Safety and Efficacy of Lemborexant in Insomnia Patients: Results of a Postmarketing Observational Study of Dayvigo® Tablets.

BACKGROUND AND OBJECTIVE: A prospective, postmarketing observational study was conducted to evaluate the safety and efficacy of lemborexant (LEM) tablets in daily clinical practice in Japan. No other studies of a similar size have been conducted since the marketing approval of LEM, making this the first report of its kind. METHODS: Insomnia patients (n = 550) administered LEM (5-10 mg daily) for the first time were enrolled. Adverse events were collected for target events (somnolence, parasomnia, narcolepsy and associated conditions, suicidal ideation and suicidal behavior). Overall improvement of insomnia symptoms was assessed by the investigator based on the patient's complaint. Subjective sleep onset latency (sSOL) and subjective total sleep time (sTST) were investigated as sleep parameters. RESULTS: A case report form was obtained from 539 patients. The incidence of adverse drug reactions (ADRs) was 7.65% for somnolence, 1.76% for nightmares, 0.59% for abnormal dreams, and 0.20% for sleep paralysis. No serious ADRs or ADRs related to suicidal ideation or suicidal behavior were observed. The efficacy rate at the final evaluation was 80.83%. Decreased sSOL and increased sTST were observed as assessed starting from Week 8 of treatment. CONCLUSION: Based on the results of this study, the safety result was consistent with the safety profile described in the current package insert. Efficacy results also indicated that LEM is clinically useful.

Linguistic and Psychometric Validation of the Cognition Bolt-On Version of the Japanese EQ-5D-5L for the Elderly.

BACKGROUND: The need for a cognition bolt-on version of the EQ-5D, which would capture cognitive impairment by adding a dimension to the generic instrument assessing health status, has been increasing in Japan. OBJECTIVE: To develop a cognition bolt-on version of the 5-level EQ-5D (EQ-5D-5L+C), we linguistically validated a cognition dimension and psychometrically validated the EQ-5D-5L+C. METHODS: Following linguistic validation of the cognition dimension, psychometric validation of the EQ-5D-5L+C proxy version utilized anonymized data collected from nursing home residents between October 2021 to April 2022. The validity, reliability, and sensitivity to change were evaluated. RESULTS: Data from 254 participants, including the finalized Japanese EQ-5D-5L+C proxy version, were analyzed for the psychometric validation. Mean (±standard deviation) age and Mini-Mental State Examination (MMSE) scores were 87.14±7.29 years and 15.76±8.46, respectively. The correlation was strongest between the cognition dimension and MMSE scores (rs = -0.640). Test-retest reliability was good in the cognition dimension in both baseline and two-time points (3 months: k = 0.644; 6 months: k = 0.656). Although a correlation between changes in the cognition dimension and those in the MMSE score from baseline was weak (3 months: rs = -0.191; 6 months: rs = -0.267), a correlation with changes in the MMSE score was higher when the cognition dimension was added compared to the EQ-5D alone (3 months: rs = -0.142 versus rs = -0.074). CONCLUSION: The Japanese EQ-5D-5L+C proxy version developed is a valid tool that captures health status including cognitive function, with a consideration for an over-time assessment. The benefits in adding the cognition dimension to the EQ-5D-5L to assess health state were suggested.

Correction to: Prevalence, incidence, and medications of narcolepsy in Japan: a descriptive observational study using a health insurance claims database.

[This corrects the article DOI: 10.1007/s41105-022-00406-4.].

Real-world evaluation of perampanel effectiveness in Japanese adolescents with epilepsy

Objective: Real-world data from adolescents treated with perampanel in a routine clinical setting are lacking in Japan. We evaluated the safety and efficacy of perampanel for adolescent patients (aged 12-17 years) with drug-resistant, refractory epilepsy in real-world settings. Methods: This was a large-scale, prospective, observational post-marketing study, with a 104-week observation period. Safety was assessed by monitoring adverse effects (adverse drug reactions). For efficacy assessments, seizure frequency was compared between the four weeks immediately prior to the last observation and the four weeks before the commencement of perampanel. Results: In total, 519 patients were enrolled; 505 and 484 patients were included in the safety and efficacy analysis sets, respectively. The mean age was 14.4 years. The mean daily dose of perampanel was 4.4 mg/day. The main reasons for discontinuation at 104 weeks were adverse events (48.4%) and inadequate efficacy (46.8%). The retention rate at 104 weeks was 50.5%. Adverse effect and severe adverse effect incidences were 42.2% and 1.8%, respectively. The most common adverse effects were somnolence (13.5%), irritability (8.5%), dizziness (5.1%), and agitation (4.8%). There were significant differences in the occurrence of adverse effects between the initial titration interval of <2 weeks and 2-4 weeks (odds ratio=0.441, p=0.029) and 4-8 weeks (odds ratio=0.462, p=0.027). The median percent change in seizure frequency at the last observation carried forward was −50.0 for focal aware seizures with motor signs, −73.3 for focal aware seizures without motor signs, −28.6 for focal impaired awareness seizures, −62.6 for focal to bilateral tonic-clonic seizures, and −20.0 for generalized tonic-clonic seizures. Significance: In adolescent patients, perampanel was well tolerated and efficacious in reducing seizure frequency. No unexpected safety issues were observed, and slow titration may reduce the incidence of adverse effects.

Neu1 deficiency increases the susceptibility of zebrafish to Edwardsiella piscicida infection via lysosomal dysfunction.

Neu1 is a lysosomal glycosidase that catalyzes the removal of sialic acids from glycoconjugates. Although Neu1 sialidase is highly conserved among vertebrates, the role of fish Neu1 is not fully understood because of its unique aquatic living situation. Compared to land animals, fish have a higher chance of bacterial infection, and to understand the role of fish Neu1, the susceptibility of Neu1 knockout zebrafish (Neu1-KO) was evaluated using Edwardsiella piscicida, a fish pathogen. Neu1-KO larvae showed high susceptibility to E. piscicida, despite the activation of macrophages, and presented increased lysosomal signals induced by the accumulation of Sia α2-3 linked oligosaccharides. The accumulation coincided with the signal of the macrophage marker, suggesting that the dysfunction of lysosomes in macrophages would result in a high susceptibility of Neu1-KO to E. piscicida. Chloroquine, an inhibitor of lysosomal degradation, induced high mortality of wild type zebrafish with E. piscicida infection accompanied by increased lysosomal accumulation, similar to Neu1-KO zebrafish. This study revealed that Neu1 sialidase plays a crucial role in the lysosomal degradation of macrophages with a bacterial infection.

Cost-effectiveness analysis of lemborexant for treating insomnia in Japan: a model-based projection, incorporating the risk of falls, motor vehicle collisions, and workplace accidents.

BACKGROUND: Lemborexant has demonstrated statistically significant improvements in sleep onset and sleep maintenance compared with placebo and zolpidem tartrate extended release, measured both objectively using polysomnography and subjectively using sleep diaries, in the phase 3 clinical trial SUNRISE 1. This study evaluated the cost-effectiveness of lemborexant compared with suvorexant, zolpidem immediate release (IR), and untreated insomnia. METHODS: A decision-tree model was developed for falls, motor vehicle collisions, and workplace accidents associated with insomnia and insomnia treatments from a Japanese healthcare perspective and with a 6-month time horizon. The model extracted subjective sleep onset latency treatment responses and disutility values for non-responders from SUNRISE 1. Cost-effectiveness was assessed using incremental cost per quality-adjusted life year (QALY) gained. One-way and probabilistic sensitivity analyses were conducted to evaluate the impact of parameter uncertainty on the results. RESULTS: In the base-case analysis, the mean estimated QALYs for lemborexant, suvorexant, zolpidem-IR, and untreated insomnia were 0.4220, 0.4204, 0.4113, and 0.4163, and expected medical costs were JPY 34 034, JPY 38 371, JPY 38 139, and JPY 15 383, respectively. Lemborexant saved JPY 4337 and JPY 4105 compared with suvorexant or zolpidem-IR, respectively, while conferring QALY benefits. The incremental cost-effectiveness ratio (ICER) of lemborexant compared with that of untreated insomnia was JPY 3 220 975 /QALY. Lemborexant was dominant over suvorexant and zolpidem-IR and was cost-effective when compared with untreated insomnia. Sensitivity analyses supported the results' robustness. CONCLUSIONS: In a Japanese clinical practice setting, lemborexant may represent a better investment for treating insomnia in the healthcare system in Japan.

Comparative analysis of medical costs after hepatectomy versus radiofrequency ablation in patients with hepatocellular carcinoma in real-world clinical practice.

AIM: To compare the total medical costs and treatment outcomes in patients with primary hepatocellular carcinoma (HCC) according to their initial treatment, that is, hepatectomy or radiofrequency ablation (RFA), in real-world clinical practice in Japan. METHODS: This retrospective observational study was conducted using a medical claims database. Patients who underwent hepatectomy or RFA for primary HCC were matched using propensity score matching methods for available baseline characteristics. The average per-patient total medical costs from the date of initial treatment to up to 3 years were estimated. The 3-year survival and recurrence rates were estimated using the Kaplan-Meier method. RESULTS: Data of 1726 patients (863 in each group) were analyzed. The average 3-year medical costs were USD 8000 lower in the RFA group than in the hepatectomy group (USD 35,000 vs. USD 43,000). Patients in the RFA group had comparable 3-year overall survival to those in the hepatectomy group (87.6% vs. 90.4%). However, the 3-year recurrence rate was significantly higher in the RFA group than in the hepatectomy group (41.5% vs. 30.8%; hazard ratio = 1.56, 95% confidence interval: 1.31-1.87). CONCLUSIONS: In this 3-year study, patients achieved similar survival rates irrespective of initial treatment, but the RFA group had a lower total medical cost burden than the hepatectomy group. If both treatments are equally feasible, RFA may be a preferable initial curative treatment for primary HCC. However, careful consideration and adequate treatment should be given due to its higher recurrence risk.

[Safety and Efficacy of Rimabotulinumtoxin B in Patients with Cervical Dystonia in Observational Study].

This post-marketing observational study was conducted on botulinum toxin type B (NerBloc® 2500 units) in 1537 patients with cervical dystonia, a sample size larger than the previous studies. The incidence of adverse drug reactions was 12.6% (188/1487 patients); the most common adverse drug reactions were dysphagia, thirst, injection site pain, and dry mouth, which were similar to those reported previously and no new problems were found. Dry mouth and thirst were considered characteristic to this product and thought to be reflective of the strong action on autonomic nerves, suggesting potential application in other disorders. The efficacy did not decrease substantially with an increased number of doses; the efficacy shown as the total of "significantly improved" and "improved" in clinical global impression up to 12 doses in at least 100 patients was around 45%, indicating an efficacy similar to type A. The efficacy at final observation shown as total of "significant improved" and "improved" was 38.5%, while the total of these and "moderately improved" was 76.9%. There was no significant difference in efficacy with different maximum doses of the product, with a dose as low as 5000 IU≤ thought to be effective in some patients.

Evaluation of real-world effectiveness of perampanel in Japanese adults and older adults with epilepsy.

OBJECTIVE: While previous studies have demonstrated the safety and effectiveness of perampanel (PER) in combination with other anti-seizure medications in adult patients, data for older patients are limited. This study aimed to confirm real-world safety and effectiveness of combination treatment with PER in Japanese patients with focal seizures with or without focal to bilateral tonic-clonic seizures (FBTCS) or generalised tonic-clonic seizures (GTCS) according to age subgroups (<65 and ≥65 years of age). METHODS: This large-sample prospective post-marketing observational study included a 24-52-week observation period after the first PER treatment. Safety was assessed according to adverse drug reactions (ADRs) and efficacy was evaluated based on the 50% responder rate and rates of overall symptom improvement. RESULTS: Among the 3,808 patients who were enrolled, 3,716 (3,026 patients aged <65 years and 690 patients aged ≥65 years) and 3,272 were included in the safety and efficacy analysis datasets, respectively. ADRs were reported for 1,247 patients (33.6%) in the safety analysis dataset. Of these, 36.2% and 22.2% were aged <65 years and ≥65 years, respectively, and the most common ADRs were somnolence (11.6%, 5.5%) and dizziness (9.7%, 5.4%). The 50% responder rates in patients aged <65 years and those ≥65 years were 60.1% and 89.0% for those with focal aware seizures (FAS) with motor signs; 48.0% and 60.0% for FAS without motor signs; 47.4% and 80.2% for focal impaired awareness seizures; 70.8% and 93.4% for FBTCS; and 63.6% and 88.9% for GTCS, respectively. The improvement rates of symptoms/conditions were also higher in patients aged ≥65 years than those <65 years. SIGNIFICANCE: PER was effective in reducing seizure frequency and was safe, especially in older patients. PER may be a clinical treatment option for older patients with seizure disorders.

Prevalence, incidence, and medications of narcolepsy in Japan: a descriptive observational study using a health insurance claims database.

The objectives of this study were to describe prevalence, incidence, and medications among patients who were diagnosed with narcolepsy in Japan using a claims database. Patients diagnosed with narcolepsy were identified from January 2010 to December 2019 using an employment-based health insurance claims database compiled by JMDC Inc. The prevalence and incidence of narcolepsy were estimated annually in the overall population and by age and sex among employees and their dependents aged < 75 years. Medications, examined for each quarter in the overall population, were modafinil, methylphenidate, pemoline, tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors. We identified 1539 patients with narcolepsy. The overall annual prevalence increased from 5.7 to 18.5/100,000 persons in 2010 and 2019, respectively. Large increases were found from 2010 to 2019 in patients aged 20-29 years and 10-19 years, with the highest prevalence in 2019 (9.7-37.5/100,000 persons and 5.0-27.1/100,000 persons). The overall incidence slightly increased from 3.6 to 4.3/100,000 person-year from 2010 to 2019, and the highest incidence was found in patients aged 20-29 years and 10-19 years (5.8-11.3/100,000 person-year, and 3.8-7.4/100,000 person-year from 2010 to 2019, respectively). Methylphenidate and modafinil were commonly prescribed in 2010 (27.3-38.9% and 17.5-45.5%, respectively). Methylphenidate prescriptions declined during the 10 years, whereas modafinil prescriptions increased (15.6-17.1% and 43.8-45.8% in 2019, respectively). The estimated prevalence and incidence of narcolepsy appeared to increase from 2010 to 2019, especially in teenagers and 20-year olds. Supplementary Information: The online version contains supplementary material available at 10.1007/s41105-022-00406-4.

Efficacy of botulinum toxin type B (rimabotulinumtoxinB) in patients with cervical dystonia previously treated with botulinum toxin type A: A post-marketing observational study in Japan.

To date, efficacy data on botulinum toxin type B (rimabotulinumtoxinB) in patients with cervical dystonia (CD) previously treated with botulinum toxin type A in a large population are lacking; thus, we aimed to evaluate type B efficacy in this patient population. In a post-marketing observational cohort study, 150 patients previously treated with botulinum toxin type A were enrolled, of whom 138 were followed up for 1 year after the initial type B injection. Final observation data were available for 122 patients. Efficacy was evaluated using the Toronto Western Spasmodic Torticollis Rating Scale. Total score improved from 39.9 at baseline to 34.3 at 4 weeks after the first injection, and pain score improved from 8.9 to 7.9. Improvements were maintained through six further injections in two subpopulations: patients who showed resistance to botulinum toxin type A and patients who were not type A resistant but switched to type B. For a number of patients, even low doses (<5000 units) of botulinum toxin type B demonstrated efficacy. These findings support the efficacy of botulinum toxin type B in clinical settings for the management of CD symptoms, including pain, even at low doses, regardless of the patient's botulinum toxin type A resistance status.

Effectiveness of drug safety measures for reducing the incidence of adverse drug reactions: Post-hoc analysis of data from all-case surveillance of iguratimod using generalized estimating equations.

A post-marketing study was performed on all patients who had started treatment with iguratimod, a conventional synthetic disease-modifying antirheumatic drug approved in Japan. During the study period, various safety measures were implemented to reduce risks. We investigated the frequency of adverse drug reactions before and after implementation of each safety measure to examine the preventive effect of these measures. Post-hoc analysis was performed using data from all-case surveillance of iguratimod. The subjects were all of the patients receiving iguratimod for whom safety information was obtained. To identify the time after starting administration when adverse drug reactions were most likely to occur, a generalized linear mixed-effect model was applied for the period from initiation of administration until occurrence of reactions in each patient. The mean incidence of adverse drug reactions per patient was compared before and after the implementation of safety measures by using generalized estimating equations based on a two-sided test, 95% confidence interval, and 5% significance level. The number of patients treated with iguratimod was not related to changes in the number of patients with adverse drug reactions. After implementing precautions regarding co-administration with warfarin and liver dysfunction, the estimated mean incidence rate of adverse drug reactions (95% confidence interval) decreased significantly to 0.73 (0.59-0.90) and 0.72 (0.55-0.94), respectively. Accordingly, some of the implementation of safety measures significantly reduced adverse drug reactions. The effectiveness of safety measures implemented during the all-case surveillance of iguratimod was evaluated, revealing that early implementation of safety measures decreased the incidence of adverse drug reactions.

Treatment patterns and medical costs after hepatectomy in real-world practice for patients with hepatocellular carcinoma in Japan.

AIM: To examine the treatment patterns and medical costs in real-world practice among patients who received hepatectomy for hepatocellular carcinoma (HCC) in Japan. METHODS: Data of patients who underwent hepatectomy as an initial therapy for primary HCC were extracted from a Japanese medical claims database from April 2008 to December 2019. The types of additional treatments for recurrent HCC and medical costs for up to 3 years from the first hepatectomy were analyzed. The average cumulative cost per patient starting on the date of the first hepatectomy was calculated using the Kaplan-Meier sample-average method. RESULTS: Data from 2 342 patients (median age, 71 years) were analyzed. Overall, 35.6% of patients received at least one HCC treatment within 3 years of the first hepatectomy. The total average cumulative 3-years medical cost was JPY 4 993 300 (95% confidence interval [CI]: 4 804 100 to 5 220 500). Surgical procedures were the most costly components in the first month after hepatectomy, whereas the costs of drugs, which mainly included antiviral and antineoplastic medications, increased thereafter. Patients with advanced stage HCC, hepatitis C, or a higher Charlson Comorbidity Index at hepatectomy, or those who required additional treatment, especially with antineoplastic drugs for recurrent HCC, incurred higher medical costs. CONCLUSIONS: Patients with HCC after hepatectomy experienced a large economic burden, which was more serious for those with advanced stage HCC, higher comorbidities, and hepatitis at baseline and for patients treated with antineoplastic drugs. A treatment selection that considers its medical cost burden would help to reduce some of these economic burdens.

Cost-Effectiveness of Lenvatinib in the Treatment of Patients With Unresectable Hepatocellular Carcinomas in Japan: An Analysis Using Data From Japanese Patients in the REFLECT Trial.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality in Japan. Prognosis is poor, and until recently sorafenib was the only treatment option available for patients with unresectable disease. Lenvatinib is the first therapy to demonstrate noninferiority to sorafenib. An analysis was conducted using clinical data from Japanese patients in the phase III REFLECT trial to assess the cost-effectiveness of lenvatinib versus sorafenib for first-line treatment of unresectable HCC in Japan. METHODS: A partitioned survival model was implemented adopting the perspective of the Japanese healthcare system, with costs and outcomes modeled over a lifetime horizon and using a discount rate of 2%, as per Japanese guidelines. Population data from the Japanese subpopulation of REFLECT were used to extrapolate outcomes, and costs and resource use were based on Japanese sources. The Japanese tariff was applied to EQ-5D data collected during the REFLECT clinical trial to obtain utility values reflecting the preferences of the Japanese population. RESULTS: Compared with sorafenib, lenvatinib is dominant because it is associated with a reduction in incremental costs of ¥156 799 and incremental quality-adjusted life-years of 0.31. These results were robust to changes in key assumptions, and probabilistic outcomes aligned with deterministic outcomes. CONCLUSION: Given the use of Japan-specific data in the cost-effectiveness model, it is expected that the use of lenvatinib as a first-line treatment in Japan will be associated with cost savings and improved clinical outcomes versus sorafenib for patients with unresectable HCC.

Factors influencing physician decisions to discontinue treatment after onset of liver dysfunction: Post-hoc analysis of an all-case post-marketing surveillance study of iguratimod.

Objectives: Adverse drug reactions (ADRs) related to liver dysfunction are a common problem in patients with rheumatoid arthritis (RA) receiving iguratimod, but which patient subgroups go on to discontinue iguratimod treatment is unclear. A post-hoc analysis of a post-marketing surveillance study was performed to investigate factors influencing treatment continuation after the onset of liver dysfunction.Methods: Types of ADR were compared between patients in whom iguratimod treatment was discontinued or continued in accordance with the judgment of the patient's physician after the patient developed liver dysfunction as an ADR. Stepwise logistic regression analysis was also conducted to investigate factors associated with treatment discontinuation.Results: The multivariate analysis found that concomitant use of methotrexate (MTX) at >8 mg/week (vs. no use) was associated with a significantly lower risk of discontinuation (OR: 0.136; 95%CI: 0.030-0.620), and previous treatment with MTX (vs. no use) was associated with a significantly higher discontinuation risk (OR: 4.045; 95%CI: 1.098-14.908).Conclusion: Although concomitant use of MTX during iguratimod treatment does not appear to influence treatment discontinuation due to abnormal liver function, liver function tests are of importance to continued treatment in patients receiving iguratimod who have a history of MTX use.

Investigation of the predictors of the response to Iguratimod therapy: A post-hoc analysis of post-marketing surveillance study.

Objectives: The treatment response according to patient disease activity during Iguratimod therapy for rheumatoid arthritis has not been sufficiently assessed. A post-hoc analysis of post-marketing surveillance was performed. The treatment effect was evaluated using the European League against Rheumatism (EULAR) response criteria.Methods: Disease Activity Score (DAS) 28 was assessed at various time points. Patients showing a moderate or good response according to the EULAR response criteria at 24 weeks after the start of Iguratimod therapy were considered Responders. Propensity score matching was also performed, after which the factors with the greatest effect on the treatment evaluation were investigated.Results: The mean DAS28 at the start of administration and after 24 weeks was 4.31 and 2.52, respectively, in the Responder and 3.48 and 3.48, respectively, in the Non-responder. After propensity score matching for patient characteristics, the primary factors found to be related to being a Responder were concomitant use of methotrexate (MTX) with Iguratimod, and prior treatment with MTX before the start of Iguratimod.Conclusion: As factors related to the treatment effect, the concomitant use of MTX may contribute to achieving a better effect, and this study has shown that real-world are consistent with the results of clinical trials.

Use of a Healthcare Claims Database for Post-Marketing Safety Assessments of Eribulin in Japan: A Comparative Assessment with a Prospective Post-Marketing Surveillance Study.

BACKGROUND: To understand the extent to which a large-scale healthcare claims database (DB) captures the safety profile of eribulin mesylate (Halaven®, Eisai Co., Ltd., Japan), we compared patient characteristics, drug use, and adverse events (AEs) between data for patients treated with eribulin retrieved from a DB and data for metastatic breast cancer patients from a conventional prospective post-marketing surveillance (PMS). METHODS: We descriptively summarized patient characteristics and AEs of 551 and 951 patients retrieved from DB and PMS, respectively, during 2011‒2013. Using 2814 patient data from the DB during 2011‒2016, the drug use and AE incidence over time were assessed. RESULTS: In both datasets, 99.8% were females, and the mean age was 57.8 ± 10.7 years. The mean number of eribulin administration was 11.1 ± 10.9 and 10.1 ± 7.8 in DB and PMS, respectively. Although, overall, the difference in AE incidence between the two datasets was moderate, gaps were larger for nausea (DB: 73.32% vs. PMS: 15.77%), neutropenia (20.87% vs. 66.67%), stomatitis (37.39% vs. 10.94%), and alopecia (0.36% vs. 12.09%). During 2011‒2016, the observed incidence of anemia or pyrexia significantly decreased (trend test, p = 0.0009 for both). CONCLUSION: Generally, patient characteristics, drug use, and AE incidence between the DB and PMS were comparable; however, AEs such as neutropenia may require defining based on the laboratory data to achieve more comparable results in DBs. Besides the usefulness of healthcare claims DBs for long-term assessments, they may also serve as a good complementary to PMS in the pharmacovigilance of eribulin.

Cost-effectiveness analysis of lenvatinib treatment for patients with unresectable hepatocellular carcinoma (uHCC) compared with sorafenib in Japan.

BACKGROUND: Lenvatinib demonstrated a treatment effect on overall survival by the statistical confirmation of non-inferiority to sorafenib for the first-line treatment of uHCC. The objective of this study was to evaluate the cost-effectiveness of lenvatinib compared with sorafenib for patients with uHCC in Japan. METHODS: A partitioned-survival model was developed to estimate the cost-effectiveness of lenvatinib versus sorafenib when treating uHCC patients over a lifetime horizon and considering total public healthcare expenditure. Efficacy and safety data were extracted from the REFLECT trial. Utility values were derived from the European Quality-of-Life 5-Dimension Questionnaire, conducted with patients enrolled in the REFLECT trial. Direct medical costs, such as primary drug therapy, outpatient visits, diagnostic tests, hospitalization, post-progression therapy, and adverse-event treatments, were included. Cost parameters unavailable in the clinical trial or publications were obtained based on the consolidated clinical standards from a Delphi panel of four Japanese medical experts. RESULTS: For lenvatinib versus sorafenib, the incremental cost was - 406,307 Japanese Yen (JPY), and the incremental life years and quality-adjusted life years (QALYs) were 0.27 and 0.23, respectively. Thus, lenvatinib dominated sorafenib, due to the mean incremental cost-effectiveness ratio falling in the fourth quadrant, conferring more benefit at lower costs compared with sorafenib. The probabilistic sensitivity analysis showed that 81.3% of the simulations were favorable to lenvatinib compared with sorafenib, with a payer's willingness-to-pay-per-QALY of 5 million JPY. CONCLUSIONS: Lenvatinib was cost-effective compared with sorafenib for the first-line treatment of uHCC in Japan.

Disease state changes and safety of long-term donepezil hydrochloride administration in patients with Alzheimer's disease: Japan-Great Outcome of Long-term trial with Donepezil (J-GOLD).

BACKGROUND: A long-term, large-scale study of donepezil hydrochloride in patients with Alzheimer's disease (AD) was conducted. Previously, two interim reports were published during this study. We have now completed the study and herein present our analysis of the final results. METHODS: The subjects of this study included AD patients who received the drug for the first time (newly treated patients), as well as AD patients who were already receiving the drug at the start of the study (continuously treated patients). The observation period was 48 months. Changes in cognitive function and severity of dementia associated with the drug administration and its safety were assessed. RESULTS: Cognitive function decreased significantly after 24 months in newly treated patients and after 6 months in continuously treated patients, compared with baseline. The percentages of patients whose dementia severity improved or remained the same compared with baseline were 59.27% at 48 months in the newly treated patients and 57.09% at 48 months in the continuously treated patients. There were no major safety problems with the drug. CONCLUSIONS: We conducted a large-scale study of AD patients in Japan. Here, we present our analysis of the final results and describe current clinical practice with the drug, changes in cognitive function and dementia severity associated with long-term administration of the drug, and the drug's safety.