Safety and effectiveness of nusinersen, a treatment for spinal muscular atrophy, in 524 patients: results from an interim analysis of post-marketing surveillance in Japan.

PURPOSE: Nusinersen is an antisense oligonucleotide approved for the treatment of spinal muscular atrophy (SMA). A post-marketing surveillance (PMS) has been ongoing (August 2017-August 2025) in all patients in Japan who were administered nusinersen intrathecally in real-world clinical settings. We report the interim analysis results for safety and effectiveness. METHODS: This interim analysis was conducted using data collected from 524 patients whose case report forms were obtained at least once by May 30, 2022. Collected data included patient demographics and adverse events (AEs) for safety, and motor function assessments and Clinical Global Impressions of Improvement (CGI-I) for effectiveness. RESULTS: Of the 524 patients in the safety analysis set, 522 patients who were diagnosed with SMA were included in the effectiveness analysis (infantile-onset SMA [n = 153, 29.3%], later-onset SMA [n = 369, 70.7%]). The median duration of treatment was 785.0 (range 1-1549) days. AEs occurred in 35.9% of patients (49.0% in infantile-onset SMA and 30.6% in later-onset SMA). Nusinersen treatment significantly improved Hammersmith Infant Neurological Examination scores in patients with infantile-onset SMA and Hammersmith Functional Motor Scale-Expanded scores in patients with later-onset SMA for up to nearly 3 years. Based on CGI-I assessments, 98.5-100% of patients receiving nusinersen 'improved' or remain 'unchanged'. CONCLUSIONS: This interim analysis of the large-scale, all-case PMS in patients who were administered nusinersen in Japan supports the safety and effectiveness of nusinersen. The benefit-risk balance of nusinersen treatment remains favorable.

Real-world safety and effectiveness of nusinersen, a treatment for spinal muscular atrophy, in 401 Japanese patients: results from an interim analysis of post-marketing surveillance.

Purpose: Nusinersen is an antisense oligonucleotide for the treatment of spinal muscular atrophy (SMA). A post-marketing surveillance (PMS) has been ongoing (August 2017-August 2025) in all patients in Japan who received intrathecal nusinersen in real-world clinical settings. We report the interim analysis results of safety and effectiveness.Methods: This interim analysis was conducted using data collected from 401 patients whose case report forms were obtained at least once by 30 May 2020. Collected data included patient demographics and adverse events (AEs) for safety, and motor function assessments and Clinical Global Impressions of Improvement (CGI-I) for effectiveness.Results: All 401 patients were diagnosed with SMA and were included in the safety and effectiveness analysis (infantile-onset SMA [n = 126, 31.4%], later-onset SMA [n = 275, 68.6%]). The median duration of treatment was 330 days (range 1-823 days). The incidence proportion of AEs was 31.7% (37.3% in infantile-onset SMA and 29.1% in later-onset SMA). The most common AEs were headache (4.5%), pyrexia (4.2%), and pneumonia (3.7%). The incidence proportion of serious AEs was 11.5%. Nusinersen improved motor function scores and was assessed as 'effective' based on CGI-I in 99.7-100% of patients.Conclusions: This interim analysis of the PMS in Japanese patients treated with nusinersen found no new safety concerns, with the type of AEs consistent with the expected safety profile. The benefit-risk balance of nusinersen treatment remains favorable.

Analyses of natural courses of Japanese patients with Alzheimer's disease using placebo data from placebo-controlled, randomized clinical trials: Japanese Study on the Estimation of Clinical course of Alzheimer's disease.

INTRODUCTION: Symptomatic anti-Alzheimer's disease (AD) drugs have been commonly used for the treatment of AD. Knowing the natural courses of patients with AD on placebo is highly relevant for clinicians to understand their efficacy and for investigators to design clinical studies. METHODS: The data on rating scales for dementia such as Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Severe Impairment Battery were extracted from eight previous Japanese Phase II and III studies. Natural courses of Japanese AD patients in placebo groups were evaluated and statistically analyzed in a pooled and retrospective fashion. RESULTS: Decreases in ADAS-cog and Severe Impairment Battery was larger at week 22 or 24 than at week 12. Scores of ADAS-cog appeared to deteriorate faster in moderate AD than in mild AD. DISCUSSION: The present data will provide clinicians following up patients with AD with helpful information on how to manage AD patients and investigators with instruction for clinical study design.

Incidence and risk factors for recurrent spontaneous preterm birth: A retrospective cohort study in Japan.

AIM: The aim of this study was to assess the incidence and risk factors for recurrent spontaneous preterm birth (PTB) in Japan. MATERIAL AND METHODS: A retrospective cohort study was conducted at five tertiary perinatal centers in Osaka, Japan from 2008 through 2012. Perinatal data were collected from medical records of women with a singleton gestation and a previous spontaneous PTB. Exclusion criteria were first-trimester spontaneous abortion, first antenatal visit beyond 14 weeks of gestation, and previous PTB with medical indications, placenta previa, abruptio placenta, multiple pregnancy, fetal anomaly, and antepartum fetal demise. The associations between recurrent spontaneous PTB and perinatal factors were evaluated by logistic regression analysis. RESULTS: Of 547 women with a previous spontaneous PTB, 89 (16.3%) suffered a recurrent spontaneous PTB. The risk factors for recurrence included multiple previous spontaneous PTB (adjusted odds ratio [aOR]: 2.26; 95% confidence interval [CI]: 1.19-4.30; P = 0.013), no previous term birth (aOR: 2.08; 95%CI: 1.24-3.49; P = 0.005), and interpregnancy interval < 12 months (aOR: 2.13; 95%CI: 1.17-3.85; P = 0.013). CONCLUSION: Approximately one in six women with a previous spontaneous PTB suffered a recurrent spontaneous PTB. Multiple previous spontaneous PTB, no previous term birth, and short interpregnancy interval were independent risk factors for recurrence.

Investigation of influencing factors on higher placebo response in East Asian versus Western clinical trials for partial epilepsy: a meta-analysis.

BACKGROUND: Placebo response in clinical trials for anti-epileptic drugs (AEDs) has been examined and a recent meta-analysis revealed that East Asian trials showed unexpectedly higher placebo response. As multi-national trials have become common, it is important to understand placebo response in different settings, including regions/countries for future clinical trials. OBJECTIVE: The present meta-analysis aims to investigate the potential factors that contribute to higher placebo response in clinical trials for add-on therapy to adult patients with refractory partial epilepsy in East Asian and Western populations. METHODS: A database was established based on published clinical trials conducted in East Asian and Western countries. The relationship between the degree of placebo response and potential influencing factors was examined by logistic regression analyses. RESULTS: The database included 33 trials from five AEDs: gabapentin, topiramate, levetiracetam, pregabalin, and zonisamide. Placebo response was associated with patient characteristics such as disease duration, percentage of patients with complex partial seizure (CPS) at baseline, percentage of patients treated with two AEDs, protocol-required seizure frequency at baseline, and year of publication. Logistic regression analysis demonstrated that the placebo response in East Asian trials was statistically higher than that in Western trials. CONCLUSION: Patient characteristics such as longer disease duration and CPS at baseline contribute to a reduction in placebo response in clinical trials of AEDs for partial epilepsy. While the reasons for the geographical difference in placebo response are not clear, these and other patient characteristics contributing to placebo response should be carefully considered in the design of future clinical trials of AEDs for partial epilepsy.

Reliability study on the Japanese version of the Clinician's Interview-Based Impression of Change. Analysis of subscale items and 'clinician's impression'.

BACKGROUND/AIMS: The Japanese version of the Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus J) consists of 3 subscales: Disability Assessment of Dementia Scale (DAD), Behavioral Pathology in Alzheimer's Disease Rating Scale (Behave-AD), and Mental Function Impairment Scale (MENFIS), as well as the Clinician's Global Impression of Change (CGIC). While the interrater reliability of CGIC has already been reported, that of the 3 subscales has not. The aim of the present report was to examine the reliabilities of the subscale items and investigate their relationships with CGIC. METHODS: Eleven raters who were clinical physicians watched videotapes of 20 patients with Alzheimer's disease, completed the CIBIC-plus J assessment form, and assigned a CGIC score to the patients. Reliability was assessed using the kappa coefficient. RESULTS: The kappa coefficient of the subscale items was in most instances higher than that of CGIC (0.453) and substantial reliability was observed. The Spearman rank correlation that was calculated between CGIC and the total score change of items was very high for MENFIS (0.990) and DAD (0.910), and moderate for Behave-AD items (0.576). The incidence of comments by the raters was highest for MENFIS (89%), followed by DAD (70%). The incidence was low for Behave-AD items (48%). CONCLUSION: Based on the results, it is concluded that DAD, Behave-AD, and MENFIS are necessary constituents of CIBIC-plus J, and indispensable for the reliability of CGIC.