Levels and spatial profile of per- and polyfluoroalkyl substances in edible shrimp products from Japan and neighboring countries; a potential source of dietary exposure to humans.

Exposure to per- and polyfluoroalkyl substances (PFAS) is of great concern for human health because of their persistence and potentially adverse effects. Dietary intake, particularly through aquatic products, is a significant route of human exposure to PFAS. We analyzed perfluoroalkyl sulfonic acid (PFSA with carbon numbers from 6 to 8 and 10 (C６-C8, C10)) and perfluorooctanesulfonamide (FOSA), and perfluoroalkyl carboxylic acid (PFCA with carbon numbers from 6 to 15 (C6-C15)) in 30 retail packs of edible shrimps, which included seven species from eight coastal areas of Japan and neighboring countries. The most prevalent compounds were perfluorooctane sulfonate (PFOS, C8) and perfluoroundecanoic acid (PFUnDA, C11), accounting for 46 % of total PFAS. The concentrations ranged from 6.5 to 44 ng/g dry weight (dw) (equivalent to 1.5 to 10 ng/g wet weight (ww)) and varied according to species and location. For example, Alaskan pink shrimp (Pandalus eous) from the Hokuriku coast, Japan contained high levels of long-chain PFCAs (38 ng/g dw (equivalent to 8.7 ng/g ww)), while red rice prawn (Metapenaeopsis barbata) from Yamaguchi, Japan contained a high concentration of PFOS (29 ng/g dw (equivalent to 6.7 ng/g ww)). We also observed regional differences in the PFAS levels with higher concentrations of long-chain PFCAs in Japanese coastal waters than in the South China Sea. The PFAS profiles in shrimp were consistent with those in the diet and serum of Japanese consumers, suggesting that consumption of seafood such as shrimp may be an important source of exposure. The estimated daily intake of sum of all PFAS from shrimp from Japanese coastal water was 0.43 ng/kg body weight/day in average, which could reach the weekly tolerable values (4.4 ng/kg body weight /week) for the sum of the four PFSA set by the EFSA for heavy consumers. The high concentration of PFAS in shrimp warrants further investigation.

A study to investigate the prevalence of headache disorders and migraine conducted using medical claims data and linked results from online surveys: post-hoc analysis of other headache disorders.

BACKGROUND: Surveys using questionnaires to collect epidemiologic data may be subject to misclassification. Here, we analyzed a headache questionnaire to evaluate which questions led to a classification other than migraine. METHODS: Anonymized surveys coupled with medical claims data from individuals 19-74 years old were obtained from DeSC Healthcare Inc. to examine proportions of patients with primary headache disorders (i.e.; migraine, tension-type headache, cluster headache, and "other headache disorders"). Six criteria that determined migraine were used to explore how people with other headache disorders responded to these questions. RESULTS: Among the 21480 respondents, 7331 (34.0%) reported having headaches. 691 (3.2%) respondents reported migraine, 1441 (6.7%) had tension-type headache, 21 (0.1%) had cluster headache, and 5208 (24.2%) reported other headache disorders. Responses of participants with other headache disorders were analyzed, and the top 3 criteria combined with "Symptoms associated with headache" were "Site of pain" (7.3%), "Headache changes in severity during daily activities" (6.4%), and the 3 criteria combined (8.8%). The symptoms associated with headache were "Stiff shoulders" (13.6%), "Stiff neck" (9.4%), or "Nausea or vomiting" (8.7%), Photophobia" (3.3%) and "Phonophobia" (2.5%). CONCLUSIONS: Prevalence of migraine as diagnosed by questionnaire was much lower than expected while the prevalence of "other headache" was higher than expected. We believe the reason for this observation was due to misclassification, and resulted from the failure of the questionnaire to identify some features of migraine that would have been revealed by clinical history taking. Questionnaires should, therefore, be carefully designed, and doctors should be educated, on how to ask questions and record information when conducting semi-structured interviews with patients, to obtain more precise information about their symptoms, including photophobia and phonophobia.

Characteristics of patients who seek medical attention for headache and those who do not: cross-sectional survey and linked medical claims data analysis in Japan.

OBJECTIVE: To describe the characteristics of patients who sought medical attention for headache and those who did not. DESIGN: This observational study used a cross-sectional online survey and linked medical claims data. SETTING: Data from an online self-administered questionnaire survey conducted in November 2020 as well as linked medical claims data spanning December 2017 and November 2020 were provided by DeSC Healthcare Inc. PARTICIPANTS: Of 21 480 respondents aged 19-74 years whose sex and age data matched the claims data, 7311 reported experiencing headache. MEASURES: Outcomes included participant characteristics, status of medical attention seeking, medication use, quality of life (QOL) measured by Migraine-Specific QOL (MSQ) questionnaire V.2.1 and headache intensity. RESULTS: Of the 7311 respondents with headache, 735 sought medical attention and 6576 did not. Compared with those who did not seek medical attention, those who sought medical attention had more frequent headaches (median: 5 days/3 months vs 10 days/3 months in those who did not vs those who sought medical attention, respectively) had lower MSQ score (mean (SD) MSQ total score: 87.6 (13.0) vs 77.1 (18.1)) and were likely to experience moderately severe to severe headache (19.0% (1252/6576) vs 41.2% (303/735)) without headache medication. The inability to tolerate headache (36.5% (268/735)) was a common reason for seeking medical attention. Since the pain was not severe enough, 35.3% (2323/6576) of patients did not seek medical attention. Furthermore, a subgroup of respondents experiencing headache for ≥15 days were uncertain about which hospital or department to attend. CONCLUSIONS: Patients typically seek help when the pain becomes unbearable. Still, some of them did not seek medical attention while they were experiencing headache for ≥15 days per month. Therefore, it is important to raise awareness and encourage seeking early medical attention before symptoms and associated burdens become too severe to be managed effectively.

Adjunctive brexpiprazole 1 mg and 2 mg daily for Japanese patients with major depressive disorder following inadequate response to antidepressants: a phase 2/3, randomized, double-blind (BLESS) study.

AIMS: Inadequate antidepressant response interrupts effective treatment of major depressive disorder (MDD). The BLESS study evaluates the dosage, efficacy, and safety of brexpiprazole adjunctive therapy in Japanese patients with inadequate antidepressant therapy (ADT) response. METHODS: This placebo-controlled, randomized, multicenter, parallel-group phase 2/3 study randomized Japanese MDD patients (Hamilton Rating Scale for Depression 17-item total score ≥ 14; historical inadequate response to 1-3 ADTs) with inadequate response to 8-week single-blind, prospective SSRI/SNRI treatment to 6-week adjunctive treatment with brexpiprazole 1 mg, 2 mg, or placebo. The primary endpoint was change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline. Secondary endpoints included MADRS response, remission rate, and Clinical Global Impression-Improvement score. Safety was comprehensively evaluated, especially regarding antipsychotic adverse events (AEs). RESULTS: Of 1194 screened patients, 740 were randomized and 736 (1 mg, n = 248; 2 mg, n = 245; placebo, n = 243) had ≥1 baseline/post-baseline MADRS total score. The LSM (SE) change from baseline in MADRS total score at Week 6 by MMRM analysis was -8.5 (0.47) with brexpiprazole 1 mg, -8.2 (0.47) with brexpiprazole 2 mg, and -6.7 (0.47) with placebo (placebo-adjusted LSM difference [95% CI]: 1 mg, -1.7 [-3.0, -0.4]; P = 0.0089; 2 mg, -1.4 [-2.7, -0.1]; P = 0.0312). Secondary efficacy results supported the primary endpoint. Brexpiprazole was generally well tolerated. CONCLUSION: Brexpiprazole 1 mg daily was an appropriate starting dose and both 1 mg and 2 mg daily were effective and well tolerated as adjunctive therapy for Japanese MDD patients not adequately responsive to ADT.

Effects of Fremanezumab on Medication Overuse in Japanese Chronic Migraine Patients: Post Hoc Analysis of a Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial.

INTRODUCTION: Chronic migraine (CM) patients commonly take acute headache medications, often resulting in medication overuse (MO). This post hoc analysis evaluated the efficacy of fremanezumab in CM patients from Japan with and without MO, which is not yet established. METHODS: A multicenter, double-blind, parallel-group, phase 2b/3 trial randomized patients (1:1:1) to monthly fremanezumab via subcutaneous injection (initial dose: 675 mg, second/third doses: 225 mg), quarterly fremanezumab (initial dose: 675 mg, second/third doses: placebo), or placebo for 3 months. This post hoc analysis analyzed data from Japanese patients with and without MO (monthly use of acute headache medication ≥ 15 days, migraine-specific acute medication ≥ 10 days, or combination medication ≥ 10 days). Outcomes included the original primary endpoint of average headache days of moderate or greater severity per month (HDs), the proportion of patients with ≥ 50% reduction in HDs and the proportion of patients changing status from with to without MO. RESULTS: Of 479 patients enrolled, 320 (66.8%) had baseline MO. Monthly average HDs were significantly reduced versus placebo with fremanezumab in both patients with MO (mean [standard error] difference vs. placebo: monthly - 2.0 [0.6], p = 0.0012; quarterly - 1.8 [0.6], p = 0.0042) and without MO (- 1.6 [0.8], p = 0.0437; - 1.5 [0.8], p = 0.0441). Significantly more fremanezumab-treated patients with MO (monthly 28/108 [25.9%], p = 0.0040 quarterly 25/99 [25.3%], p = 0.0070) or without MO (18/50 [36.0%], p = 0.0132; and 21/60 [35.0%], p = 0.0126) had ≥ 50% reduction in HDs versus placebo (12/111 [10.8%] and 7/49 [14.3%], respectively). A significantly greater proportion of fremanezumab-treated patients reverted to no MO (monthly 50/108 [46.3%], p = 0.0115; quarterly 44/99 [44.4%], p = 0.0272) vs. placebo (33/111 [29.7%]). CONCLUSION: Fremanezumab appears effective as preventive migraine treatment in Japanese CM patients with or without MO while also being beneficial in reducing MO.

Improved quality of life with fremanezumab in Japanese and Korean patients with episodic and chronic migraine: Results of two multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trials.

OBJECTIVE: To evaluate quality of life (QoL) endpoints from two 12-week trials investigating fremanezumab efficacy and safety in Japanese/Korean patients with chronic (CM) or episodic (EM) migraine. BACKGROUND: Migraine is a leading cause of disability and affects QoL considerably, interfering with work and daily activities, social and family life, and emotional wellbeing. METHODS: This planned exploratory analysis used data from two multicenter, randomized, double-blind, placebo-controlled, parallel-group studies in which Migraine-Specific QoL (MSQoL; Role Function-Restrictive [RR], Role Function-Preventive [RP], and Emotional Function [EF] domains) scores and Patient Global Impression of Change (PGIC) scores were pre-specified QoL outcomes in individuals receiving monthly or quarterly fremanezumab or placebo. In both trials, MSQoL was assessed at baseline, and MSQoL and PGIC at Weeks 4, 8, and 12. PGIC responders had a score of ≥5 points, indicating significant improvement. RESULTS: Mean baseline MSQoL scores were similar across groups in both CM (N = 565; RR, 60.3-61.5; RP, 78.5-80.0; EF, 69.0-71.4) and EM (N = 353; RR, 68.6-71.1; RP, 83.1-85.7; EF, 76.7-81.9) trials. In the CM trial, all three MSQoL domains improved in both fremanezumab groups at 12 weeks compared with placebo: least squares mean (LSM) and standard error (SE) change from baseline, p versus placebo (quarterly; monthly; placebo): RR 14.9 (1.3), p = 0.030; 15.1 (1.4), p = 0.020; 11.6 (1.3); RP 8.9 (1.1), p = 0.007; 8.6 (1.1), p = 0.013; 5.4 (1.1); EF 13.3 (1.5), p < 0.001; 12.5 (1.5), p = 0.003; 7.5 (1.5). In the EM trial, RR/EF domains improved in both fremanezumab groups compared with placebo: LSM change from baseline, p versus placebo (quarterly; monthly; placebo): RR 16.3 (1.4), p = 0.003; 16.4 (1.3), p = 0.002; 11.6 (1.4); EF 13.0 (1.3), p < 0.001; 11.5 (1.2), p = 0.004; 7.4 (1.3); RP improved in the quarterly group RP 8.6 (1.1), p = 0.010; 7.6 (1.1), p = 0.066; 5.4 (1.1). The proportion of PGIC responders at Week 12 was greater in the monthly and quarterly fremanezumab groups compared with the placebo group in the CM (96/182 [52.7%] and 98/180 [54.4%] vs. 68/179 [38.0%]; p < 0.05) and EM trial (81/118 [68.6%] and 86/113 [76.1%] vs. 38/111 [34.2%]; p < 0.001). CONCLUSION: Patients with EM/CM receiving monthly or quarterly fremanezumab, for a duration of 12 weeks, showed significant improvements in their QoL.

Fremanezumab for Episodic Migraine Prevention in Japanese Patients: Subgroup Analysis from Two International Trials.

Purpose: The monoclonal antibody fremanezumab has been shown effective and well tolerated in numerous Phase 2 and Phase 3 trials. This subgroup analysis of the international HALO episodic migraine (EM; [NCT02629861]) trial and a similarly designed phase 2b/3 trial in Japanese and Korean patients (NCT03303092) sought to evaluate the efficacy and safety of fremanezumab in Japanese patients with EM. Patients and Methods: In both trials, eligible patients were randomly assigned at baseline to receive subcutaneous monthly fremanezumab, quarterly fremanezumab, or placebo in a 1:1:1 ratio. The primary endpoint was the mean change from baseline in the monthly (28-day) average number of migraine days during the 12-week period after the first dose of fremanezumab or placebo. Secondary endpoints assessed other aspects of efficacy, including disability and medication use. Results: A total of 301 patients in the Japanese and Korean phase 2b/3 trial and 75 patients in the HALO EM trial were Japanese with baseline and treatment characteristics similar between treatment groups. According to ANCOVA analysis of the primary endpoint, both fremanezumab quarterly and monthly led to greater reductions in the monthly (28-day) average number of migraine days than placebo. This was supported by MMRM analysis of the primary endpoint over the initial 4 weeks, highlighting the rapid onset of action of fremanezumab. Results of secondary endpoint analysis supported the primary endpoint analyses. Fremanezumab was well tolerated with no new safety signals seen in this population of Japanese patients. Conclusion: Fremanezumab appears to be an effective and well-tolerated preventive medication for Japanese patients with EM.

Fremanezumab for Chronic Migraine Prevention in Japanese Patients: Subgroup Analysis from Two International Trials.

Purpose: Fremanezumab monoclonal antibody therapy has demonstrated efficacy for chronic migraine (CM) with rapid onset and good tolerability. This subgroup analysis of two clinical trials (Japanese and Korean CM Phase 2b/3 [NCT03303079] and HALO CM Phase 3 [NCT02621931]) aimed to evaluate the efficacy and safety of fremanezumab in Japanese patients. Patients and Methods: Both trials randomly assigned eligible patients at baseline (1:1:1 ratio) to subcutaneous monthly fremanezumab, quarterly fremanezumab, or placebo at 4-week intervals. The primary endpoint was the mean change from baseline in the monthly (28-day) average number of headache days of at least moderate severity during the 12-week period after the first dose of study medication (analyzed by ANCOVA over 12 weeks and MMRM over initial 4 weeks). Secondary endpoints examined other aspects of efficacy, including medication use and disability. Results: A total of 479 and 109 patients were Japanese in the Japanese and Korean CM Phase 2b/3 and HALO CM trials, respectively. Baseline and treatment characteristics were generally similar between treatment groups for both trials. Results of subgroup analyses for the primary endpoint according to ANCOVA demonstrated the superiority of fremanezumab over placebo in Japanese patients (quarterly fremanezumab, p=0.0005; monthly fremanezumab, p=0.0002 in both trials). Results using the MMRM analysis confirmed the rapid onset of action in this population. Results of the secondary endpoints further supported the efficacy of fremanezumab in Japanese patients. Fremanezumab was well tolerated with nasopharyngitis and injection-site reactions representing the most common adverse events in all treatment groups. Conclusion: Despite the limitations of subgroup analyses, these consistent results confirm the efficacy and tolerability of fremanezumab in Japanese patients with CM.

Clinical characteristics, medication use, and impact of primary headache on daily activities: an observational study using linked online survey and medical claims data in Japan.

BACKGROUND: Limited epidemiological data are available for headache disorders in Japan, and no recent studies have reported the impact of several primary headache disorders in Japan. This study aimed to report the up-to-date epidemiological data and impact of primary headaches on daily activities as well as the use of medical care, clinical features, and pain severity/activity impairment using nationwide data in Japan. METHODS: We used anonymized online survey data coupled with medical claims data, from individuals aged 19-74 years old, that were provided by DeSC Healthcare Inc. The outcomes included the prevalence of migraine, tension-type headache, cluster headache, and other headache types stratified by age and sex, use of medical care, clinical features, medication use, and severity of pain/activity impairment. All outcomes were examined separately for each headache type. This is the second paper reported concurrently with this research. RESULTS: The study population comprised 691/1,441/21/5,208 individuals with migraine/tension-type headache/cluster headache/other headache types, respectively. The prevalence of migraine and tension-type headache was higher in women than in men but was similar for cluster headache (male vs. female, 1.7% vs. 7.4%, 5.3% vs. 10.8%, and 0.1% vs. 0.1%, respectively). The percentage of individuals with migraine, tension-type headache, cluster headache who had not seen a doctor was 81.0%, 92.0%, 57.1%, respectively. The common headache triggers were fatigue in migraine and tension-type headache, and weather-related phenomena and turning of the seasons in migraine. Common activities refrained from or reduced by headaches were "operating a computer or smartphone", "drinking alcohol", and "going to crowded places" in all three headache types and housework-related activities in women. Among individuals taking medicines, 16.8%, 15.8%, 47.6% with migraine, tension-type headache, and cluster headache reported moderate to severe pain, respectively, and 12.6%, 7.7%, 19.0% reported moderate to severe disability, respectively. CONCLUSIONS: This study found various triggers of headache attacks, and daily activities refrained from or reduced by headaches. Additionally, this study suggested that the disease burden in people possibly experiencing tension-type headaches, many of whom had not seen a doctor. The study findings are of clinical value for the diagnosis and treatment of primary headaches.

A multicenter, open-label, phase 3 study to evaluate the safety of fremanezumab for migraine, subcutaneously self-administered with an auto-injection device at institutional sites and at home.

BACKGROUND: Fremanezumab is a humanized monoclonal antibody against calcitonin gene-related peptide for subcutaneous use to suppress migraine attacks. A phase 3 study was conducted to investigate the safety of autoinjector (AI)-assisted self-injection of fremanezumab 225 mg. RESEARCH DESIGN AND METHODS: The multicenter, open-label study involving 71 patients with migraine was conducted between June 2020 and November 2020 at ten institutions in Japan. The study consisted of a 4-week (28-day) screening period and an 8-week (57-day) treatment period. According to the investigator's instructions, all patients successfully performed self-injection for 4 weeks at the institutional site and at home and maintained eDiaries of their headaches. The primary endpoint was safety of the drug based on treatment-emergent adverse events (TEAEs). RESULTS: Treatment-emergent adverse events were more frequent after at-home injection than after at-site injection, but they were mainly injection site reactions and mostly mild. The safety profile was comparable, raising no concerns compared with what has been reported in previous studies. Both migraine days and headache days were decreased considerably. CONCLUSIONS: Overall, AI-assisted, at-home self-injection of fremanezumab was found to be generally safe and well-tolerated. This injection strategy is considered clinically meaningful in view of improved utility of and adherence to the drug.

Profiles and determinants of dicofol, endosulfans, mirex, and toxaphenes in breast milk samples from 10 prefectures in Japan.

Human exposure to persistent organic pollutants (POPs) is reflected by POP concentrations in breast milk. Many studies of POPs in breast milk have been performed in Japan, but insufficient information is available about some legacy POPs (e.g., mirex and toxaphenes, included in the Stockholm Convention in 2001) and novel POPs (e.g., dicofol and endosulfans, included in the Stockholm Convention in 2019 and 2011, respectively). In this study, dicofol, endosulfan, mirex, and toxaphene concentrations in breast milk from 10 prefectures in Japan were determined. The samples were collected between 2005 and 2010, before Stockholm Convention restrictions on endosulfans and mirex were implemented. Common POPs (e.g., polychlorinated biphenyls) were also analyzed to allow the contamination statuses to be compared. The α-endosulfan and ß-endosulfan concentrations were 0.26-13 and 0.012-0.82 ng/g lipid, respectively. The toxaphene #26 and #50 concentrations were <0.08-5.6 and < 0.1-8.5 ng/g lipid, respectively. The dicofol concentrations were <0.01-4.8 ng/g lipid. The mirex concentrations were <0.2-3.5 ng/g lipid. The α- and ß-endosulfan concentrations on a lipid weight basis negatively correlated with the lipid contents of the milk samples (ρ = -0.65, p < 0.01 for α-endosulfan; ρ = -0.58, p < 0.01 for ß-endosulfan). The toxaphene concentrations positively correlated with the lipid contents. The mirex concentrations positively correlated with the maternal age but negatively correlated with the maternal body mass index. No correlations between the dicofol concentrations and the factors were found. Principal component analysis divided the data into four groups, (1) chlordanes, dichlorodiphenyltrichloroethanes and related compounds, hexachlorobenzene, hexachlorocyclohexanes, hexachloroethane, and polychlorinated biphenyls, (2) endosulfans, (3) dicofol, dieldrin, and toxaphenes, and (4) bromodiphenyl ether 47. This indicated that bromodiphenyl ether 47, dicofol, endosulfans, and toxaphenes have different exposure routes or different kinetics to the other legacy POPs.

A study to investigate the prevalence of headache disorders and migraine among people registered in a health insurance association in Japan.

BACKGROUND: Migraine is a chronic disease characterized by episodic headache attacks. No recent studies have, however been conducted on the epidemiology of migraine or the treatment landscape in Japan. This study was conducted as a fact-finding survey using medical claims data and an online survey on migraine and headaches, conducted among members of health insurance associations with the objective of gaining an understanding of migraine prevalence and the treatment status in Japan. METHODS: The study methodology utilized a unique approach of combined data sources. The data sources used in this study are medical claims data and linked online survey data provided by DeSC Healthcare Inc (DeSC). The primary outcomes (from survey responses) were: the overall number and proportion of migraine patients; and the overall prevalence of migraine, stratified by age and sex. The secondary outcomes (from survey responses) were use of medical care; and clinical features/headache symptoms. The analysis population included all individuals who had response data for surveys conducted by DeSC. The online survey data and medical claims data were summarized. RESULTS: The data population comprised 21,480 individuals. On the basis of the survey results, including probable cases, the overall prevalence of migraine was 3.2%. The highest prevalence of migraine was observed in patients aged 30-39 years. The prevalence of migraine in women was 4.4 times higher than in men. The percentage of migraine patients who had not been seen by a doctor was 81.0%. More than 80% of patients were taking over-the-counter drugs and 4.8% took prescription medicines only. Approximately 52.9% of patients considered that the intensity of pain symptoms was severe. Moreover, the majority of patients (72.9%) considered that the impairment of daily life activities was of moderate or severe degree. CONCLUSIONS: In Japan, the percentage of people with migraine who did not receive medical attention is as high as 80%. Additionally, the majority of patients tend to endure symptoms and continue with everyday activities. With innovative treatment approaches becoming available it is necessary to disseminate information that migraine is not a simple headache but an illness that requires medical treatment and consultation.

Early onset of efficacy with fremanezumab in patients with episodic and chronic migraine: subanalysis of two phase 2b/3 trials in Japanese and Korean patients.

BACKGROUND: Early onset of action has become recognized as an important efficacy feature of preventive migraine treatment, which can help overcome adherence issues commonly associated with older medications. Preventive treatments that target the calcitonin gene-related peptide (CGRP) or the CGRP receptor have been previously shown to provide early onset of action. METHODS: This subanalysis of primary endpoints of two separate phase 2b/3 studies sought to determine the onset of action of fremanezumab in Japanese and Korean patients with episodic migraine (EM) and chronic migraine (CM). RESULTS: In EM patients (n = 357), both fremanezumab quarterly and fremanezumab monthly led to greater reductions in weekly migraine days (days/week) than placebo from the first week after the initial injection and thereafter during the remainder of the study period. Similarly, CM patients (n = 571) had a greater reduction in headache days of at least moderate severity (days/week) with fremanezumab (total) than placebo. The percentage of patients with a migraine day (EM) or headache day at least moderate severity (CM) was lower in those treated with fremanezumab than placebo and this effect was apparent from as early as Day 2 (1 day after first injection). CONCLUSIONS: These results suggest that fremanezumab has an early onset of action, as noted in previous post hoc analyses of anti-CGRP monoclonal antibodies. TRIAL REGISTRATION: ClinicalTrials.gov. NCT03303092 , Registered 5 October 2017, NCT03303079 , Registered 5 October 2017.

Long-Term Safety and Tolerability of Fremanezumab for Migraine Preventive Treatment in Japanese Outpatients: A Multicenter, Randomized, Open-Label Study.

INTRODUCTION: Early discontinuation and poor adherence are common limitations of conventional preventive migraine medications that limit their long-term efficacy. Therefore, a migraine preventive medication with favorable long-term safety is warranted. OBJECTIVE: This study aimed to evaluate the long-term safety and tolerability of fremanezumab for the preventive treatment of chronic or episodic migraine in Japanese patients. METHODS: In this 52-week, randomized, open-label, parallel-group study, fremanezumab monthly or quarterly was administered in newly enrolled Japanese patients with chronic migraine or episodic migraine. Safety was assessed by monitoring of treatment-emergent adverse events, including injection-site reactions, laboratory and vital sign assessments. Newly enrolled patients and rollover patients from previous phase IIb/III trials who did not receive fremanezumab in this study were included in the immunogenicity testing cohort (n = 587). Efficacy outcomes included changes from baseline in the average monthly migraine days and headache days of at least moderate severity. Other efficacy outcomes included changes in disability scores. RESULTS: A total of 50 patients were enrolled with chronic migraine (monthly, n = 17; quarterly, n = 17) or episodic migraine (monthly, n = 8; quarterly, n = 8). The most commonly reported treatment-emergent adverse events were nasopharyngitis (64.0%) and injection-site reactions (erythema, 24.0%; induration, 10.0%; pain, 8.0%; pruritus, 6.0%). The discontinuation rate was low (4.0% from adverse events, 2.0% from a lack of efficacy) and no deaths were reported. The incidence of anti-drug antibody development was low (2.4%). Fremanezumab reduced monthly migraine days and headache days of at least moderate severity from 1 month after initial administration, and this effect was maintained with no worsening throughout 12 months. Fremanezumab also led to sustained reductions in any acute headache medication use and headache-related disability at 12 months. CONCLUSIONS: Fremanezumab administered monthly and quarterly was well tolerated in patients with chronic migraine and episodic migraine and led to sustained improvements in monthly migraine days and headache days of at least moderate severity throughout 12 months. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03303105.

Efficacy and safety of fremanezumab for chronic migraine prevention: Multicenter, randomized, double-blind, placebo-controlled, parallel-group trial in Japanese and Korean patients.

OBJECTIVE: To determine the efficacy and safety of fremanezumab administration in Japanese and Korean patients with chronic migraine (CM). BACKGROUND: Available preventive treatments for CM are limited by various efficacy and safety issues. Fremanezumab, a monoclonal antibody that targets the calcitonin gene-related peptide pathway involved in migraine pathogenesis, has been shown to be effective and well tolerated in large-scale, international Phase 3 trials. METHODS: Randomized, placebo-controlled trial of patients with CM who received subcutaneous fremanezumab monthly (675 mg at baseline and 225 mg at weeks 4 and 8), fremanezumab quarterly (675 mg at baseline and placebo at weeks 4 and 8), or matching placebo. Primary endpoint was the mean change from baseline in the monthly (28-day) average number of headache days of at least moderate severity during the 12 weeks after the first dose. RESULTS: Among 571 patients randomized (safety set, n = 569; full analysis set, n = 566), the least-squares mean (±standard error [SE]) reduction in the average number of headache days of at least moderate severity per month during 12 weeks was significantly greater with fremanezumab monthly (-4.1 ± 0.4) and fremanezumab quarterly (-4.1 ± 0.4) than with placebo (-2.4 ± 0.4). The difference from the placebo group in the mean change (95% confidence interval [CI]) was -1.7 days (-2.54, -0.80) for the fremanezumab monthly group and -1.7 days (-2.55, -0.82) for the fremanezumab quarterly group (p < 0.001 vs. placebo for both fremanezumab groups). The percentage of patients with a ≥50% reduction in the average number of headache days of at least moderate severity per month (response rate) was higher with fremanezumab monthly (29.0%) and fremanezumab quarterly (29.1%) than with placebo (13.2%) in addition to other improvements in secondary endpoints, including reduction of acute medication use (mean change from baseline during 12-week period ± SE: fremanezumab monthly, -3.7 ± 0.4; fremanezumab quarterly, -3.9 ± 0.4; placebo, -2.4 ± 0.4) and improvements in disability scores (mean change from baseline in six-item Headache Impact Test score at 4 weeks after third injection ± SE: fremanezumab monthly, -8.1 ± 0.7; fremanezumab quarterly, -8.0 ± 0.7; placebo, -6.5 ± 0.7). Fremanezumab was well tolerated with a similar incidence of adverse events including injection-site reactions as placebo (patients with at least one treatment-emergent adverse event: fremanezumab total, n = 232 [61.4%]; placebo, n = 118 [61.8%]). CONCLUSION: Fremanezumab effectively prevents CM in Japanese and Korean patients and was well tolerated. No safety signal was detected.

Efficacy and safety of fremanezumab for episodic migraine prevention: Multicenter, randomized, double-blind, placebo-controlled, parallel-group trial in Japanese and Korean patients.

OBJECTIVE: To evaluate the efficacy and safety of two dosing regimens of fremanezumab in Japanese and Korean patients with episodic migraine. BACKGROUND: Episodic migraine, which accounts for more than 90% of migraine cases, is inadequately addressed by widely available preventive therapies. Fremanezumab, a monoclonal antibody that selectively targets the trigeminal sensory neuropeptide calcitonin gene-related peptide involved in migraine pathogenesis, has demonstrated efficacy in international Phase 3 trials of patients with both chronic and episodic migraine. METHODS: This Phase 3 randomized, placebo-controlled trial randomly assigned patients with episodic migraine to receive subcutaneous fremanezumab monthly (225 mg at baseline, week 4, and week 8), fremanezumab quarterly (675 mg at baseline and placebo at weeks 4 and 8), or matching placebo. The primary endpoint was the mean change from baseline in the monthly average number of migraine days during the 12-week treatment period after the first dose. RESULTS: Of 357 patients enrolled (safety set, n = 356; full analysis set, n = 354), the least-squares mean (±standard error) reductions in the average number of migraine days per month during 12 weeks were significantly greater with fremanezumab monthly (-4.0 ± 0.4, n = 121) and fremanezumab quarterly (-4.0 ± 0.4, n = 117) than with placebo (-1.0 ± 0.4, n = 116; p < 0.0001 for both comparisons). The proportion of patients reaching at least a 50% reduction in the monthly average number of migraine days during the 12-week period after initial administration was also significantly improved with fremanezumab (fremanezumab monthly, 41.3%; fremanezumab quarterly, 45.3%; placebo, 11.2%; p < 0.0001 for both comparisons) as were other secondary endpoints (p < 0.001 for all comparisons between fremanezumab and placebo). Injection-site reactions were more common in fremanezumab-treated patients (fremanezumab monthly, 25.6%; fremanezumab quarterly, 29.7%; placebo, 21.4%). CONCLUSION: Fremanezumab prevents episodic migraine in Japanese and Korean patients to a similar extent than in previously reported populations with no new safety concerns.

Effects of perfluoroalkyl carboxylic acids on the uptake of sulfobromophthalein via organic anion transporting polypeptides in human intestinal Caco-2 cells.

We performed a detailed investigation of the uptake of sulfobromophthalein (BSP) from the apical membrane of Caco-2 cells, which is a substrate for organic anion transporting polypeptides (OATPs), and calculated the kinetic parameters of BSP uptake as follows: Km = 13.9 ± 1.3 µM, Vmax = 1.15 ± 0.07 nmol (mg protein)-1 (5 min)-1, and kd = 38.2 ± 0.53 µL (mg protein)-1 (5 min)-1. Coincubation with medium-chain (C7-C11) perfluoroalkyl carboxylic acids (PFCAs), such as perfluoroheptanoic acid (PFHpA, C7), perfluorooctanoic acid (PFOA, C8), perfluorononanoic acid (PFNA, C9), perfluorodecanoic acid (PFDA, C10) and perfluoroundecanoic acid (PFUnDA, C11), significantly decreased BSP uptake by 27-55%, while coincubation with short- (C3-C6) and long-chain (C12-C14) PFCAs decreased the uptake only slightly. Dixon plotting suggested that PFOA, PFNA and PFDA competitively inhibited the BSP uptake with inhibition constant (Ki) values of 62.2 ± 1.3 µM, 35.3 ± 0.1 µM and 43.2 ± 0.3 µM, respectively. PFCAs with medium-chains could be substrates for OATPs, probably OATP2B1, which is the most abundantly expressed OATP isoform in Caco-2 cells.

Kanechlor 500-mediated changes in serum and hepatic thyroxine levels primarily occur in a transthyretin-unrelated manner.

The effects of Kanechlor-500 (KC500) on the levels of serum total thyroxine (T4 ) and hepatic T4 in wild-type C57BL/6 (WT) and its transthyretin (TTR)-deficient (TTR-null) mice were comparatively examined. Four days after a single intraperitoneal injection with KC500 (100 mg/kg body weight), serum total T4 levels were significantly decreased in both WT and TTR-null mice. The KC500 pretreatment also promoted serum [125 I]T4 clearance in both strains of mice administrated with [125 I]T4 , and the promotion of serum [125 I]T4 clearance in WT mice occurred without inhibition of the [125 I]T4 -TTR complex formation. Furthermore, the KC500 pretreatment led to significant increases in liver weight, steady-state distribution volume of [125 I]T4 , hepatic accumulation level of [125 I]T4 , and concentration ratio of the liver to serum in both strains of mice. The present findings indicate that the KC500-mediated decrease in serum T4 level occurs in a TTR-unrelated manner and further suggest that KC500-promoted T4 accumulation in the liver occurs through the development of liver hypertrophy and the promotion of T4 transportation from serum to liver.

Evaluation of Bioequivalence Between the New Procaterol Hydrochloride Hydrate Dry Powder Inhaler and the Approved Dry Powder Inhaler in Patients With Asthma in a Randomized, Double-Blind, Double-Dummy, Crossover Comparison Study: A Phase 3 Study.

Procaterol hydrochloride hydrate (procaterol) is a ß2 -adrenergic receptor agonist that induces a strong bronchodilatory effect. The procaterol dry powder inhaler (DPI) has been frequently used in patients with bronchial asthma or chronic obstructive pulmonary disease. We evaluated the bioequivalence and safety between the new procaterol DPI (new DPI) and the approved procaterol DPI (approved DPI). This study was a randomized, double-blind, double-dummy, crossover comparison to evaluate the pharmacodynamic equivalence of the new DPI and the approved DPI in patients with bronchial asthma. Primary efficacy variables were area under the concentration-time curve (AUC) forced expiratory volume in the first second (FEV1 )/h and maximum FEV1 during the 480-minute measurement period. Patients were divided into 2 groups, New-DPI-First (n = 8) and Approved-DPI-First (n = 8), according to the investigational medical product that was administered first. Patients inhaled 20 µg of procaterol in each period. FEV1 was measured by a spirometer at predose and at 15, 30, 60, 90, 120, 180, 240, 360, and 480 minutes after each investigational medical product administration. Equivalence was evaluated by confirming that the 2-sided 90%CIs for the difference between the new and the approved DPI in means of AUC (FEV1 )/h and maximum FEV1 were within the acceptance criteria of -0.15 to 0.15 L. The difference in means of AUC (FEV1 )/h and maximum FEV1 was 0.041 L and 0.033 L, respectively, and the 90%CI was 0.004 to 0.078 L and -0.008 to 0.074 L, respectively. These CIs were both within the acceptance criteria. The new DPI was assessed as being bioequivalent to the approved DPI.