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Shigekazu Kitamura,1 Noboru Imai,2 Yuka Tanji,3 Akichika Ozeki,3 Mika Komori3 1Department of Neurology, Konan Kakogawa Hospital, Hyogo, Japan; 2Department of Neurology, Japanese Red Cross Shizuoka Hospital, Shizuoka, Japan; 3Japan Drug Development and Medical Affairs, Eli Lilly Japan K.K., Kobe, JapanCorrespondence: Mika Komori, Japan Drug Development and Medical Affairs, Eli Lilly Japan K.K., 5-1-28, Isogamidori, Chuo-Ku, Kobe-Shi, 651-0086, Japan, Tel +81-78-242-8391, Fax +81-78-242-9939, Email komori_mika@lilly.comBackground: Migraine is often comorbid with other disorders. People with migraine may be prescribed one or more concomitant medications. This post hoc analysis assessed the safety and efficacy of lasmiditan in Japanese people with migraine comorbidities or using concomitant medications.Patients and Methods: The MONONOFU study was a Phase 2, randomized, placebo-controlled, multicenter study of lasmiditan for acute migraine treatment in Japanese adults. Patients reported comorbidities (pre-existing or coexisting conditions) during screening. Concomitant medications (any drugs taken ± 48 hours of the study drug) and treatment-emergent adverse events (TEAEs) were recorded in a paper diary. Study drug efficacy (pain freedom 2 hours after administration of study drug) was reported in an eDiary. Logistic regression models were used for subgroup analyses of safety (incidence of TEAEs) and efficacy (pain freedom at 2 hours post dose) of lasmiditan in relation to presence/absence of comorbidities, and safety in relation to concomitant medications.Results: Common comorbidities (occurring in ≥ 10% of any lasmiditan dose group) were seasonal allergies, allergic rhinitis, tension-type headache, cervicobrachial syndrome, dysmenorrhea, nasopharyngitis, musculoskeletal stiffness, chronic gastritis, constipation, and insomnia. There was no significant interaction of treatment with comorbidity for safety or efficacy. There was also no significant interaction between treatment and concomitant medication groups of special interest (acetaminophen/nonsteroidal anti-inflammatory drugs, triptans, antiemetics, central nervous system depressant medications, serotonergic medications, antiepileptics, antihypertensive medications, Chinese herbal medicines, and contraceptives) for incidence of TEAEs.Conclusion: In Japanese people with migraine, the safety of lasmiditan appeared to be independent of common comorbidities and concomitant medications; efficacy appeared to be independent of comorbid conditions.Clinical Trials Registration: NCT03962738 (ClinicalTrials.gov).Keywords: comorbidity, drug therapy, headache, Japan, migraine disorders, safety

Galcanezumab, a humanized monoclonal antibody against calcitonin gene-related peptide, is a preventive migraine treatment. In global, randomized, placebo-controlled trials, galcanezumab reduced migraine headache severity and the frequency of migraine headaches associated with nausea and/or vomiting, photophobia and phonophobia, prodromal symptoms, or aura. We report secondary analyses from a Japanese phase 2 trial that assessed the effect of galcanezumab on migraine headache severity, frequency of migraine-associated symptoms, and frequency of migraine headaches during menstrual periods in Japanese patients with episodic migraine.Adults with migraine (International Classification of Headache Disorders, 3rd edition; 4-14 migraine headache days/month) were randomized (2:1:1) to a monthly placebo (n = 230), 120 mg galcanezumab (240 mg loading dose; n = 115), or 240 mg galcanezumab (n = 114) for 6 months (double-blind). Patients recorded migraine headache days, severity, and symptoms in an electronic diary. Changes from baseline were analyzed (mixed model for repeated measures).Both galcanezumab doses significantly reduced the number of monthly moderate-to-severe and severe migraine headache days compared with placebo, overall (difference in least-squares mean change from baseline, 120 mg/240 mg versus placebo: moderate-to-severe, -1.9/-1.8 days; severe: -0.4/-0.4 days) and in each month; mean severity score was significantly reduced in the 240 mg group. Both galcanezumab doses significantly reduced the number of migraine headache days with nausea/vomiting (-1.1/-1.0 days), photophobia/phonophobia (-2.3/-1.7 days), prodromal symptoms (-0.7/-0.8 days), and aura (-0.7/-0.7 days). In most cases, the proportion of migraine headache days with these symptoms was reduced by galcanezumab. Both galcanezumab doses reduced the number of migraine headache days occurring during menstrual periods (n = 269; -0.8/-0.9 days).Once-monthly galcanezumab significantly reduced the frequency of migraine headache days with moderate-to-severe or severe headache, migraine headache days with migraine-associated symptoms, and migraine headache days during menstrual periods in Japanese patients with episodic migraine, consistent with results from global studies.ClinicalTrials.gov (NCT02959177).

Due to potential ethnic differences in the pathophysiology of type 2 diabetes, new therapeutics need to be evaluated in Japanese patients. We aimed to assess the safety and glycaemic efficacy of tirzepatide as an add-on treatment in Japanese patients with type 2 diabetes who had inadequate glycaemic control with stable doses of various oral antihyperglycaemic monotherapies.This multicentre, open-label, parallel-group, randomised, phase 3 trial was conducted at 34 medical research centres and hospitals in Japan. Eligible participants were aged 20 years or older with inadequately controlled (HbABetween March 30, 2019, and Feb 16, 2021, with recruitment and enrolment continuing until Feb 4, 2020, 484 participants were assessed for eligibility and 443 were randomly assigned to receive at least one dose of tirzepatide (148 [33%] in the 5 mg group, 147 [33%] in the 10 mg group, and 148 [33%] in the 15 mg group). 398 (90%) participants completed the study and treatment. Most participants (343 [77%] of 443) had at least one treatment-emergent adverse event. Treatment-emergent adverse events were more frequent in the tirzepatide 15 mg group (125 [84%] of 148) than the 5 mg (109 [74%] of 148) and 10 mg groups (109 [74%] of 147). The most frequent treatment-emergent adverse events with tirzepatide were mild or moderate nasopharyngitis (75 [17%]), nausea (74 [17%]), constipation (54 [12%]), diarrhoea (51 [12%]), and decreased appetite (44 [10%]). At week 52, mean changes from baseline in bodyweight were -3·8 kg (SE 0·5; -5·1% reduction) in the 5 mg group, -7·5 kg (0·5; -10·1% reduction) in the 10 mg group, and -10·2 kg (0·5; -13·2% reduction) in the 15 mg group. Least squares mean HbATirzepatide was well tolerated as an add-on to oral antihyperglycaemic monotherapy in Japanese participants with type 2 diabetes and showed improvement in glycaemic control and bodyweight, irrespective of background oral antihyperglycaemic medication. Tirzepatide is a potential new treatment option for Japanese patients with type 2 diabetes that is inadequately controlled with single oral antihyperglycaemic medication.Eli Lilly and Company.For the Japanese translation of the abstract see Supplementary Materials section.

Hisaka Igarashi,1 Mamoru Shibata,2 Akichika Ozeki,3 Kathleen Ann Day,4 Taka Matsumura3 1Department of Internal Medicine, Fujitsu Clinic, Kawasaki, Japan; 2Department of Neurology, Tokyo Dental College Ichikawa General Hospital, Ichikawa, Japan; 3Eli Lilly Japan K.K., Kobe, Japan; 4Eli Lilly and Company, Indianapolis, IN, USACorrespondence: Taka MatsumuraMedical Science, Medicines Development Unit Japan, Eli Lilly Japan K.K., 4-15-1 Akasaka, Akasaka Garden City 13F, Minato-ku, Tokyo, 107-0052, JapanTel +81 3 5574 9169Fax +81 3 5574 9979Email matsumura_taka@lilly.comPurpose: This study aimed to extensively evaluate the onset and maintenance effect of galcanezumab compared with placebo for the prevention of episodic migraine in Japanese patients.Patients and Methods: This was a post-hoc analysis of a Phase 2, multicenter, randomized, double-blind, placebo-controlled study conducted between December 2016 and January 2019 (ClinicalTrials.gov: NCT02959177). Patients aged between 18 and 65 years with episodic migraine were randomized to receive a monthly injection of galcanezumab (120 mg: N = 115, 240 mg: N = 114) or placebo (N = 230) for 6 months. Outcome measures included onset of effect at weekly and daily intervals—assessed by change from baseline in the number of migraine headache days and the proportion of patients with migraine headache—with galcanezumab versus placebo. To further confirm the onset and maintenance effect, the 50% response rate was also evaluated.Results: The mean change from baseline in weekly migraine headache days was significantly reduced with galcanezumab (– 0.97 days) compared with placebo (– 0.10 days) at week 1 (p ≤ 0.0001), which was maintained at all subsequent weeks up to week 4 (all p ≤ 0.0001 vs placebo). A significantly smaller proportion of galcanezumab-treated patients had migraine headache compared with placebo-treated patients at day 1 after the first injection (13.6% vs 31.4%, respectively; p ≤ 0.0001), which was also maintained at all subsequent days during the first week after the first injection. Furthermore, the 50% response rate was significantly higher with galcanezumab compared with placebo from week 1 through month 6.Conclusion: The onset of the migraine preventive effect of galcanezumab was rapid compared with placebo, starting from day 1 after the first injection in Japanese patients with episodic migraine. The effect was maintained during the first week and first month, and throughout 6 months of monthly injections of galcanezumab. Galcanezumab is a promising preventive treatment in Japanese patients with episodic migraine.Keywords: calcitonin gene-related peptide, galcanezumab, Japan, migraine disorders, onset of effect, maintenance effect

This MONONOFU trial subgroup analysis evaluates the efficacy of lasmiditan across patient and migraine characteristics in Japanese patients with migraine.MONONOFU trial was a multicenter, randomized, double-blind, placebo-controlled study. The patients were randomly assigned in a 3:7:6:7 ratio to receive lasmiditan 50 mg, 100 mg, 200 mg, or placebo for a single migraine attack within 4 h of pain onset. Efficacy of lasmiditan vs placebo was evaluated at 2 h post dose for proportion of patients with headache pain freedom. Efficacy was assessed across patient characteristics (age, sex, body weight, cardiovascular risk factors (CVRF), and comorbidity of tension-type headache), migraine disease characteristics (history of migraine with aura, migraine prevention therapy, triptan response, and triptan use or nonuse), and migraine attack characteristics (headache severity, aggressive headache, attack during perimenstrual period, time to dosing, time of dosing, experienced treatment-emergent adverse event (TEAE) of dizziness, and experienced TEAE of somnolence). Logistic regression was used; all subgroup analyses were not analyzed with multiplicity-adjusted statistical tests.Treatment-by-subgroup interactions (by each arm) were not significant (p ≥ 0.05) for pain freedom at 2 h post dose across all patient subgroups and lasmiditan doses, except for CVRF (100 mg and 200 mg), migraine with aura (50 mg), triptan response (50 mg), and time to dosing (200 mg). Treatment-by-subgroup interactions (by overall) were not significant (p ≥ 0.05) for pain freedom at 2 h post dose across all patient subgroups, except for CVRFs. Higher proportions of patients were pain free at 2 h post dose when treated with lasmiditan (50 mg, 100 mg, and 200 mg) versus placebo, irrespective of most patient characteristics, migraine disease characteristics, and migraine attack characteristics.Although few interactions were observed, lasmiditan could be a promising acute treatment option in a wide range of Japanese patients with migraine, as efficacy is not generally influenced by patient and migraine characteristics.

Rapid onset and sustained efficacy are important for acute migraine treatment. Global phase 3 trials have demonstrated the early onset and sustained efficacy of the 5-HTMONONOFU was a multicenter, randomized, placebo-controlled, phase 2 study conducted in Japan (May 2019-June 2020). Eligible adults with migraine (N = 846; modified intent-to-treat population, N = 682) were randomized 7:3:7:6 to placebo, lasmiditan 50 mg, 100 mg, or 200 mg, taken orally within 4 h of moderate-to-severe migraine onset. Patients recorded headache severity and symptoms predose and 0.5-48 h postdose. Sustained and modified sustained pain freedom were defined as patients who were headache pain-free 2 h postdose and had no pain (sustained pain freedom) or had mild or no pain (modified sustained pain freedom) at 24 or 48 h without rescue/recurrence medications. Efficacy outcomes were analyzed by logistic regression. Patients also recorded the actual time of pain-free and of meaningful pain relief (Kaplan-Meier analysis).Compared with placebo, significantly more lasmiditan-treated (100 or 200 mg) patients were headache pain-free, had pain relief, were free of their most bothersome symptom, or had total migraine freedom (no headache or migraine-associated symptoms) within 30-60 min. Median time to pain-free was 9.26, 6.88, 2.75, and 2.30 h in placebo, 50-mg, 100-mg, and 200-mg lasmiditan groups, respectively. Significantly greater proportions of patients treated with 100 (19.7-29.5%) or 200 mg (21.1-35.7%) lasmiditan had sustained or modified sustained pain freedom at 24 or 48 h compared with placebo (10.4-15.8%).This prespecified analysis of data from MONONOFU has confirmed that the efficacy of lasmiditan is rapid in onset and sustained in patients with moderate-to-severe migraine in Japan.ClinicalTrials.gov (NCT03962738).

Introduction This analysis evaluated the treatment satisfaction of Japanese patients receiving galcanezumab (GMB) as a preventive medication for episodic migraine (4–14 monthly migraine headache days). Methods This phase 2, randomized, double-blind, placebo-controlled study enrolled patients aged 18–65 years at 40 centers in Japan. Patients were randomized 2:1:1 to receive monthly subcutaneous injections of placebo (PBO, n = 230), GMB 120 mg (n = 115), or GMB 240 mg (n = 114) for 6 months. Patients’ experience with treatment was measured using the Patient Global Impression of Severity (PGI-S), Patient Global Impression of Improvement (PGI-I), and Patient Satisfaction with Medication Questionnaire-Modified (PSMQ-M) scales. PGI-S was administered at baseline and months 1–6, PGI-I at months 1–6, and PSMQ-M at months 1 and 6. Prespecified analyses were differences between GMB and PBO in PGI-I and the change from baseline in PGI-S, and evaluating positive responses for the PGI-I and PSMQ-M. Results Average change ± SE from baseline across months 1–6 was − 0.09 ± 0.05 (PBO), − 0.17 ± 0.07 (GMB 120 mg, p = 0.33), and − 0.30 ± 0.07 (GMB 240 mg, p = 0.013) for PGI-S. Average PGI-I across months 1–6 was 3.39 ± 0.05 (PBO), 2.55 ± 0.07 (GMB 120 mg, p

Mamoru Shibata,1 Tomomi Nakamura,2 Akichika Ozeki,2 Kaname Ueda,2 Russell M Nichols3 1Department of Neurology, Tokyo Dental College Ichikawa General Hospital, Ichikawa, Japan; 2Medicines Development Unit Japan and Medical Affairs, Eli Lilly Japan K.K., Kobe, Japan; 3Global Medical Affairs, Eli Lilly and Company, Indianapolis, IN, USACorrespondence: Tomomi NakamuraMedicines Development Unit Japan and Medical Affairs,Eli Lilly Japan K.K., 5-1-28 Isogamidori, Chuo-Ku, Kobe 651-0086, JapanTel +81-78-242-9389Email nakamura_tomomi@lilly.comPurpose: Evaluate changes from baseline in health-related quality of life (QoL) in Japanese patients with episodic migraine receiving preventive treatment with galcanezumab (GMB).Patients and Methods: Preventive treatments for migraine have been shown to improve QoL, but few clinical trials have examined QoL outcomes in Japanese patients. This phase 2, randomized, double-blind, placebo-controlled study was conducted at 40 centers in Japan. Patients aged 18– 65 years with episodic migraine (4– 14 monthly migraine headache days) received GMB 120 mg (n=115), 240 mg (n=114), or placebo (PBO, n=230) as monthly subcutaneous injections for 6 months. QoL was measured monthly using the Migraine-Specific Quality-of-Life Questionnaire (MSQ) version 2.1. Prespecified analyses were differences between GMB and PBO for change from baseline in all 3 domains of the MSQ and MSQ-Total, for each month and the average over Months 4– 6.Results: Treatment with GMB significantly increased MSQ scores from baseline vs PBO. Average change ± SE from baseline across Months 4– 6 was 10.12± 0.72 (PBO), 17.13± 1.03 (GMB 120 mg; P< 0.001), and 15.91± 1.03 (GMB 240 mg; P< 0.001) for MSQ Role Function-Restrictive; 4.80± 0.65 (PBO), 9.64± 0.93 (GMB 120 mg; P< 0.001), and 8.35± 0.93 (GMB 240 mg; P< 0.05) for MSQ Role Function-Preventive (MSQ-RFP); 3.46± 0.77 (PBO), 10.04± 1.10 (GMB 120 mg; P< 0.001), and 7.73± 1.10 (GMB 240 mg; P< 0.05) for MSQ Emotional Function, and 7.14± 0.67 (PBO), 13.46± 0.95 (GMB 120 mg; P< 0.001), and 11.98± 0.95 (GMB 240 mg; P< 0.001) for MSQ-Total. Significantly greater improvement in scores in all MSQ domains and MSQ-Total was observed for both GMB doses vs PBO at Month 1 and was maintained for Months 1– 6 (excluding Month 5 for MSQ-RFP).Conclusion: Preventive treatment with GMB 120 mg/240 mg improves MSQ scores in Japanese patients with episodic migraine. Improvements were seen within the first month and maintained for 6 months and are similar to those seen in global studies enrolling primarily Caucasian patients.Clinical Trial Registration: ClinicalTrials.gov, NCT02959177 (registered November 7, 2016).Keywords: MeSH: preventive therapy, quality of life

MONONOFU, a multicenter, randomized, double-blind, placebo-controlled phase 2 study of Japanese patients with migraine, was pivotal for lasmiditan approval in Japan. However, treatment-emergent adverse events (TEAEs) were more common than in global studies. A detailed safety profile would assist patient management. Safety assessments in MONONOFU included specific terms reported, frequency, severity, time to onset, duration, TEAE management, common TEAE risk factors, and TEAE–efficacy associations. Of 846 participants, 691 were assessed for safety. The proportion of participants reporting ≥1 TEAE was 23.4% with placebo and 70.9% with lasmiditan; 87.3% of TEAEs with lasmiditan were mild. The most frequent TEAEs with lasmiditan, dizziness (39.4%) and somnolence (19.3%), started ≤1 hour postdose (median durations: 2.5 and 3.3 hours, respectively). Higher lasmiditan dose, but not patient factors including body size, was identified as a clinically meaningful predictor of dizziness and somnolence. There were no adverse consequences of neurological TEAEs, which did not appear to adversely affect lasmiditan efficacy. In the MONONOFU study, TEAEs appeared typically mild, transient, and self-limiting. Lasmiditan may represent a useful and well-tolerated acute treatment option for smaller (body mass index 2) patients and Asian patients with migraine.

Some migraine treatments are contraindicated for patients with cardiovascular disease (CVD) or risk factors (CVRFs). We report safety and efficacy of lasmiditan, a new oral acute migraine treatment with no cardiovascular contraindication, in Japanese patients with CVRFs. MONONOFU was a multicenter, randomized, double-blind, placebo-controlled, phase 2 study of Japanese patients with migraine (met International Headache Society criteria, Migraine Disability Assessment score ≥11, disabling migraine for ≥1 year). Eligible patients were randomized (7:3:7:6) to placebo or lasmiditan 50, 100, 200 mg. This prespecified analysis described CVDs, CVRFs, and cardiovascular treatment-emergent adverse events (TEAEs). Efficacy (proportion pain-free, experienced pain relief, most bothersome symptom-free, or disability-free 2 hours post-dose) was evaluated within CVRF subgroups (≤1, ≥2). Of 846 randomized patients, 691 were analyzed (CVRF≤1: 375; CVRF≥2: 316). The proportion of lasmiditan-treated patients with ≥1 TEAE was not related to CVRF numbers. Eighteen (3.8%) lasmiditan-treated and three (1.4%) placebo-treated patients reported likely cardiovascular TEAEs. Lasmiditan was more effective than placebo at relieving pain, symptoms, and disability in both CVRF subgroups. There was no consistent relationship between CVRF subgroups and efficacy. Lasmiditan was well tolerated and effective in Japanese patients with migraine and CVRFs. ClinicalTrials.gov: NCT03962738.

Because of the burden of migraine in Japan, there is a need for safe and effective preventive treatments. This study assessed the long-term safety and tolerability of galcanezumab in Japanese patients with episodic (EM) or chronic (CM) migraine.In this 12-month open-label study, adult patients with EM who previously completed a 6-month, double-blind, placebo-controlled trial were newly randomized to either galcanezumab dose from placebo or continued their assigned galcanezumab doses (all: 120 mg, n = 120; 240 mg, n = 126). Newly enrolled patients with CM were randomized to 120-mg (n = 32) or 240-mg (n = 33) galcanezumab. The primary outcome was long-term safety and tolerability.The incidence of TEAEs was similar between treatment groups. Nasopharyngitis was the most common TEAE, followed by injection site reactions. The discontinuation rate was low (EM = 9.3%; CM = 15.4%) and no deaths were reported. Patients with EM who received galcanezumab in the placebo-controlled trial had sustained efficacy. Both doses reduced the number of migraine headache days in patients with CM.Long-term treatment with 120-mg or 240-mg galcanezumab was safe and effective in Japanese patients with EM or CM.https://clinicaltrials.gov, identifier: NCT02959190.

Let Y denote a response variable and X denote a covariate. We consider statistical inferences in semiparametric regression models, where the parameter of interest is the upper boundary \(\theta (x)=g(x \beta )\) of the support \([0, \theta (x)]\) of the conditional distribution of Y, given \(X=x\), where the boundary structure \(g(\cdot )\) is known. By extending Le Cam’s theory of limits of experiments to include semiparametric models, we construct estimators of the boundary parameter \(\theta (x)\), with bias correction. The risk of each estimator reaches a lower bound for the one-sample problem, two-sample problem, and one continuous covariate (predictor) case. When \(g(\cdot )\) is unknown with one continuous predictor X, we propose a selection method for the boundary structure \(g(\cdot )\) under regularity conditions. This yields consistent estimators of \(g(\cdot )\) and \(\beta \), although efficiency is not proved under this general model. We conclude with a real-data study on the longevity of lung cancer patients.

Objectives To determine whether early changes in International Prostate Symptom Score predict final improvement in the quality of life and treatment satisfaction of patients with lower urinary tract symptoms from benign prostatic hyperplasia receiving tadalafil. Methods This post-hoc analysis of three randomized-controlled trials of tadalafil for lower urinary tract symptoms from benign prostatic hyperplasia used subpopulations based on treatment status (tadalafil, placebo) and region (Japan, Asia). Logistic regression, principal component analysis and hierarchical clustering analysis were applied to individual International Prostate Symptom Score and Patient Global Impression of Improvement response scores. Results From logistic regression, most individual International Prostate Symptom Score items predicted either International Prostate Symptom Score remitter or responder status; only International Prostate Symptom Score Quality of Life predicted Patient Global Impression of Improvement responder status in tadalafil-treated patients. Among tadalafil-treated patients, principal component analysis showewd that improvement of International Prostate Symptom Score items 2, 4, 7 and International Prostate Symptom Score Quality of Life at early visits were associated with Patient Global Impression of Improvement (final visit), whereas International Prostate Symptom Score items 1, 3, 5 and 6 at early visits were associated with total International Prostate Symptom Score at the final visit. No clear predictive items for Patient Global Impression of Improvement and total International Prostate Symptom Score existed for placebo-treated patients. Hierarchical clustering analysis showed that the closest association was between International Prostate Symptom Score Quality of Life and International Prostate Symptom Score item 7 in placebo- and tadalafil-treated patients, which supports the principal component analysis results. Conclusions Early changes of storage and voiding symptoms by tadalafil might lead to treatment satisfaction and overall International Prostate Symptom Score improvement, respectively. This finding could help physicians predict tadalafil treatment outcomes for patients with lower urinary tract symptoms from benign prostatic hyperplasia.

Objective:This study was designed to assess the efficacy and safety of galcanezumab in comparison with placebo for the prevention of migraine in Japanese patients with episodic migraine.Methods:In this double-blind, placebo-controlled study, which was conducted over 6 months, randomized adult patients received subcutaneous injections of galcanezumab (120 mg n = 115, 240 mg n = 114) or placebo ( n = 230) once monthly. The primary endpoint was the overall mean change from baseline in the number of monthly migraine headache days. The key secondary outcome measures were response rates (≥50%, ≥75%, and 100%); the Migraine-Specific Quality-of-Life Questionnaire Role Function-Restrictive score; monthly migraine headache days requiring acute treatment; and Patient Global Impression of Severity (PGI-S).Results:The mean change from baseline in monthly migraine headache days over months 1–6 was significantly ( p < 0.001) greater for the 120-mg galcanezumab dose (−3.60 days) and the 240-mg galcanezumab dose (−3.36 days) compared with placebo (−0.59 days). Both the 120-mg and 240-mg doses of galcanezumab were superior compared with placebo for each of the key secondary endpoints except for PGI-S (only the 240-mg dose was superior). The most commonly reported treatment-emergent adverse events were local injection-site reactions; erythema, swelling, pruritus, and pain were more commonly reported by patients who were treated with galcanezumab than those treated with placebo.Conclusion:The number of monthly migraine headache days was reduced with both doses of galcanezumab, and both doses were safe and well tolerated in Japanese patients with episodic migraine.

IMPORTANCE: Ramucirumab, a human IgG 1 antibody against vascular endothelial growth factor receptor 2, has been shown to improve progression-free survival and overall survival in patients with advanced gastric cancer in the second-line setting. OBJECTIVE: To compare progression-free survival for S-1 and oxaliplatin plus ramucirumab with that for S-1 and oxaliplatin plus placebo in patients with advanced gastric cancer. DESIGN, SETTING, AND PARTICIPANTS: This phase 2, double-blind randomized clinical trial (RAINSTORM [First-line S-1 Plus Oxaliplatin With or Without Ramucirumab Followed by Paclitaxel Plus Ramucirumab in Patients With Advanced Gastric Cancer]) was conducted from October 12, 2015, to April 11, 2018, at 36 sites in Japan, South Korea, and Taiwan. Participants were chemotherapy-naive patients (n = 189) with metastatic gastric or gastroesophageal adenocarcinoma. Analyses of the full analysis set and safety population were conducted between November 27, 2017, and June 4, 2018. INTERVENTIONS: Patients randomized to the ramucirumab plus S-1 and oxaliplatin arm received S-1, 80 to 120 mg/d twice daily, on days 1 to 14 and oxaliplatin, 100 mg/m(2), on day 1 with ramucirumab, 8 mg/kg, on days 1 and 8 in part A (21-day cycle). Patients randomized to the placebo plus S-1 and oxaliplatin arm received the same S-1 and oxaliplatin dosage as well as placebo on days 1 and 8 in part A. Eligible patients received second-line paclitaxel, 80 mg/m(2), on days 1, 8, and 15 and ramucirumab, 8 mg/kg, on days 1 and 15 in part B (28-day cycle). MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival, analyzed using the stratified log-rank test; the hazard ratio (HR) was estimated using the stratified Cox proportional hazards regression model. Secondary end points included overall survival and adverse events. RESULTS: In total, 189 patients were randomized and received treatment: 96 to the ramucirumab plus S-1 and oxaliplatin arm and 93 to the placebo plus S-1 and oxaliplatin arm. Among the 189 patients, 121 (64.0%) were male, and the median (range) age was 62.0 (26-84) years. Median progression-free survival was not prolonged in the ramucirumab plus S-1 and oxaliplatin arm compared with the placebo plus S-1 and oxaliplatin arm (6.34 [80% CI, 5.65-6.93] vs 6.74 [80% CI, 5.75-7.13] months; HR, 1.07; 80% CI, 0.86-1.33; P = .70). Median overall survival was 14.65 (80% CI, 12.39-15.67) months in the ramucirumab plus S-1 and oxaliplatin arm and 14.26 (80% CI, 13.83-17.31) months in the placebo plus S-1 and oxaliplatin arm (HR, 1.11; 80% CI, 0.89-1.40; P = .55). The most commonly reported grade 3 or higher treatment-emergent adverse events in the ramucirumab plus S-1 and oxaliplatin arm in part A were decreased neutrophil count (14 patients [14.6%]), hypertension (10 patients [10.4%]), and anemia (10 patients [10.4%]). CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, the addition of ramucirumab to first-line S-1 and oxaliplatin treatment did not prolong progression-free survival or overall survival compared with S-1 and oxaliplatin alone among East Asian patients with advanced gastric cancer; no new safety signals for ramucirumab were identified. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02539225

The goal of this study was to assess the safety and efficacy of 0.75 mg of dulaglutide, a once weekly glucagon-like peptide-1 receptor agonist, in Japanese patients with type 2 diabetes (T2D) on a single oral hypoglycemic agent (OHA). In this phase 3, nonrandomized, open-label, parallel-group, 52-week study, safety and efficacy of once weekly dulaglutide 0.75 mg were assessed in Japanese patients with T2D on a single OHA (sulfonylureas [SU], biguanides [BG], α-glucosidase inhibitors [AGI], thiazolidinedione [TZD], or glinides [GLN]). A total of 394 patients were treated with study drug, and 92.9% completed the 52-week treatment period. The most frequent treatment-emergent adverse events were nasopharyngitis and gastrointestinal disorders, including constipation, diarrhea, and nausea. Incidences of hypoglycemia varied across the combination therapy groups: incidence was greater in patients receiving SU compared with other combinations. No severe hypoglycemic episodes occurred during the study. Increases from baseline in pancreatic and total amylase, lipase, and pulse rate were observed in all 5 combination therapy groups. Significant reductions from baseline in HbA1c were observed in all 5 combination therapy groups (-1.57% to -1.69%, p < 0.001 for all). Mean body weight changes from baseline varied across the combination therapy groups: a significant increase was observed in combination with TZD, there were no significant changes in combination with SU or GLN, and significant reductions were observed in combination with BG or AGI. Once weekly dulaglutide 0.75 mg in combination with a single OHA was overall well tolerated and improved glycemic control in Japanese patients with T2D.

4036Background: RAM (a human IgG1 antibody against vascular endothelial growth factor receptor-2) plus paclitaxel has been found to improve overall survival compared with paclitaxel alone as second...

Suppose that X is a random vector with probability distribution P and suppose that P denotes a proposed model that involves interesting parameters and relationship between variables. We consider statistical inference procedures for the case where PeP constructed as follows: let hðPÞ denote the parameter of the distribution Q 2 P that minimizes a Kullback–Leibler (K–L)-type discrepancy KðQ; PÞ between Q and P. We take hðPÞ to be the parameter of interest. The estimate of hðPÞ, when it exists, is defined by ^ h ¼ hð ^

BackgroundIn the treatment of major depressive disorder (MDD), it is not fully understood how individual symptoms improve over time (trajectory) in remitters. This study compared symptom improvement trajectories, as measured with the 17-item Hamilton Depression Rating Scale (HAM-D17), in remitters and nonremitters.MethodsThis analysis is based on 10 placebo-controlled, randomized, double-blind trials of duloxetine (40–60mg/day) for treatment of MDD from baseline up to week 8. Remission was defined as a HAM-D17 total score ≤7 at week 8 (last observation carried forward). Trajectories of HAM-D17 items were assessed by mixed model repeated measures analysis for treatment and remitter-nonremitter comparisons. Grouping of the trajectories was performed by factor analysis. Predictor analysis using HAM-D17 items was conducted by logistic regression.ResultsThere were 1555 patients in the duloxetine group (489 [31.4%] remitters) and 1206 patients in the placebo group (290 [24.0%] remitters; P

Background: Fluoropyrimidine and platinum-based regimens have been established as a global standard of care, including Japan, for the 1st-line treatment of pts with mGC. RAM is a human IgG1 antibody against VEGFR-2. In the 2nd-line setting, 2 global phase 3 studies of RAM alone (REGARD) and RAM + paclitaxel (RAINBOW), demonstrated significant improvement in survival compared to placebo and paclitaxel + placebo, respectively. The subset analysis of the RAINBOW study suggested that higher RAM exposures were associated with improved survival outcome. In this study, safety, tolerability, pharmacokinetics (PK) and efficacy of a new RAM dosing schedule in combination with 3 fluoropyrimidine and platinum-based regimens in the 1st-line setting were evaluated in Japanese pts with mGC. Patients and Methods: This was a multicenter, single-arm, phase 1b study in mGC pts in the 1st-line setting. On each cycle, pts received 8 mg/kg RAM at days 1 and 8, every 3-weeks (q3w), in combination with XP q3w: capecitabine (2000 mg/m2, days 1-14, PO) + cisplatin (80 mg/m2, day 1, IV); SP every 5-weeks (q5w): S-1 (80 mg/m2/day, days 1-21, PO) + cisplatin (60 mg/m2, day 8, IV); or SOX q3w: S-1 (80 mg/m2/day, days 1-14, PO) + oxaliplatin (100 mg/m2, day 1, IV). The primary objective was to confirm safety and tolerability; secondary objectives were to evaluate PK and anti-tumor response. Results: 18 pts, 6 in each cohort, were treated. Pts received RAM for median 23.4 weeks (min 2.0 - max 69.0). Across all cohorts, only 1 dose-limiting toxicity was observed during the 1st cycle (grade 3 enterocolitis), and resolved after treatment discontinuation. Three treatment-related serious adverse events (AE) were observed: decreased appetite (n=1), pelvic venous embolism (n=1) and enterocolitis (n=1). Treatment-related AE of any grade included neutropenia (n=14), decreased appetite (n=12), constipation (n=11), nausea (n=11), and hypertension (n=9). Compared to the currently approved 8 mg/kg every 2-weeks (q2w) regimen, the new dose regimen used in this study (8 mg/kg days 1 and 8 q3w) has produced higher mean trough concentrations of RAM. Disease control rate (DCR) was 100% and overall response rate (ORR) was 45% in patients with measurable lesions (n=11). Conclusion: The new scheduling regimen of RAM (8 mg/kg, days 1 and 8, q3w) in combination with either of XP, SP or SOX, was tolerable in Japanese mGC pts in the 1st-line setting. Currently, a global phase 3 study of XP and an Asian randomized phase 2 study of SOX are ongoing to evaluate potential benefits of adding RAM to current standard 1st-line therapies. (NCT02359058) Citation Format: Shigenori Kadowaki, Kohei Shitara, Daisuke Sakai, Tomohiro Nishina, Reigetsu Yoshikawa, Yongzhe Piao, Akichika Ozeki, Koichi Inoue, Kei Muro. Phase 1b study of ramucirumab (RAM) in combination with fluoropyrimidine and platinum-based agents in Japanese patients (pts) with metastatic gastric/gastroesophageal junction adenocarcinoma (mGC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT096. doi:10.1158/1538-7445.AM2017-CT096

Basic phenomena of the twin-roll casting have been investigated by paraffin model casting, thermal analysis and steel casting experiments. The influence of the roll gap on roll-bonding behavior of the solidified shells and temperature distribution of the molten pool have been mainly investigated by paraffin model casting. On the other hand, the change of the molten pool temperature during casting has been calculated by the numerical analysis method. Based on the results of these simulations, twin-roll casting of the steel has been carried out.Through these experiments and numerical simulation, it has been recognized that roll gap relates closely to segregation, crack occurence and breakout of the cast strip, and the decrease of the molten pool temperature. An appropriate roll gap should be a gap which does not cause breakout, but minimizes the squeezing out the mushy-state layer. It is also found that the tendency of segregation and crack occurence in the steel strip are well explained by paraffin model casting.