in both study groups. The efficacy of leuprorelin acetate for patients with SBMA was statistically similar in two randomized-controlled trials, and suggested that leuprorelin acetate may be effective and safe. Further investigations are needed to clarify the promising efficacy of the drug.

Effect of Age on the Prognosis of Molecular Abnormalities in Pediatric Acute Myeloid Leukemia

[Introduction]Infant AML has been defined as AML in patients aged <1 year. Infant AML is related to high frequencies of M4, M5, and M7 subtypes in the FAB classification. Molecular analyses showed that KMT2A rearrangement (KMT2A-R), CBFA2T3-GLIS2 and NUP98-KDM5A are the most frequent abnormalities in infant AML. These findings indicate a distinct biology of infant AML. However, a more clinically adequate definition of “infant AML” by age remains controversial; a recent report by the COG defined patients aged <3 years with AML as infants because of their molecular similarities. Moreover, although Infants with AML are generally treated with dose-reduced regimens to avoid severe toxicities, it remains unknown whether patients aged 1-<3 years also require the same dose-reduced regimens as infants. Thus, further identification of AML in young pediatric patients is necessary.[Methods]This study enrolled patients aged <18 years who were diagnosed with de novo AML and who had participated in one of the two recent clinical trials in Japan: the AML99 trial and the AML-05 trial conducted by the Japanese Pediatric Leukemia/Lymphoma Study Group. In total, 723 patients were analyzed in the current study. Among them, bone marrow samples of 503 patients (70%) were screened for fusion genes and gene mutations.[Results]We first analyzed the distribution of fusion genes and FAB classification in 503 patients with clinical samples. Fusion genes were found in >50% of the patients in each age group. RUNX1-RUNX1T1, KMT2A-R, and CBFB-MYH11 were present in almost all age groups. RUNX1-RUNX1T1 was the most frequently identified fusion gene in all age groups excluding those <3 years, whereas KMT2A-R was the most frequently identified fusion gene in patients aged <3 years. Regarding other fusions, CBFA2T3-GLIS2 and NUP98-KDM5A were essentially limited to patients aged <3 years, whereas CBFB-MYH11 was detected in nearly all age groups. In the assessment of FAB classification, patients with M4 and M5 accounted for 50% of patients aged <3 years. Among patients aged <3 years, M7 was the second most common morphology. In total, approximately 80% of patients aged <3 years were classified as M4, M5, or M7. Conversely, M1 and M2, both of which display granulocytic differentiation, were the most frequent phenotypes among patients aged 3-<18 years. According to the distribution of fusion genes and FAB classification, we divided pediatric AML patients into two age groups: patients aged <3 years (patients <3y) and those aged 3-<18 years (patients 3-<18y). Further, we compared the prognostic effect of molecular characteristics between these two age groups, and identified KMT2A-R and CBFB-MYH11 as age-specific prognostic markers.Furthermore, we analyzed the prognosis of KMT2A-R and CBFB-MYH11 in all 723 patients and confirmed that these fusions had significantly different prognoses between patients<3y and those 3-<18y. In the subgroup of patients with KMT2A-R (n = 131), 5-year (5y) OS, EFS, and CIR were significantly worse in patients 3-<18y (n = 57) than in patients <3y (n = 74) (50.6% vs 73.7%, p = 0.023; 34.5% vs 61.6%, p = 0.011; and 63.2% vs 31.6%, p <0.001, respectively) (Figure 1). Conversely, in the subgroup of patients with CBFB-MYH11 (n = 46), 5y EFS and CIR were significantly worse in patients <3y (n = 14) than in patients 3-<18y (n = 32) (50.0% vs 90.3%, p<0.001 and 50.0% vs 6.6%, p <0.001, respectively) (Figure 2).In patients with KMT2A-R (n = 131), no molecular markers were identified as prognostic markers in combination with age; however, high WBC counts were related to poor prognosis regardless of age. Particularly, among patients 3-<18y (n = 57), those with WBC counts >10,000/µL (n = 37) had a significantly poorer prognosis than those with WBC <10,000/µL (n = 20) (5y OS 31.0% vs 78.8%, p = 0.002; 5y EFS 22.1% vs 54.2%, p = 0.008; and 5y CIR 77.9% vs 40.4%, p = 0.005).In patients with CBFB-MYH11 with clinical samples (n = 39), NRAS-mutated patients (n = 13) had significantly better 5y EFS and CIR than NRAS-wild-type patients (n = 26) (100% vs 60.5%, p = 0.012, and 0% vs 35.7%, respectively). Moreover, the combination of NRAS status with age identified the worst prognosis in NRAS-wild-type patients <3y (5y EFS 22.2% and 5y CIR 77.8%).[Conclusions]Although age has not been used for the risk stratification of recent pediatric AML clinical trials, it might be a useful prognostic maker of this disease in combination with some molecular makers. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Introduction of the targeted alpha therapy (with Radium-223) into clinical practice in Japan: learnings and implementation

Radium-223 dichloride (Ra-223) is the first targeted alpha therapy approved for the treatment of patients with castration-resistant prostate cancer (CRPC) with bone metastasis. Ra-223 improved overall survival in the international Phase III ALSYMPCA (ALpharadin in SYMPtomatic Prostate Cancer) study. Ra-223 was also demonstrated to be efficacious and safe in Japanese patients in Phase I and Phase II clinical trials. Ra-223 was approved in Japan for the treatment of patients with CRPC with bone metastasis in 2016. The conduct of clinical studies with radionuclides in Japan involves mandatory compliance with local and international regulations pertaining to radiation protection. Without an existing Japanese framework for the handling of α-emitters in clinical practice, we encountered many challenges to initiate the clinical studies. Therefore, we started on a project to determine best practice on the use of Ra-223 in clinical studies. For this project, we evaluated all applicable laws and regulations on the use of radionuclides in medicine, then examined whether and how the α-emitter Ra-223 could meet these legal and regulatory requirements. This included how to approach the matter of discharging patients administered Ra-223 from hospital and radiation protection for caregivers, general public and medical care professionals. Subsequently, we published Manual on the proper use of radium-223 dichloride injection in clinical trials that summarized the essential requirements necessary to allow the safe use of Ra-223 in clinical trials in Japan. As the result, we succeeded in demonstrating that clinical trials of an α-emitter, Ra-223, could be implemented safely in Japan. Our experience in Japan highlights the importance of a multidisciplinary team-based approach and continued professional training in a clinical setting. This article summarizes the rationale behind the development of this manual. We hope that by sharing our experience and information, we can help other countries considering the introduction of radionuclides for clinical use, and support the future development of radionuclide therapies in a safe and effective manner.

Comparison Between Valsartan and Amlodipine Regarding Cardiovascular Morbidity and Mortality in Hypertensive Patients With Glucose Intolerance: NAGOYA HEART Study.

Comparison Between Valsartan and Amlodipine Regarding Cardiovascular Morbidity and Mortality in Hypertensive Patients With Glucose Intolerance: NAGOYA HEART Study.

Points to keep in mind when carrying out clinical trials in Japan on advanced pancreatic cancer cases without alternative treatments: Analysis of 367 cases.

243 Background: We commenced a physician-led clinical trial to examine the efficacy of a combined treatment of peptide vaccine therapy for advanced pancreatic cancer that has no effective treatment. During this trial, there were inquiries from 367 cases, of which 145 cases (40%) were examined at our outpatient clinic. The purpose of this study was to examine these cases in detail and to consider the points to be noted in executing clinical trials for poor prognosis cases. Methods: We examined the timing of inquiry, medical condition, the person(s) they inquired, and other relevant information regarding the 367 subjects who made inquiries. For the 145 cases visited the outpatient clinic of our hospital, we examined their medical condition, treatment and whether or not they have participated in a clinical trial. Results: 140 of the 367 cases (38%) of inquiry were concentrated within the first two months after the start. During these two months, there was a concentration of patients who had completed standard treatments and were a few months into BSC, but were unable to participate in the clinical trial due to deterioration of their general condition. Many of the inquiries were made by family members (spouse or child) of the patients, around twice the number of inquiries made by patients themselves. Even among the 145 subjects that were examined in the outpatient clinic of our hospital, severe cases, in particular, were seen several months after the start of the study. There were many cases that required urgent hospitalization during outpatient visits or patients whose general condition rapidly deteriorated during the screening tests. 23 cases (16%) underwent the clinical trial. Conclusions: In clinical trials such as this one, which handles cases with poor prognosis, many of the subjects are in poor general condition at the inquiry stage, and most of these inquiries are concentrated immediately after the start of the study. Therefore, it is very important to deal with inquiries and make judgments during the outpatient examination on whether or not clinical trial participation is possible.

Edaravone in Amyotrophic Lateral Sclerosis’Lessons from the Clinical Development Program and the Importance of a Strategic Clinical Trial Design

Edaravone significantly slows progression of amyotrophic lateral sclerosis (ALS), and is the first therapy to receive approval by the Food and Drug Administration (FDA) for the disease in 22 years. Approval of edaravone has marked a new chapter in pharmaceutical development since the key trial included a novel strategic clinical design involving cohort enrichment. In addition, approval was based on clinical trials that had a relatively small patient number and were performed outside of the US. Edaravone was developed through a series of clinical trials in Japan where it was determined that a well-defined subgroup of patients was required to reveal a treatment effect within the study period. Amyotrophic lateral sclerosis is associated with wide-ranging disease heterogeneity (both within the spectrum of ALS phenotypes as well as in the rate of progression). The patient cohort enrichment strategy aimed to address this heterogeneity and should now be considered as a viable, and perhaps preferred, trial design for future studies. Future research incorporating relevant biomarkers may help to better elucidate edaravone’s mechanism of action, pharmacodynamics, and subsequently ALS phenotypes that may preferentially benefit from treatment. In this review, we discuss the edaravone clinical development program, outline the strategic clinical trial design, and highlight important lessons for future trials.

Surveillance on The Safety and Efficacy of Ambrisentan (Volibris Tablet 2.5 mg) in Patients with Pulmonary Arterial Hypertension in Real Clinical Practice: Post-marketing Surveillance (Interim Analysis Report).

Pulmonary arterial hypertension (PAH) is an intractable and rare disease and the accumulation of clinical evidence under real-world setting is needed. A post-marketing surveillance for the endothelin receptor antagonist ambrisentan (Volibris tablet) has been conducted by all-case investigation since September 2010. This paper is an interim report on the safety and efficacy of ambrisentan in 702 patients with PAH. PAH patients aged 15 years or older were subjected to the analysis. The safety analysis by overall cases or stratification of patient backgrounds and the efficacy analysis were investigated. Regarding patient characteristics, the 702 patients subjected to safety analysis included 543 (77.4%) women and 546 (77.8%) patients at WHO functional class II/III. The mean observational time was 392.7 days. A total of 324 adverse drug reaction (ADR) occurred in 204 (29.1%) patients. Common ADRs (≥2%) included anemia (4.6%), peripheral edema (4.1%), headache (3.6%), edema and face edema (2.6% each), abnormal hepatic function (2.3%), and epistaxis (2.1%). There were 82 serious ADRs occurring in 44 (6.3%) patients (385 serious adverse events in 184 (26.2%) patients). Although 11 (1.6%) interstitial lung disease (ILD) cases were reported, all were observed in patients with disease that may contribute to ILD and therefore it is difficult to assess if ambrisentan was associated with these events. There was no difference in safety in relation to the presence/absence of connective tissue disease-related PAH (CTD-PAH) or combination therapy. Among 677 patients subjected to efficacy analysis, those in whom hemodynamic status was determined before and after treatment showed improvement in the mean pulmonary arterial pressure and pulmonary vascular resistance after treatment. The interim results showed safety consistent with the known profile of ambrisentan in terms of the types and frequencies of ADRs in patients with PAH in real clinical practice, in comparison with previous clinical trials in Japan and the rest of the world. Thus, these results provided another corroboration of the tolerability of ambrisentan and we continue to monitor proper use information via the post-marketing surveillance to ensure any new safety signals are identified in a timely manner (ClinTrial.gov: NCT01406327).

Qualitative analysis of clinical research coordinators' role in phase I cancer clinical trials.

BackgroundClinical research coordinators play a pivotal role in phase I cancer clinical trials.PurposeWe clarified the care coordination and practice for patients provided by clinical research coordinators in phase I cancer clinical trials in Japan and elucidated clinical research coordinators' perspective on patients' expectations and understanding of these trials.MethodFifteen clinical research coordinators participated in semi-structured interviews regarding clinical practices; perceptions of patients' expectations; and the challenges that occur before, during, and after phase I cancer clinical trials.DiscussionQualitative content analysis showed that most clinical research coordinators observed that patients have high expectations from the trials. Most listened to patients to confirm patients' understanding and reflected on responses to maintain hope, but to avoid excessive expectations; clinical research coordinators considered avoiding unplanned endings; and they aimed to establish good relationships between patients, medical staff, and among the professional team.ConclusionsClinical research coordinators were insightful about the needs of patients and took a meticulous approach to the phase I cancer clinical trial process, allowing time to connect with patients and to coordinate the inter-professional research team. Additionally, education in advanced oncology care was valuable for comforting participants in cancer clinical trials.

BP.06.01] THE EFFECTS OF FEBUXOSTAT ON ANGIOTENSIN II-INDUCED VASCULAR REMODELING

Objective: A xanthine oxidase (XO) inhibitor, febuxostat (FEB) is often used in patients with hyperuricemia. Several reports have suggested that uric acid contributes to endothelial dysfunction and kidney injury. Because XO produces hydrogen peroxide with uric acid in the nucleic acid metabolism, XO inhibitors can also have the anti-oxidative properties. From these reasons, XO inhibitors have the possibilities to suppress cardiovascular diseases. Actually, the effects of FEB on cardiovascular events have been examined in several clinical trials in Japan and several basic researches have suggested that FEB suppressed cardiac fibrosis and renal inflammation, however, those mechanisms remain unclear. In this study, we investigated the effects of FEB on angiotensin II (Ang II)-induced vascular remodeling. Design and method: To induce vascular remodeling, Ang II (2 mg/kg/day, s.c.) was infused by osmotic minipump into the mice. FEB was suspended in 1% carboxymethyl cellulose and administrated daily for 14 days. The mice were divided into four groups: control, FEB alone, Ang II alone, and Ang II+FEB. Medial thickening and vascular fibrosis were assessed by Elastica van Gieson stain. Blood pressure was measured by tail-cuff method. The macrophage infiltration and XO localization in the aortic tissue were assessed by immunofluorescence. In our in vitro studies, protein phosphorylation and cell proliferation were measured by western blotting and MTT assay, respectively. Results: Serum XO activity was lower in the Ang II+FEB group than in the Ang II alone group. FEB administration suppressed Ang II-induced blood pressure elevation and aortic fibrosis, however it did not affect medial thickening of the aortae. In our in vitro studies, FEB did not change the aortic smooth muscle cell proliferation and ERK1/2 phosphorylation induced by Ang II stimulation. We found that XO was expressed strongly in the macrophages, and Ang II-induced macrophage infiltration in the aortae tended to be suppressed by FEB. Conclusions: Our results suggested that FEB affects the mechanisms of fibrosis in vascular cells more than those of smooth muscle cell proliferation induced by Ang II. We supposed that FEB suppresses macrophage-derived XO activity in the mouse model of Ang II-induced vascular remodeling.