花岡 英紀

Japan is lagging in cervical cancer prevention. The effectiveness of a self-sampling human papillomavirus (HPV) test, a possible measure to overcome this situation, has not yet been evaluated. A randomized controlled trial was performed to evaluate the effectiveness of a self-sampling HPV test on detection of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and screening uptake. Women between 30 and 58 years old who did not participate in the cervical cancer screening program for ≥3 years were eligible and assigned to the intervention group (cytology or self-sampling HPV test) or control group (cytology). Participants assigned to the intervention group were sent a self-sampling kit according to their ordering (opt-in strategy). A total of 7337 and 7772 women were assigned to the intervention and control groups, respectively. Screening uptake in the intervention group was significantly higher than that in the control group (20.0% vs. 6.4%; risk ratio: 3.10; 95% confidence interval [CI]: 2.82, 3.42). The compliance rate with cytology triage for HPV-positive women was 46.8% (95% CI: 35.5%, 58.4%). CIN2+ was detected in five and four participants in the intervention and control groups, respectively; there was no difference for intention-to-screen analysis (risk ratio: 1.32; 95% CI: 0.36, 4.93). Self-sampling of HPV test increased screening uptake; however, no difference was observed in the detection of CIN2+, probably due to the low compliance rate for cytology triage in HPV-positive women. Efforts to increase cytology triage are essential to maximize precancer detections.

We examined the development strategies of new molecular entities approved during a 10-year period (fiscal years of 2012-2021) in Japan to determine the differences in drug lag between Japan and foreign companies. The results demonstrated a clear difference in development strategies. For example, products were usually developed through a "only-Japan" strategy by Japan companies (51.1% of products), compared to a "MRCT (multi-regional clinical trials)" strategy by foreign companies (54.9% of products). Regarding types of licenses, for Japan companies, the percentage of original products was higher in the category of less drug lag, such as "no approval in the US and EU" (59.1%), whereas the percentage of "license-in" products was markedly higher in the "drug lag ≥ 5 years" category (52.5%). Such differences were not observed for products developed by foreign companies. Of 64 license-in products developed by Japan companies with a drug lag > 5 years, 51 (79.7%) had already been approved in the US or EU at initiation of clinical development in Japan. The origin of approximately half (34) of the products was from the emerging companies (non-member foreign companies of the Japan Pharmaceutical Manufacture Association). These results suggest that more global cooperation of Japan companies, particularly with emerging foreign companies, is necessary in terms of the earlier timing of license-in and development strategies of products to promote drug development without drug lag or drug loss in Japan.

INTRODUCTION: Insomnia is a common health problem and cognitive-behavioural therapy (CBT) is recommended as a treatment. As there is a critical shortage of CBT-trained therapists, we developed a digital CBT application (IIIP MED: Sleepy Med) as Software as a Medical Device for insomnia. This paper describes the study protocol for an exploratory randomised controlled trial (RCT) to evaluate effectiveness and safety of our developed digital CBT (dCBT) for 5 weeks compared with zolpidem tartrate for patients with insomnia disorder. METHODS AND ANALYSIS: This proposed multicentre exploratory RCT will be conducted at the outpatient clinic of Chiba University Hospital, Akita University Hospital and Yoyogi Sleep Disorder Center, Japan. The study population comprises two parallel groups (dCBT and zolpidem) consisting of 15 participants each (n=30 in total) diagnosed with insomnia disorder who remain symptomatic at 4 weeks after sleep hygiene education. We will evaluate the effectiveness at baseline, week 5 (post-intervention) and week 10 (follow-up). The primary outcome will be the change of subjective sleep onset latency at week 5 from baseline. Secondary outcomes include sleep-related outcomes, such as objective sleep onset latency measured by mobile electroencephalography, functional improvement during the daytime and quality of life. ETHICS AND DISSEMINATION: Ethics approval was granted by the Institutional Review Board of Chiba University Hospital (K2023001). All participants will be required to provide written informed consent. Results will be published in international journals. TRIAL REGISTRATION NUMBER: jRCT2032230353.

PURPOSE: Auto-antibodies (auto-abs) to type I interferons (IFNs) have been identified in patients with life-threatening coronavirus disease 2019 (COVID-19), suggesting that the presence of auto-abs may be a risk factor for disease severity. We therefore investigated the mechanism underlying COVID-19 exacerbation induced by auto-abs to type I IFNs. METHODS: We evaluated plasma from 123 patients with COVID-19 to measure auto-abs to type I IFNs. We performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells from the patients with auto-abs and conducted epitope mapping of the auto-abs. RESULTS: Three of 19 severe and 4 of 42 critical COVID-19 patients had neutralizing auto-abs to type I IFNs. Patients with auto-abs to type I IFNs showed no characteristic clinical features. scRNA-seq from 38 patients with COVID-19 revealed that IFN signaling in conventional dendritic cells and canonical monocytes was attenuated, and SARS-CoV-2-specific BCR repertoires were decreased in patients with auto-abs. Furthermore, auto-abs to IFN-α2 from COVID-19 patients with auto-abs recognized characteristic epitopes of IFN-α2, which binds to the receptor. CONCLUSION: Auto-abs to type I IFN found in COVID-19 patients inhibited IFN signaling in dendritic cells and monocytes by blocking the binding of type I IFN to its receptor. The failure to properly induce production of an antibody to SARS-CoV-2 may be a causative factor of COVID-19 severity.

BACKGROUND: Endometriosis-related pain encompassing dysmenorrhea, dyspareunia, and chronic pelvic pain, reduces the quality of life in premenopausal women. Although treatment options for endometriosis alleviate this pain, approximately one-third of women still experience pain even after receiving treatment, indicating the need for novel approaches to pain relief in those women. The Angel Touch device (AT-04) is a portable magnetic fields irradiation device that incorporates a combination of mixed alternative magnetic fields at 2 kHz and 83.3 MHz. A phase III trial confirmed the efficacy and safety of AT-02, a prototype of AT-04, for pain relief in patients with fibromyalgia. METHODS: This is a phase III, multicenter, prospective, randomized, sham device-controlled, double-blind, parallel study. The participants will be premenopausal women aged > 18 years who have endometriosis-related pain with at least moderate severity. Considering dropouts, 50 participants have been deemed appropriate. Eligible women will be centrally registered, and the data center will randomly allocate them in a 1:1 ratio to the intervention and control groups. Women in the intervention group will receive electromagnetic wave irradiation generated by AT-04 and those who in the control group will wear a sham device for 16 weeks, and both groups will wear AT-04 for another 4 weeks. The primary outcome measure is the change in the Numeric Rating Scale score at 16 weeks compared with the baseline. Secondary outcome measures are efficacy for pelvic pain including dysmenorrhea and non-menstrual pain, and chronic pelvic pain not related to menstruation, dysmenorrhea, and dyspareunia, and improvement of quality of life during the study period. Safety will be evaluated by device defects and the frequency of adverse events. The study protocol has been approved by the Clinical Study Review Board of Chiba University Hospital, Chiba, Japan, and will be conducted in accordance with the principles of the Declaration of Helsinki and the Japanese Clinical Trials Act and relevant notifications. DISCUSSION: This study aims to develop a novel method of managing endometriosis-related pain. The AT-04 is an ultralow-invasive device that can be used without inhibiting ovulation, suggesting potential benefits to women of reproductive-age. Trial registration number Japan Registry of Clinical Trials (jRCTs032230278).

BACKGROUND: No effective treatment for NAION with strong evidence has been established till date. The aim of this investigator-led, prospective, non-randomized, open-label, uncontrolled multi-center exploratory clinical trial is to evaluate the efficacy and safety of transdermal electrical stimulation (TdES) using skin electrodes in patients with NAION. METHODS: Five patients with monocular NAION underwent TdES (10-ms biphasic pulses, 1.0 mA, 20 Hz, 30 min) of the affected eye six times at 2-week intervals. The primary endpoint was the logarithm of the mini-mum angle of resolution (logMAR) visual acuity at 12 weeks compared with 0 weeks. The secondary endpoints were changes in the best-corrected logMAR visual acuity, Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity, and mean deviation (MD) of the Humphrey field analyzer (HFA) 10-2 and HFA Esterman test scores. Additionally, the safety of TdES was evaluated. RESULTS: LogMAR visual acuity improved by ≥ 0.1 in two eyes, and ETDRS visual acu-ity improved by ≥ 5 characters in one eye. The mean change in logMAR visual acuity from week 0 showed an increasing trend. The mean MD of HFA 10-2 showed no obvious change, while HFA Esterman score improved in four eyes. All patients completed the study according to the protocol, and no treatment-related adverse events were observed. CONCLUSIONS: TdES treatment may have improved visual acuity and visual field in some patients. Further sham-controlled study in larger cohort is needed on its effectiveness. TRIAL REGISTRATION: UMIN, UMIN000036220. Registered 15 March, 2019, https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000041261 .

INTRODUCTION: Cognitive behavioural therapy for psychosis (CBTp) has demonstrated effectiveness in reducing positive symptoms, improving depression, enhancing coping skills and increasing awareness of illness. However, compared with cognitive behavioural therapy for depression and anxiety, the spread of CBTp in clinical practice is minimal. The present study designed a randomised controlled trial (RCT) research protocol to evaluate whether real-time remote video-conference CBTp (vCBTp) could facilitate access to psychosocial interventions and effectively improve symptoms compared with usual care (UC) for patients with schizophrenia. METHODS AND ANALYSIS: This exploratory RCT will consist of two parallel groups (vCBTp+UC and UC alone) of 12 participants (n=24) diagnosed with schizophrenia, schizoaffective disorder or paranoid disorder, who remain symptomatic following pharmacotherapy. Seven 50-min weekly vCBTp interventions will be administered to test efficacy. The primary outcome will be the positive and negative syndrome scale score at week 8. The secondary outcome will be the Beck Cognitive Insight Scale to assess insight, the Patient Health Questionnaire-9 to assess depression, the Generalised Anxiety Disorder-7 to assess anxiety, the 5-level EuroQol 5-dimensional questionnaire to assess quality of life and the Impact of Event Scale-Revised to assess subjective distress about a specific stressful life event. We will take all measurements at 0 weeks (baseline) and at 8 weeks (post-intervention), and apply intention-to-treat analysis. ETHICS AND DISSEMINATION: We will conduct this study in the outpatient department of Cognitive Behavioral Therapy Center at Chiba University Hospital. Further, all participants will be informed of the study and will be asked to sign consent forms. We will report according to the Consolidated Standards of Reporting Trials. TRIAL REGISTRATION NUMBER: UMIN000043396.

We conducted a phase Ib study to examine the safety of a combination of carbon-ion RT (CIRT) with durvalumab (MEDI4736; AstraZeneca) in patients with locally advanced cervical cancer. This was an open-label, single-arm study with a modified 3 + 3 design. Patients with newly diagnosed histologically proven locally advanced cervical cancer were enrolled. All patients received 74.4 Gy of CIRT in 20 fractions and concurrent weekly cisplatin (chemo-CIRT) at a dose of 40 mg/m2. Durvalumab was administered (1500 mg/body) at weeks two and six. The primary endpoint was the incidence of adverse events (AEs) and serious AEs (SAEs), including dose-limiting toxicity (DLT). All three enrolled patients completed the treatment without interruption. One patient developed hypothyroidism after treatment and was determined to be an SAE. No other SAEs were observed. The patient recovered after levothyroxine sodium hydrate treatment. None of the AEs, including hypothyroidism, were associated with DLT in the present study. All three patients achieved complete responses within the CIRT region concerning treatment efficacy. This phase 1b trial demonstrates the safety of combining chemo-CIRT and durvalumab for locally advanced cervical cancer in the early phase. Further research is required as only three patients were included in this study.

The anti-HIV drug nelfinavir suppresses the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro . However, its efficacy in patients with COVID-19 has not been studied.

BACKGROUND: To investigate risk factors for coronary arterial abnormalities (CAAs) and resistance to treatment in patients with Kawasaki disease (KD) receiving intravenous immunoglobulin (IVIG) plus ciclosporin A (CsA) as the first-line treatment, we performed a subanalysis of baseline data of participants in the KAICA trial, a phase 3, randomized study (JMA-ILA00174). METHODS: All data of the patients enrolled in the KAICA trial, who had a Gunma score ≥5 at diagnosis and had been randomly assigned to either IVIG (2 g/kg/24 h) plus CsA (5 mg/kg/day for 5 days) (n = 86) or IVIG alone (n = 87), were subjected to this study. CAA was defined by a Z score ≥2.5 observed within 4 weeks after treatment initiation. Baseline data including genotypes of KD susceptibility genes were compared between subgroups of patients for CAA or treatment response for each treatment group. Backword-forward stepwise logistic regression analyses were performed. RESULTS: Pre-Z-max, defined as the maximum among Z scores on four coronary artery branches before treatment, was higher in patients with CAA in both treatment groups and was associated with CAA in IVIG plus CsA treatment group [odds ratio (OR) = 17.0]. High serum total bilirubin level was relevant to treatment resistance only in the IVIG plus CsA group (OR = 2.34). CONCLUSIONS: Coronary artery enlargement before treatment is a major determinant of CAA even in KD patients treated with initial IVIG treatment intensified by addition of CsA. Baseline serum total bilirubin level was a risk factor associated with resistance to IVIG plus CsA.

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

PURPOSE: To evaluate the efficacy and safety of transdermal electrical stimulation (TdES) using skin electrodes in patients with central retinal artery occlusion (CRAO). METHODS: Five eyes of five patients with CRAO underwent TdES (10-ms biphasic pulses, 20 Hz, 30 min) six times at 2-week intervals. Only the affected eye was stimulated with 1.0-mA pulses in all patients. The primary endpoint was the best-corrected logMAR visual acuity. The secondary endpoints were changes in the best-corrected logMAR visual acuity, Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity, mean deviation of the Humphrey field analyzer (HFA) 10-2, and HFA Esterman test score. We also evaluated its safety. RESULTS: The logMAR visual acuity at 12 weeks was improved by 0.1 or more in two patients and was maintained in two patients compared to the baseline. No obvious changes in the mean logMAR visual acuity, ETDRS visual acuity, mean deviation, and HFA Esterman score were observed at 12 weeks compared to the baseline. All five enrolled patients completed the study according to the protocol. No treatment-related adverse events were observed during this study. CONCLUSION: In this study, logMAR visual acuity was slightly improved in two patients, confirming the safety of TdES. Since CRAO has no established treatment method, further research into the effects of TdES treatment in CRAO patients may be beneficial.

BACKGROUND: Familial lecithin: cholesterol acyltransferase (LCAT) deficiency (FLD) is a severe inherited disease without effective treatment. Patients with FLD develop severe low HDL, corneal opacity, hemolytic anemia, and renal injury. OBJECTIVE: We developed genetically modified adipocytes (GMAC) secreting LCAT (LCAT-GMAC) for ex vivo gene therapy. GMACs were prepared from the patient's adipocytes to express LCAT by retroviral gene transduction to secrete functional enzymes. This study aimed to evaluate the safety and efficacy of LCAT-GMAC implantation in an FLD patient. METHODS: Proliferative preadipocytes were obtained from a patient using a ceiling culture and retrovirally transduced with LCAT. After obtaining enough cells by expansion culture of the transduced cells, the resulting LCAT-GMACs were implanted into a patient with FLD. To evaluate the safety and efficacy, we analyzed the outcome of the autologous implantation for 24 weeks of observation and subsequent 240 weeks of the follow-up periods. RESULTS: This first-in-human autologous implantation of LCAT-GMACs was shown to be safe by evaluating adverse events. The LCAT-GMAC implantation increased serum LCAT activity by approximately 50% of the baseline and sustained over three years. Consistent with increased LCAT activity, intermediate-density lipoprotein (IDL) and free cholesterol levels of the small and very small HDL fractions decreased. We found the hemoglobin/haptoglobin complex in the hemolyzed pre-implantation sera of the patient. After one week of the implantation, the hemoglobin/haptoglobin complex almost disappeared. Immediately after the implantation, the patient's proteinuria decreased temporarily to mild levels and gradually increased to the baseline. At 48 weeks after implantation, the patient's proteinuria deteriorated with the development of mild hypertension. By the treatment with antihypertensives, the patient's blood pressure normalized. With the normalization of blood pressure, the proteinuria rapidly decreased to mild proteinuria levels. CONCLUSIONS: LCAT-GMAC implantation in a patient with FLD is shown to be safe and appears to be effective, in part, for treating anemia and proteinuria in FLD.

OBJECTIVE: We compared the incidences of four opportunistic infections (OI) in patients with rheumatoid arthritis (RA) treated with molecular-targeted drugs from big claims data. MATERIALS AND METHODS: We identified 205 906 patients with RA who were prescribed molecular-targeted drugs 2010-2017 from the National Database of Japan, and calculated the incidence of four OIs (Pneumocystis pneumonia [PCP], tuberculosis [TB], nontuberculous mycobacterial infection [NTM], and herpes zoster [HZ]). RESULTS: The total number of PCP, TB, NTM, and HZ patients with biological disease-modifying antirheumatic drugs (bDMARDs) or tofacitinib treatment history in RA were 765, 1158, 834, and 18 336, respectively. The incidence rates (IRs) of each OI for all bDMARDs were 0.14, 0.14, 0.09, and 2.40 per 100 person-years, respectively; while for tofacitinib they were 0.22, 0.22, 0.07, and 7.00 per 100 person-years. No big difference was observed among bDMARDs. All OIs showed higher incidence in those older than 65 years; but PCP, NTM and HZ showed no difference between those 65-74 years old and those over 75 years old. The median of occurrence was the third, seventh, ninth, and thirteenth month after treatment, respectively. CONCLUSION: We counted real IRs of OIs for the whole nation from big claims data.

Symptoms of adverse reactions to vaccines evolve over time, but traditional studies have focused only on the frequency and intensity of symptoms. Here, we attempt to extract the dynamic changes in vaccine adverse reaction symptoms as a small number of interpretable components by using non-negative tensor factorization. We recruited healthcare workers who received two doses of the BNT162b2 mRNA COVID-19 vaccine at Chiba University Hospital and collected information on adverse reactions using a smartphone/web-based platform. We analyzed the adverse-reaction data after each dose obtained for 1,516 participants who received two doses of vaccine. The non-negative tensor factorization revealed four time-evolving components that represent typical temporal patterns of adverse reactions for both doses. These components were differently associated with background factors and post-vaccine antibody titers. These results demonstrate that complex adverse reactions against vaccines can be explained by a limited number of time-evolving components identified by tensor factorization.

Abstract A self-sampling human papillomavirus (HPV) test could improve the morbidity and mortality of cervical cancer in Japan. However, its effectiveness and feasibility have not been demonstrated sufficiently. Hence, we launched a randomized controlled trial, which is ongoing, and report the results of a secondary analysis. To ensure autonomous participation with a minimum selection bias, opt-out consent was obtained from women who met the inclusion criteria, and written consent was obtained from those who underwent a self-sampling test. The number of women who met the inclusion criteria was 20,555; 4283 and 1138 opted out before and after the assignment, respectively. Of the 7340 women in the self-sampling arm, 1372 (18.7%) ordered and 1196 (16.3%) underwent the test. Younger women in their 30 s and 40 s tended to undertake the test more frequently than older women in their 50 s (P for trend &lt; 0.001). Invalid HPV test results were rare (1.3%), and neither adverse events nor serious complaints were reported. Despite adopting the opt-out procedure, more women than expected declined to participate, suggesting the need for a waiver of consent or assignment before consent to reduce selection bias. A self-sampling HPV test can be implemented in Japan and would be more accessible to young women, the predominant group affected by cervical cancer.

The mortality of coronavirus disease 2019 (COVID-19) is strongly correlated with pulmonary vascular pathology accompanied by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-triggered immune dysregulation and aberrant activation of platelets. We combined histological analyses using field emission scanning electron microscopy with energy-dispersive X-ray spectroscopy analyses of the lungs from autopsy samples and single-cell RNA sequencing of peripheral blood mononuclear cells to investigate the pathogenesis of vasculitis and immunothrombosis in COVID-19. We found that SARS-CoV-2 accumulated in the pulmonary vessels, causing exudative vasculitis accompanied by the emergence of thrombospondin-1-expressing noncanonical monocytes and the formation of myosin light chain 9 (Myl9)-containing microthrombi in the lung of COVID-19 patients with fatal disease. The amount of plasma Myl9 in COVID-19 was correlated with the clinical severity, and measuring plasma Myl9 together with other markers allowed us to predict the severity of the disease more accurately. This study provides detailed insight into the pathogenesis of vasculitis and immunothrombosis, which may lead to optimal medical treatment for COVID-19.

Backgrounds: Despite the absolute need for life-long treatment of inherited and genetic diseases, there has been little effort to develop such treatments for most of these conditions due to their rarity. Familial lecithin:cholesterol acyltransferase (LCAT) deficiency is recognized as one such orphan disease. We have been developing an adipocyte-based ex vivo gene therapy/regenerative medicine, a novel methodology that differs from the adeno-associated virus-mediated in vivo gene therapy or ex vivo gene-transduced hematopoietic cell therapy, to treat familial LCAT deficiency. Recently, a first-in-human (FIH) clinical study was conducted under the Act on Securement of Safety of Regenerative Medicine, wherein a patient with familial LCAT deficiency was treated. To obtain approval to put this treatment into practical use, a clinical trial has been designed with reference to the FIH clinical study. Methods: An interventional, open-label, unblinded dose-escalation trial was planned, referring to previous FIH clinical study. The trial aims to evaluate the safety of the investigational product in relation to the characteristics of the investigational product (ex vivo gene/cell therapy product by retroviral vector-mediated LCAT gene transduction) using two doses, and the efficacy of the treatment will be evaluated exploratively. A total of three patients will be enrolled sequentially and followed for 24 weeks after administration. This study is designed as a multicenter trial, with Chiba University Hospital administering and evaluating the safety/efficacy of the investigational products at the prescribed visit. Conclusion: This clinical trial is expected to facilitate the provision of lifelong treatment to many patients with LCAT deficiency. Trial registration number: Japan Registry of Clinical Trials (jRCT2033200096).

INTRODUCTION: Previously, we conducted a clinical trial to evaluate the safety and efficacy of transdermal electrical stimulation (TdES) with skin electrodes to improve the visual functions in patients with retinitis pigmentosa (RP). No adverse events were related to the treatment during follow-up examinations, and TdES significantly improved the mean visual acuity and visual field sensitivity. METHODS AND ANALYSIS: We developed a study protocol for a prospective, multicentre, randomised, double-masked and sham-controlled clinical trial, planned to commence on June 2021. We intend to compare the maintenance or improvement in best-corrected visual acuity, and safety of TdES using skin electrodes between patients with RP and the sham group. The primary endpoint comprises the superiority of the logarithm of the minimum angle of resolution (logMAR) visual acuity change at week 24 from baseline in the treatment and sham groups. Secondary endpoints involve the comparison of the treatment and sham groups at week 24 for the logMAR visual acuity, early treatment diabetic retinopathy study visual acuity, the mean deviation value of Humphrey field analyser 10-2, monocular Humphrey Esterman visual field test score, ellipsoid zone length, central foveal thickness and 25-item National Eye Institute Visual Function Questionnaire score. We intend to enrol 50 patients from three Japanese institutions within 1 year and follow them up for 1 years. ETHICS AND DISSEMINATION: The protocol was approved by the institutional review board at the Chiba University Hospital and two other institutions, and was registered with the Japan Registry of Clinical Trials on 17 May 2021. The trial will be conducted in accordance with the principles of the Declaration of Helsinki, and is in accordance with Good Clinical Practice standards. The findings will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: JRCT2032210094.

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

BACKGROUND: Several lines of evidence suggest that glutamatergic neurotransmission via the N-methyl-D-aspartate (NMDA) receptor plays a role in certain behavioral manifestations common to Post-Traumatic Stress Disorder (PTSD). Ifenprodil tartrate is a neuroprotective agent that binds to the GluN2B subunit of the NMDA receptor. The aim of this study is to confirm whether ifenprodil tartrate is effective in the adolescent PTSD patients. METHODS: This is a randomized, double-blind, placebo-controlled trial. Ten adolescent (13 to 18 years old) PTSD patients were randomized into two arms: placebo (n = 4), 40 mg/day ifenprodil tartrate (n = 6) for 4 weeks. All of the patients were assessed by IES-R-J (Primary outcome measure), TSCC-J, CDRS-R, DSRS-C-J and CGI-I. RESULTS: A comparison of baseline IES-R-J total scores and 4-week end-point scores showed a mild trend of improvement (p = 0.0895) and the difference score was -9.314. A comparison of baseline scores and 2-week intermediate-point scores showed that IES-R-J hyperarousal subscores and TSCC-J subscores (dissociation subscores, sexual concerns subscores) improved significantly. A comparison of baseline TSCC-J sexual concerns subscores and 4-week end-point scores improved significantly. CONCLUSIONS: Our study may prove to be an short-term effective alternative safe treatment for adolescent patients with PTSD.

INTRODUCTION: Advanced hepatocellular carcinoma (HCC) with macrovascular invasion (MVI) has the worst prognosis among all phenotypes. This trial aims to evaluate whether treatment with durvalumab, alone or in combination with tremelimumab, plus particle therapy is a safe and synergistically effective treatment in patients with advanced HCC and MVI. METHODS AND ANALYSIS: This phase Ib, multicentre (two sites in Japan), open-label, single-arm, investigator-initiated clinical trial will assess durvalumab monotherapy in combination with particle therapy (cohort A) and that of durvalumab plus tremelimumab in combination with particle therapy (cohort B) for patients with advanced HCC with MVI. Cohort A will receive 1500 mg durvalumab every 4 weeks. Cohort B will receive 1500 mg durvalumab every 4 weeks in principle and 300 mg tremelimumab only on day 1 of the first cycle. Carbon-ion radiotherapy will be administered after day 8 of the first cycle. The primary endpoints are rates of any and severe adverse events, including dose-limiting toxicities (DLTs); secondary endpoints are overall survival, 6-month survival, objective response, 6-month progression-free survival and time to progression. Patients are initially enrolled into cohort A. If cohort A treatment is confirmed to be tolerated (ie, no DLT in three patients or one DLT in six patients), the trial proceeds to enrol more patients into cohort B. Similarly, if cohort B treatment is confirmed to be tolerated (ie, no DLT in three patients or one DLT in six patients), a total of 15 patients will be enrolled into cohort B. ETHICS AND DISSEMINATION: This study was approved by the ethics committees of the two participating institutions (Chiba University Hospital and National Institutes for Quantum (approval number: 2020040) and Radiological Science and Technology, QST Hospital (approval number: C20-001)). Participants will be required to provide written informed consent. Trial results will be reported in a peer-reviewed journal publication. TRIAL REGISTRATION NUMBER: jRCT2031210046.

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

BACKGROUND: The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) is undertaking a major revision of ICH E6 Good Clinical Practice (GCP) decided to involve external stakeholders in ICH-GCP renovation. Activities such as surveys and public conferences have taken place in the United States, European Union, and Japan. For stakeholder engagement in Japan, a designated research group conducted a survey of academic stakeholders. METHODS: A total of 105 academic stakeholders from 18 institutions responded to the survey. The research group developed recommendations reflecting the survey results and the opinions from patients and the public. RESULTS: The survey showed the top four principles needing renovation were (i) informed consent (Chapter 2.9, 12.4% of respondents believed it needed renovation), (ii) systems for quality assurance (Chapter 2.13, 9.5%), (iii) information on an investigational product (Chapter 2.4, 5.7%), and (iv) procedures on clinical trial information (Chapter 2.10, 5.7%). The top three sections identified as needing renovation were: (i) informed consent (Chapter 4.8, 27.6%), (ii) monitoring (Chapter 5.18, 22.9%), and (iii) composition, functions, and operations of the ethics committee (Chapter 3.2, 14.3%). Recommendations included clarification of ICH-GCP's scope, proportionality in various aspects of clinical trials, diversity and liquidity of ethics committee members, modernization of informed consent procedures, variations in monitoring, and regulatory grade when using real-world data. CONCLUSION: The recommendations from Japanese investigators and patients have been submitted to the ICH E6 Expert Working Group, which will strengthen the robustness of the GCP renovation.

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

INTRODUCTION: Recently, the incidence of cervical cancer has increased in Japan, probably because of an interruption in human papillomavirus (HPV) vaccination and a low cervical cancer screening rate. There is a lack of evidence for self-sampling HPV testing as a cervical cancer screening tool in Japan. The Accelerating Cervical Cancer Elimination by Self-Sampling test trial aims to compare the effectiveness of screening using the self-sampling HPV test with that of routine screening concerning screening uptake and precancer detection. METHODS AND ANALYSIS: This trial has a single-municipality, open-label, parallel, superiority and randomised design. Approximately 20 000 women who have not undergone cervical cancer screening for at least 3 years will be assigned randomly to the self-sampling arm and the control arm using a 1:1 ratio. Participants assigned to the control arm will undergo routine cervical cancer screening (cytology test) provided by Ichihara City, while those assigned to the self-sampling arm will choose the routine screening or self-sampling HPV test. HPV tests will be performed using the cobas 8800 system (Roche Diagnostics, Rotkreuz, Switzerland). Participants who will undergo the self-sampling HPV testing will be recommended to undergo routine screening. The results of the cytology test and further tests, such as colposcopy and biopsy, will be collected and used for this trial. The risk ratio and risk difference in the proportion of participants with cervical intraepithelial neoplasia two or worse between the two arms will be calculated. The test for the null hypothesis (the detection rates are equal between the two arms) will be performed using Pearson's χ2 test. ETHICS AND DISSEMINATION: This trial was approved by the Research Ethics Committees of the Chiba Foundation for Health Promotion and Disease Prevention and the collaborating research institutes. The results will be disseminated through peer-reviewed journals and conference presentations. TRIAL REGISTRATION NUMBER: jRCT1030200276. Pre-results.

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

OBJECTIVES: This study aimed to determine antibody responses in healthcare workers who receive the BNT162b2 mRNA COVID-19 vaccine and identify factors that predict the response. METHODS: We recruited healthcare workers receiving the BNT162b2 mRNA COVID-19 vaccine at the Chiba University Hospital COVID-19 Vaccine Center. Blood samples were obtained before the 1st dose and after the 2nd dose vaccination, and serum antibody titers were determined using Elecsys® Anti-SARS-CoV-2S, an electrochemiluminescence immunoassay. We established a model to identify the baseline factors predicting post-vaccine antibody titers using univariate and multivariate linear regression analyses. RESULTS: Two thousand fifteen individuals (median age 37-year-old, 64.3% female) were enrolled in this study, of which 10 had a history of COVID-19. Before vaccination, 21 participants (1.1%) had a detectable antibody titer (≥0.4 U/mL) with a median titer of 35.9 U/mL (interquartile range [IQR] 7.8 - 65.7). After vaccination, serum anti-SARS-CoV-2S antibodies (≥0.4 U/mL) were detected in all 1774 participants who received the 2nd dose with a median titer of 2060.0 U/mL (IQR 1250.0 - 2650.0). Immunosuppressive medication (p < 0.001), age (p < 0.001), time from 2nd dose to sample collection (p < 0.001), glucocorticoids (p = 0.020), and drinking alcohol (p = 0.037) were identified as factors predicting lower antibody titers after vaccination, whereas previous COVID-19 (p < 0.001), female (p < 0.001), time between 2 doses (p < 0.001), and medication for allergy (p = 0.024) were identified as factors predicting higher serum antibody titers. CONCLUSIONS: Our data demonstrate that healthcare workers universally have good antibody responses to the BNT162b2 mRNA COVID-19 vaccine. The predictive factors identified in our study may help optimize the vaccination strategy.

BACKGROUND: The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) is undertaking a major revision of ICH E6 Good Clinical Practice (GCP) decided to involve external stakeholders in ICH-GCP renovation. Activities such as surveys and public conferences have taken place in the United States, European Union, and Japan. For stakeholder engagement in Japan, a designated research group conducted a survey of academic stakeholders. METHODS: A total of 105 academic stakeholders from 18 institutions responded to the survey. The research group developed recommendations reflecting the survey results and the opinions from patients and the public. RESULTS: The survey showed the top four principles needing renovation were (i) informed consent (Chapter 2.9, 12.4% of respondents believed it needed renovation), (ii) systems for quality assurance (Chapter 2.13, 9.5%), (iii) information on an investigational product (Chapter 2.4, 5.7%), and (iv) procedures on clinical trial information (Chapter 2.10, 5.7%). The top three sections identified as needing renovation were: (i) informed consent (Chapter 4.8, 27.6%), (ii) monitoring (Chapter 5.18, 22.9%), and (iii) composition, functions, and operations of the ethics committee (Chapter 3.2, 14.3%). Recommendations included clarification of ICH-GCP's scope, proportionality in various aspects of clinical trials, diversity and liquidity of ethics committee members, modernization of informed consent procedures, variations in monitoring, and regulatory grade when using real-world data. CONCLUSION: The recommendations from Japanese investigators and patients have been submitted to the ICH E6 Expert Working Group, which will strengthen the robustness of the GCP renovation.

OBJECTIVE: Indocyanine green fluorescent lymphography may be useful in patients undergoing lymphatic surgery for secondary lymphedema. This clinical trial aimed to confirm whether indocyanine green fluorescent lymphography is useful for evaluating lymphedema, identifying lymphatic vessels suitable for anastomosis, and confirming patency of a lymphaticovenular anastomosis in patients with secondary lymphedema. METHODS: This phase III, multicenter, single-arm, open-label clinical trial (HAMAMATSU-ICG study) investigated the accuracy of lymphedema diagnosis via indocyanine green fluorescent lymphography compared with lymphoscintigraphy, the identification rate of lymphatic vessels at the incision site, and the efficacy for confirming patency of a lymphaticovenular anastomosis. The external diameter of the identified lymphatic vessels and the distance from the skin surface to the lymphatic vessels based on preoperative indocyanine green fluorescent lymphography were measured intraoperatively under surgical microscopy. RESULTS: When the clinical decision for surgical indication at each research site was made, the standard diagnosis of lymphedema was considered to be correct. In 26 upper extremities, a central judgment committee blinded to the clinical presentation confirmed the imaging diagnosis as accurate in 100.0% of cases, whether assessments were made via lymphoscintigraphy or indocyanine green lymphography. In contrast, in 88 lower extremities, the accuracy rates of diagnosis based on those made by the central judgment committee were 70.5% and 88.2% for lymphoscintigraphy and indocyanine green lymphography, respectively. The external diameter of the identified lymphatic vessels was significantly greater in the lower extremities than in the upper extremities (0.54 ± 0.21 mm vs. 0.42 ± 0.14 mm, p < 0.0001), and the distance from the skin surface to the lymphatic vessels was significantly longer in the lower extremities than in the upper extremities (5.8 ± 3.5 mm vs. 4.4 ± 2.6 mm, p = 0.01). In 263 skin incisions determined using indocyanine green fluorescent lymphography findings, the identification rate of lymphatics vessels suitable for anastomosis was 97.7% (95% confidence interval: 95.1-99.2). In total, 267 lymphaticovenular anastomoses were performed. Indocyanine green fluorescent lymphography was judged as "useful" in confirming patency after anastomosis in 95.1% of cases. CONCLUSIONS: Indocyanine green fluorescent lymphography may be useful for improving the management of patients with secondary lymphedema from the outpatient setting to the operating room.

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

Importance: The current standard induction therapy for antineutrophil cytoplasm antibody (ANCA)-associated vasculitis is the combination of high-dose glucocorticoids and cyclophosphamide or rituximab. Although these regimens have high remission rates, they are associated with considerable adverse events presumably due to high-dose glucocorticoids. Objective: To compare efficacy and adverse events between a reduced-dose glucocorticoid plus rituximab regimen and the standard high-dose glucocorticoid plus rituximab regimen in remission induction of ANCA-associated vasculitis. Design, Setting, and Participants: This was a phase 4, multicenter, open-label, randomized, noninferiority trial. A total of 140 patients with newly diagnosed ANCA-associated vasculitis without severe glomerulonephritis or alveolar hemorrhage were enrolled between November 2014 and June 2019 at 21 hospitals in Japan. Follow-up ended in December 2019. Interventions: Patients were randomized to receive reduced-dose prednisolone (0.5 mg/kg/d) plus rituximab (375 mg/m2/wk, 4 doses) (n = 70) or high-dose prednisolone (1 mg/kg/d) plus rituximab (n = 70). Main Outcomes and Measures: The primary end point was the remission rate at 6 months, and the prespecified noninferiority margin was -20 percentage points. There were 8 secondary efficacy outcomes and 6 secondary safety outcomes, including serious adverse events and infections. Results: Among 140 patients who were randomized (median age, 73 years; 81 women [57.8%]), 134 (95.7%) completed the trial. At 6 months, 49 of 69 patients (71.0%) in the reduced-dose group and 45 of 65 patients (69.2%) in the high-dose group achieved remission with the protocolized treatments. The treatment difference of 1.8 percentage points (1-sided 97.5% CI, -13.7 to ∞) between the groups met the noninferiority criterion (P = .003 for noninferiority). Twenty-one serious adverse events occurred in 13 patients in the reduced-dose group (18.8%), while 41 occurred in 24 patients in the high-dose group (36.9%) (difference, -18.1% [95% CI, -33.0% to -3.2%]; P = .02). Seven serious infections occurred in 5 patients in the reduced-dose group (7.2%), while 20 occurred in 13 patients in the high-dose group (20.0%) (difference, -12.8% [95% CI, -24.2% to -1.3%]; P = .04). Conclusions and Relevance: Among patients with newly diagnosed ANCA-associated vasculitis without severe glomerulonephritis or alveolar hemorrhage, a reduced-dose glucocorticoid plus rituximab regimen was noninferior to a high-dose glucocorticoid plus rituximab regimen with regard to induction of disease remission at 6 months. Trial Registration: ClinicalTrials.gov Identifier: NCT02198248.

OBJECTIVES: The aim of this trial is to evaluate the antiviral efficacy, clinical efficacy, and safety of nelfinavir in patients with asymptomatic and mild COVID-19. TRIAL DESIGN: The study is designed as a multicenter, open-label, blinded outcome assessment, parallel group, investigator-initiated, exploratory, randomized (1:1 ratio) controlled clinical trial. PARTICIPANTS: Asymptomatic and mild COVID-19 patients will be enrolled in 10 university and teaching hospitals in Japan. The inclusion and exclusion criteria are as follows: Inclusion criteria: (1) Japanese male or female patients aged ≥ 20 years (2) SARS-CoV-2 detected from a respiratory tract specimen (e.g., nasopharyngeal swab or saliva) using PCR, LAMP, or an antigen test within 3 days before obtaining the informed consent (3) Provide informed consent Exclusion criteria: (1) Symptoms developed ≥ 8 days prior to enrolment (2) SpO2 < 96 % (room air) (3) Any of the following screening criteria: a) ALT or AST ≥ 5 × upper limit of the reference range b) Child-Pugh class B or C c) Serum creatinine ≥ 2 × upper limit of the reference range and creatinine clearance < 30 mL/min (4) Poorly controlled diabetes (random blood glucose ≥ 200 mg/dL or HbA1c ≥ 7.0%, despite treatment) (5) Unsuitable serious complications based on the assessment of either the principal investigator or the sub-investigator (6) Hemophiliac or patients with a marked hemorrhagic tendency (7) Severe diarrhea (8) Hypersensitivity to the investigational drug (9) Breastfeeding or pregnancy (10) With childbearing potential and rejecting contraceptive methods during the study period from the initial administration of the investigational drug (11) Receiving rifampicin within the previous 2 weeks (12) Participated in other clinical trials and received drugs within the previous 12 weeks (13) Undergoing treatment for HIV infection (14) History of SARS-CoV-2 vaccination or wishes to be vaccinated against SARS-CoV-2 (15) Deemed inappropriate (for miscellaneous reasons) based on the assessment of either the principal investigator or the sub-investigator INTERVENTION AND COMPARATOR: Patients who meet the inclusion criteria and do not meet any of the exclusion criteria will be randomized to either the nelfinavir group or the symptomatic treatment group. The nelfinavir group will be administered 750 mg of nelfinavir orally, three times daily for 14 days (treatment period). However, if a participant tests negative on two consecutive PCR tests of saliva samples, administration of the investigational drug for that participant can be discontinued at the discretion of the investigators. The symptomatic treatment group will not be administered the investigational drug, but all other study procedures and conditions will be the same for both groups for the duration of the treatment period. After the treatment period of 14 days, each group will be followed up for 14 days (observational period). MAIN OUTCOMES: The primary endpoint is the time to negative conversion of SARS-CoV-2. During the study period from Day 1 to Day 28, two consecutive negative PCR results of saliva samples will be considered as the negative conversion of the virus. The secondary efficacy endpoints are as follows: For patients with both asymptomatic and mild disease: area under the curve of viral load, half decay period of viral load, body temperature at each time point, all-cause mortality, incidence rate of pneumonia, percentage of patients with newly developed pneumonia, rate of oxygen administration, and the percentage of patients who require oxygen administration. For asymptomatic patients: incidence of symptomatic COVID-19, incidence of fever (≥ 37.0 °C for two consecutive days), incidence of cough For patients with mild disease: incidence of defervescence (< 37.0 °C), incidence of recovery from clinical symptoms, incidence of improvement of each symptom The secondary safety endpoints are adverse events and clinical examinations. RANDOMIZATION: Patients will be randomized to either the nelfinavir group or the symptomatic treatment group using the electric data capture system (1:1 ratio, dynamic allocation based on severity [asymptomatic], and age [< 60 years]). BLINDING (MASKING): Only the assessors of the primary outcome will be blinded (blinded outcome assessment). NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): The sample size was determined based on our power analysis to reject the null hypothesis, S (t | z =1) = S (t | z = 0) where S is a survival function, t is time to negative conversion, and z denotes randomization group, by the log-rank test with a two-sided p value of 0.05. We estimated viral dynamic parameters by fitting a nonlinear mixed-effects model to reported viral load data, and simulated our primary endpoint from viral-load time-courses that were realized from sets of viral dynamics parameters sampled from the estimated probability distribution of the parameters (sample size: 2000; 1000 each for randomization group). From this estimation of the hazard ratio between the randomization groups for the event of negative conversion using this simulation dataset, the required number of events for rejecting our null hypothesis with a power of 0.80 felled 97.345 by plugging the estimated hazard ratio, 1.79, in Freedman's equation. Therefore, we decided the required number of randomizations to be 120 after consideration of the frequency of censoring and the anticipated rate of withdrawal caused by factors such as withdrawal of consent. TRIAL STATUS: Protocol version 6.0 of February 12, 2021. Recruitment started on July 22, 2020 and is anticipated to be completed by March 31, 2022. TRIAL REGISTRATION: This trial was registered in Japan Registry of Clinical Trials (jRCT) ( jRCT2071200023 ) on 21 July 21, 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

Attenuation of the secondary injury of spinal cord injury (SCI) can suppress the spread of spinal cord tissue damage, possibly resulting in spinal cord sparing that can improve functional prognoses. Granulocyte colony-stimulating factor (G-CSF) is a haematological cytokine commonly used to treat neutropenia. Previous reports have shown that G-CSF promotes functional recovery in rodent models of SCI. Based on preclinical results, we conducted early phase clinical trials, showing safety/feasibility and suggestive efficacy. These lines of evidence demonstrate that G-CSF might have therapeutic benefits for acute SCI in humans. To confirm this efficacy and to obtain strong evidence for pharmaceutical approval of G-CSF therapy for SCI, we conducted a phase 3 clinical trial designed as a prospective, randomized, double-blinded and placebo-controlled comparative trial. The current trial included cervical SCI [severity of American Spinal Injury Association (ASIA) Impairment Scale (AIS) B or C] within 48 h after injury. Patients are randomly assigned to G-CSF and placebo groups. The G-CSF group was administered 400 μg/m2/day × 5 days of G-CSF in normal saline via intravenous infusion for five consecutive days. The placebo group was similarly administered a placebo. Allocation was concealed between blinded evaluators of efficacy/safety and those for laboratory data, as G-CSF markedly increases white blood cell counts that can reveal patient treatment. Efficacy and safety were evaluated by blinded observer. Our primary end point was changes in ASIA motor scores from baseline to 3 months after drug administration. Each group includes 44 patients (88 total patients). Our protocol was approved by the Pharmaceuticals and Medical Device Agency in Japan and this trial is funded by the Center for Clinical Trials, Japan Medical Association. There was no significant difference in the primary end point between the G-CSF and the placebo control groups. In contrast, one of the secondary end points showed that the ASIA motor score 6 months (P = 0.062) and 1 year (P = 0.073) after drug administration tend to be higher in the G-CSF group compared with the placebo control group. Moreover, in patients aged over 65 years old, motor recovery 6 months after drug administration showed a strong trend towards a better recovery in the G-CSF treated group (P = 0.056) compared with the control group. The present trial failed to show a significant effect of G-CSF in primary end point although the subanalyses of the present trial suggested potential G-CSF benefits for specific population.

Revisions of drug package inserts (PIs) may be made immediately after approval or after considerable clinical experience; however, it is unclear whether there is a relationship between the characteristics of these safety measures and the period since drug approval. Here, we analyzed 209 cases of safety measures (revisions of the PIs) taken in Japan over 5 years (FY2014 to FY2018). The median, minimum, and maximum period from approval date in Japan to PI revision date was 6.29 years (interquartile range 2.68-15.53 years), 0.16 years, and 59.69 years, respectively. The cases were classified into four groups depending on types of adverse reaction and therapeutic category in relation to the national approval date and international birth date, resulting in the grouping together of particular adverse reactions and therapeutic drugs. For example, "Hepatobiliary disorders", "Blood and lymphatic system disorders", "Respiratory, thoracic and mediastinal disorders", "Antineoplastics", "Chemotherapeutics", and "Other agents affecting metabolism" were associated with the group of safety measures taken early after approval of a drug soon after the international birth date, suggesting that careful attention at an earlier stage after approval is necessary for these adverse reactions and drugs. Understanding such features of PI revisions makes pharmacovigilance planning more appropriate, contributing to the implementation of rapid and proper safety measures after drug approval.

The development of gene therapy products has been expanding globally, and among them, the recombinant adeno-associated virus (rAAV) vector is one of the most promising vectors for gene transfer. For efficient and rapid development of the manufacturing process and quality control strategy, the quality by design (QbD) approach can be as effective for gene therapy products as it is for gene recombinant proteins, which have been developed for decades. However, prior available knowledge required for the QbD approach is limited in the field of gene therapy. Here, we comprehensively review rAAV study results that can form the basis of QbD-based development and propose a critical quality attribute identification method suitable for gene therapy development. As a case study for rAAV, we propose a series of practical development steps, including a quality target product profile (QTPP) setting, identification of critical quality attributes (CQAs), repetitive risk assessment associated with process optimization, design space (DS) establishment, and control strategy using the QbD method. Our case study, which was based on publicly available literature, is a basic model that can be augmented by unique data pertaining to specific products. An improvement in rAAV development is expected using this model as the first step.

Introduction: Secondary lymphoedema of the extremities is an important quality-of-life issue for patients who were treated for their malignancies. Indocyanine green (ICG) fluorescent lymphography may be helpful for assessing lymphoedema and for planning lymphaticovenular anastomosis (LVA). The objective of the present clinical trial is to confirm whether or not ICG fluorescent lymphography using the near-infrared monitoring camera is useful for assessing the indication for LVA, for the identification of the lymphatic vessels before the conduct of LVA, and for the confirmation of the patency of the anastomosis site during surgery. Methods and analysis: This trial is a phase III, multicentre, single-arm, open-label clinical trial to assess the efficacy and safety of ICG fluorescent lymphography when assessing and treating lymphoedema of patients with secondary lymphoedema who are under consideration for LVA. The primary endpoint is the identification rate of the lymphatic vessels at the incision site based on ICG fluorescent lymphograms obtained before surgery. The secondary endpoints are 1) the sensitivity and specificity of dermal back flow determined by ICG fluorescent lymphography as compared with 99mTc lymphoscintigraphy-one of the standard diagnostic methods and 2) the usefulness of ICG fluorescent lymphography when confirming the patency of the anastomosis site after LVA. Ethics and dissemination: The protocol for the study was approved by the Institutional Review Board of each institution. The trial was filed for and registered at the Pharmaceuticals and Medical Devices Agency in Japan. The trial is currently on-going and is scheduled to end in June 2020. Trial registration number: jRCT2031190064; Pre-results.

We conducted a phase I study of the trans-bronchial injection of α-galactosylceramide (αGalCer)-pulsed antigen presenting cells (APCs) to evaluate their safety, immune responses, and anti-tumor activities. Patients with advanced or recurrent non-small cell lung cancer (NSCLC) refractory to standard treatments were eligible. αGalCer-pulsed APCs were administered intratumorally or intranodally by bronchoscopy. Twenty-one patients were enrolled in this study. No severe adverse events related to the cell therapy were observed during this study in any patient. After αGalCer-pulsed APCs were administrated, increased iNKT cell numbers were observed in PBMCs from eight cases, and IFN-γ producing cells were increased in the peripheral blood of 10 cases. Regarding clinical responses, one case exhibited a partial response and eight were classified as stable disease. In the tumor microenvironment, IFN-γ expression was upregulated after treatment in partial response or stable disease cases and TGF-β was upregulated in progressive disease cases.

BACKGROUND: Invariant natural killer T (iNKT) cells produce copious amounts of cytokines in response to specific glycolipid antigens such as α-galactosylceramide (αGalCer) presented by CD1d-expressing antigen-presenting cells (APCs), thus orchestrating other immune cells to fight tumors. Because of their ability to induce strong antitumor responses activated by αGalCer, iNKT cells have been studied for their application in cancer immunotherapy. In our previous phase I/II trial in non-small cell lung cancer (NSCLC) patients who had completed the standard treatment, we showed a relatively long median survival time without severe treatment-related adverse events. Based on these results, we performed a phase II trial to evaluate clinical responses, safety profiles and immune responses as a second-line treatment for advanced NSCLC. METHODS: Patients with advanced or recurrent NSCLC refractory to first-line chemotherapy were eligible. αGalCer-pulsed APCs were intravenously administered four times. Overall survival time was evaluated as the primary endpoint. The safety profile and immune responses after APC injection were also monitored. This study was an open label, single-arm, phase II clinical trial performed at Chiba University Hospital, Japan. RESULTS: Thirty-five patients were enrolled in this study, of which 32 (91.4%) completed the trial. No severe adverse events related to the treatment were observed. The estimated median survival time of the 35 cases was 21.9 months (95% CI, 14.8 to 26.0). One case (2.9%) showed a partial response, 14 cases (40.0%) remained as stable disease, and 19 cases (54.3%) were evaluated as progressive disease. The geometric mean number of iNKT cells in all cases was significantly decreased and the mean numbers of natural killer (NK) cells, interferon-γ-producing cells in response to αGalCer, and effector CD8+ T cells were significantly increased after the administration of αGalCer-pulsed APCs. CONCLUSIONS: The intravenous administration of αGalCer-pulsed APCs was well-tolerated and was accompanied by prolonged overall survival. These results are encouraging and warrant further evaluation in a randomized phase III trial to demonstrate the survival benefit of this immunotherapy. TRIAL REGISTRATION NUMBER: UMIN000007321.

INTRODUCTION: Progestin therapy is the only fertility-sparing treatment option for patients with atypical endometrial hyperplasia (AEH) and endometrial cancer (EC). However, the results of three meta-analyses revealed a high remission rate, as well as an association with a high rate of relapse. We previously conducted a phase II of medroxyprogesterone acetate (MPA) plus metformin as a fertility-sparing treatment for AEH and EC patients, and reported that metformin inhibited disease relapse after remission. METHODS AND ANALYSIS: A randomised, open, blinded-endpoint design phase IIb dose response trial was planned to commence in July 2019. The trial aims to identify the appropriate dose of metformin to be combined with MPA therapy for fertility-sparing treatment of patients with AEH and EC. The primary endpoint of the trial is the 3-year relapse-free survival (RFS) rate. The secondary endpoints are RFS rate, the overall rate of response to MPA therapy, the conception rate after treatment, the outcome of pregnancy, toxicity evaluation and changes in insulin resistance and body mass index. A total of 120 patients will be enrolled from 15 Japanese institutions within a 2.5-year period and followed up for at least 3 years. ETHICS AND DISSEMINATION: The protocol was approved by the institutional review board at Chiba University Hospital and boards at 14 other institutions. The trial will be conducted according to the principles of the World Medical Association's Declaration of Helsinki and in accordance with Good Clinical Practice (GCP) standards. The trial findings will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: Japan Registry of Clinical Trials (jRCT2031190065).

AIM: An investigator-initiated clinical study was carried out to evaluate the therapeutic potency of SR-0379 for the treatment of leg ulcers in patients with Werner syndrome. METHODS: A multicenter, open-label study was carried out from September 2017 to February 2018. The inclusion criteria for leg ulcers were: (i) leg ulcers in patients with Werner syndrome, diabetes or critical limb ischemia/venous stasis; and (ii) a wound size of >1 cm and <6 cm in diameter. Four individuals with Werner syndrome and diabetic ulcers, respectively, were enrolled. SR-0379 (0.1%) was sprayed on skin ulcers once per day for 4 weeks. Efficacy was evaluated by determining the rate of wound size reduction as a primary end-point at 4 weeks after the first treatment compared with the pretreatment wound size. As secondary end-points, the DESIGN-R score index, the 50% wound size reduction ratio, time to wound closure and quantification of wound bacteria were also evaluated. The safety of SR-0379 was evaluated during the study period. RESULTS: The reduction rate of ulcer size treated with 0.1% SR-0379 was 22.90% (mean) in the Werner syndrome ulcers group (n = 4) and 35.70% (mean) in the diabetic ulcers group (n = 4), respectively. The DESIGN-R score decreased by 4.0 points in the Werner syndrome ulcers group and 4.3 points in the diabetic ulcers group. Two mild adverse events were reported in two patients, and causal relationships were denied in any events. CONCLUSION: Treatment with SR-0379 was safe, well-tolerated, and effective for leg ulcers of both Werner syndrome and diabetes patients. Geriatr Gerontol Int 2019; 19: 1118-1123.

To evaluate the safety and efficacy of transdermal electrical stimulation (TdES) with skin electrodes on improving the visual functions of patients with retinitis pigmentosa (RP), twenty eyes of 10 patients with RP underwent TdES (10-ms biphasic pulses, 20 Hz, 30 min) 6 times at 2 week intervals. All patients were stimulated bilaterally with 1.0 mA pulses. The primary endpoint was safety, and the secondary endpoints were the changes in the best-corrected visual acuity (BCVA), visual fields determined by the Humphrey field analyzer (HFA) 10-2 and Goldmann perimetry, and answers to the Visual Function Questionnaire-25. All of the 10 enrolled patients completed the study according to the protocol. No adverse events related to the treatments were reported during the follow-up examinations. The mean BCVA and Early Treatment Diabetic Retinopathy Study visual acuity were significantly improved after the TdES (P = 0.0078 and P = 0.001, respectively). The mean deviation of the HFA 10-2 was also significantly improved (P = 0.0076). We conclude that TdES with skin electrode is a safe therapeutic option and should be considered as a treatment option for patients with RP.

We investigated impacts of increased generic drug use on spontaneous adverse event reports (SAERs), because SAERs have been a major source of data for drug safety assessment at the postmarket stage. Reporting proportion of SAERs for the generic drugs was consistently and significantly lower than that for the original branded drugs. The reporting proportion targeting for 55 active product ingredients, which had the longest follow-up period after generic drug marketed, gradually decreased for the original branded drugs and increased for the generic drugs. However, these transitions did not parallel the changes in market share over the same period. These results suggest that the reporting proportion of SAERs for generic drugs may not keep pace with growth in market share. When generic drugs account for the majority of market share, utilization of multiple sources of information and data, in addition to SAERs, may be a key to assuring drug safety at the postmarket stage.

BACKGROUND: There is still no definite treatment for refractory Kawasaki disease (KD). In this pilot study, we evaluated the safety and efficacy of a new protocol consisting of sivelestat sodium hydrate (SSH) combined with additional i.v. immunoglobulin (IVIG) for KD resistant to initial IVIG therapy. METHODS: This study is a prospective non-randomized, open-label and single-arm study undertaken in a population of refractory KD patients at Chiba University Hospital from December 2006 to March 2016. The subjects had KD resistant to initial IVIG (2 g/kg) and received SSH (0.2 mg/kg/h for 5 days) combined with additional IVIG (2 g/kg) as a second-line therapy. We evaluated the safety and efficacy of the treatment during the study period. RESULTS: Forty-six KD patients were enrolled in this study and no serious adverse event was noted. Of these, 45 patients were evaluated for the incidence of coronary artery lesions, which occurred in one patient (2.2%; 95% CI: 0.5-15.2). Twenty-eight (62.2%) responded promptly and were afebrile after the therapy. The median total duration of fever was 8 days (range, 6-28 days). CONCLUSIONS: Additional IVIG combined with SSH as a second-line therapy for KD refractory to initial IVIG therapy was safe and well tolerated and could be a promising option for severe KD. Further investigations are expected to clarify the safety and timing of SSH treatment for KD.

BACKGROUND: Genetic studies have indicated possible involvement of the upregulated calcium-nuclear factor of activated T cells pathway in the pathogenesis of Kawasaki disease. We aimed to assess safety and efficacy of ciclosporin, an immunosuppressant targeting this pathway, for protection of patients with Kawasaki disease against coronary artery abnormalities. METHODS: We did a randomised, open-label, blinded endpoints trial involving 22 hospitals in Japan between May 29, 2014, and Dec 27, 2016. Eligible patients predicted to be at higher risk for intravenous immunoglobulin (IVIG) resistance were randomly assigned to IVIG plus ciclosporin (5 mg/kg per day for 5 days; study treatment) or IVIG (conventional treatment) groups, stratified by risk score, age, and sex. The primary endpoint was incidence of coronary artery abnormalities using Japanese criteria during the 12-week trial, assessed in participants who received at least one dose of study drug and who visited the study institution at least once during treatment. This trial is registered to Center for Clinical Trials, Japan Medical Association, number JMA-IIA00174. FINDINGS: We enrolled 175 participants. One patient withdrew consent after enrolment and was excluded and one patient (in the study treatment group) was excluded from analysis because of lost echocardiography data. Incidence of coronary artery abnormalities was lower in the study treatment group than in the conventional treatment group (12 [14%] of 86 patients vs 27 [31%] of 87 patients; risk ratio 0·46; 95% CI 0·25-0·86; p=0·010). No difference was found in the incidence of adverse events between the groups (9% vs 7%; p=0·78). INTERPRETATION: Combined primary therapy with IVIG and ciclosporin was safe and effective for favourable coronary artery outcomes in Kawasaki disease patients who were predicted to be unresponsive to IVIG. FUNDING: Japan Agency for Medical Research and Development (grant CCT-B-2503).