Galcanezumab Effects on Migraine Severity and Symptoms in Japanese Patients with Episodic Migraine: Secondary Analysis of a Phase 2 Randomized Trial.

INTRODUCTION: 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. METHODS: 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). RESULTS: 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). CONCLUSION: 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. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02959177).

Treatment Satisfaction of Galcanezumab in Japanese Patients with Episodic Migraine: A Phase 2 Randomized Controlled Study.

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 < 0.05), and 2.71 ± 0.07 (GMB 240 mg, p < 0.05). Reductions of 2.8-3.0 monthly migraine headache days corresponded to 25-31% higher positive PGI-I response rates with GMB compared with PBO. Positive PSMQ-M response rates for satisfaction and preference were statistically significantly higher for GMB compared with PBO (odds ratio [95% confidence interval], all p < 0.05 vs. PBO): satisfaction GMB 120 mg (3.142 [1.936-5.098]) and GMB 240 mg (3.924 [2.417-6.369]), and preference GMB 120 mg (3.691 [2.265-6.017]) and GMB 240 mg (3.510 [2.180-5.652]). CONCLUSION: Japanese patients with episodic migraine receiving preventive treatment with GMB are significantly more satisfied than those receiving PBO. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02959177 (registered November 7, 2016).

Early Onset and Maintenance Effect of Galcanezumab in Japanese Patients with Episodic Migraine.

PURPOSE: 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.

Costs and resource use of community-dwelling patients with Alzheimer's disease in Japan: 18-month results from the GERAS-J study.

OBJECTIVE: To determine the longitudinal societal costs and burden of community-dwelling patients with Alzheimer's disease (AD) and their caregivers in Japan. METHODS: GERAS-J was an 18-month, prospective, longitudinal, observational study. Using the Mini-Mental State Examination (MMSE), patients routinely visiting memory clinics were stratified into groups based on AD severity at baseline (mild, moderate, and moderately severe/severe [MS/S]). Healthcare resource utilization and caregiver burden were assessed using the Resource Utilization in Dementia and Zarit "Caregiver" Burden Interview questionnaires, respectively. Total monthly societal costs were estimated using Japan-specific unit costs of services and products (patient direct healthcare use, patient social care use, and informal caregiving time). RESULTS: Overall, 553 patients (156 mild; 209 moderate; 188 MS/S) were enrolled. MMSE scores declined (1.73, 1.38, and 0.95 points for the mild, moderate, and MS/S AD groups, respectively) and caregiver burden and resource utilization increased over 18 months in each of the AD severity groups. Cumulative total societal costs per patient over 18 months were 3.1, 3.8, and 5.3 million Japanese yen (29,006, 35,662, and 49,725 USD) for mild, moderate, and MS/S AD, respectively. Both patient social care costs and caregiver informal care costs increased with baseline disease severity, with >50% of total costs due to caregiver informal care in each disease severity subgroup. CONCLUSIONS: Total treatment costs increased with AD severity over 18 months due to increases in both patient social care costs and caregiver informal care costs. Our data suggest current social care services in Japan are insufficient to alleviate the negative impact of AD on caregiver burden.

[Safety and Effectiveness of NEPTIS Plug-01 and Florbetapir (18F) in Daily Clinical Setting: Based on the Post-Marketing Surveillance Study].

OBJECTIVE: Obtaining the information on safety and effectiveness of radiopharmaceutical synthesizer NEPTIS plug - 01 and florbetapir (18F) injection solution synthesized by NEPTIS plug - 01 from the post marketing surveillance study. METHODS: Regarding the safety evaluation, failure of device and adverse events were recorded. Regarding the effectiveness evaluation, we assessed the quality of PET images and the impact on the clinical diagnosis. RESULT: During the study period, 12 patients were enrolled. No adverse event was reported from those 12 patients. Two events in 2 patients were reported as a failure of device (In a subsequent investigation, those failures were thought to be caused by inadequacy of procedure manual, which has been revised now). For the quality of PET images, all 12 cases were "good" or "excellent", regardless of the positive or negative of amyloid plaque. The attending physician's diagnosis was changed in 9 patients following the PET imaging. CONCLUSION: NEPTIS plug-01 and florbetapir (18F) were safe and has a favorable effectiveness profile in 12 patients under daily clinical setting.

The increasing use of pediatric emergency facilities in the evening.

OBJECTIVES: In Japan, the demand for pediatric emergency medicine has been increasing, especially in the evening. The purpose of this study was to identify the reasons for overcrowding of pediatric emergency facilities in the evening. METHODS: A population-based survey was conducted in Yokohama City, Japan, that targeted parents of children 1 or 3 years of age. These children participate in regular health checkups. Questionnaires about their child's illnesses and the pediatric emergency system were mailed to 30,000 parents of a child expected to undergo a health checkup between May 2004 and January 2005. RESULTS: Data obtained from the completed questionnaires indicated that many parents noticed their child's illness or injury most frequently during the evening, when most medical facilities are closed. The peak period when parents noticed their child's illness was the evening (4:00 pm-12 midnight, 54.4%), followed by the daytime (8:00 am-4:00 pm, 30.3%) and then the nighttime (12 midnight-8:00 am, 15.3%). During all 3 periods, parents felt it difficult to judge their child's condition and thus many used emergency facilities unnecessarily. CONCLUSIONS: The overcrowding of pediatric emergency facilities in the evening is likely due mainly to a mismatch between the peak time of children's illnesses and the office hours of pediatric clinics. Parents' difficulties in assessing their child's condition and anxiety over their child's illness and injuries seem to be other factors that contribute to this imbalance.

Ready conversion of patients with well-controlled, moderate to severe, chronic malignant tumor-related pain on other opioids to tapentadol extended release.

BACKGROUND AND OBJECTIVES: The effectiveness and tolerability of tapentadol extended release (ER), a centrally acting analgesic with µ-opioid receptor agonist and norepinephrine (noradrenaline) reuptake inhibitor activities, have been demonstrated in patients with chronic pain, including those switching directly from prior opioid therapy. The objective of the current study was to evaluate the effectiveness and safety of conversion to oral tapentadol ER (50-250 mg twice daily) from previous around-the-clock strong opioid therapy in patients with moderate to severe, chronic malignant tumor-related cancer pain that was well-controlled. METHODS: This randomized, open-label, phase III study, which was conducted in Japan, included a 1- to 2-week screening period (on previous opioid) and an 8-week, open-label treatment period. Eligible patients, who were taking a strong opioid analgesic and had a mean pain intensity score <4 during the 3 days prior to randomization (adequate pain control on previous strong opioid), were randomized (1:1) to receive twice-daily treatment with tapentadol ER (100-500 mg/day) or morphine sustained release (SR; 20-140 mg/day; reference for assay sensitivity). Initial doses were estimated based on the conversion ratio of tapentadol ER:oxycodone:morphine:fentanyl = 10:2:3:0.03. The primary effectiveness endpoint was the proportion of patients who maintained pain control [change from baseline in mean pain intensity (11-point numerical rating scale) less than +1.5 for 3 consecutive days and no more than two doses of rescue medication per day for 3 consecutive days) during the first week of open-label treatment. RESULTS: In the tapentadol ER group (n = 50), 84.0 % of patients (42/50; 95 % CI, 70.89-92.83) maintained pain control during Week 1. On the Patient Global Impression of Change, 2.1 % (1/48), 2.1 % (1/48), 22.9 % (11/48), and 50.0 % (24/48) of patients in the tapentadol ER group reported that their overall condition was "very much improved," "much improved," "minimally improved," and "not changed," respectively, at Week 1 compared with 0 %, 10.7 % (3/28), 28.6 % (8/28), and 53.6 % (15/28) reporting these ratings at Week 8. The sensitivity of effectiveness analyses was validated based on results using morphine SR; 98.0 % (49/50; 95 % CI, 89.35-99.95) of patients in the morphine SR group maintained pain control after 1 week of treatment. The overall safety profile was similar to that demonstrated in previous studies; tapentadol ER was associated with a lower incidence of gastrointestinal treatment-emergent adverse events than morphine SR [38.0 % (19/50) vs. 54.0 % (27/50)], including constipation [12.0 % (6/50) vs. 20.0 % (10/50)] and vomiting [6.0 % (3/50) vs. 26.0 % (13/50)]. CONCLUSIONS: Overall, results indicate that conversion from previous strong opioids to tapentadol ER (50-250 mg twice daily) was successful and resulted in safe and effective pain control with improved gastrointestinal tolerability versus morphine SR in patients with moderate to severe cancer-related pain that was well-controlled on their previous opioid.

A randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of osmotic-controlled release oral delivery system methylphenidate HCl in adults with attention-deficit/hyperactivity disorder in Japan.

OBJECTIVES: To evaluate the safety and efficacy of osmotic-controlled release oral delivery system (OROS) methylphenidate (MPH) HCl in adults with attention-deficit/hyperactivity disorder (ADHD). METHODS: In this study, 284 adults with ADHD were randomized to OROS MPH or placebo. During the 4-week titration period, patients were titrated from a starting dose of 18 mg once daily to an individually-optimized dose of up to 72 mg once daily in weekly 18-mg increments. Patients continued on their individualized dose during the 4-week efficacy assessment period. The primary efficacy endpoint was change in DSM-IV Total ADHD Symptoms subscale score of Conners' Adult ADHD Rating Scale-Observer: Screening Version (CAARS-O:SV) from baseline to endpoint. RESULTS: The mean change in DSM-IV Total ADHD Symptoms subscale score of CAARS-O:SV was significantly larger with OROS MPH compared with placebo (P < 0.0001, ANCOVA). Similar results were observed for the majority of secondary endpoints, including CAARS-O:SV total score and other subscale scores. Although treatment-emergent adverse events were reported more frequently in the OROS MPH group (81.8%) versus the placebo group (53.9%), OROS-MPH showed a well-tolerated safety profile overall. CONCLUSIONS: OROS MPH in a dose range of 18-72 mg once daily was effective and well-tolerated in adult patients with ADHD.

Randomized, placebo-controlled, double-blind study assessing the efficacy and safety of paliperidone palmitate in Asian patients with schizophrenia.

BACKGROUND: This 13-week, double-blind study was conducted to confirm the efficacy and safety of paliperidone palmitate (PP), at dosing regimens approved in other countries, in Asian patients with schizophrenia. METHODS: Asian patients (aged ≥20 years) diagnosed with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revision criteria), and having a Positive and Negative Syndrome Scale (PANSS) total score of 60 to 120 were enrolled and randomized (1:1) to a PP or placebo group. Patients received PP intramuscularly at recommended doses: initiation dose 150 mg equivalent (eq) PP on day 1 and 100 mg eq PP on day 8 (deltoid); and a monthly maintenance dose of 75 mg eq PP on days 36 and 64 (deltoid or gluteal). The change from baseline to week 13 in PANSS total scores (primary endpoint), Clinical Global Impression-Severity (CGI-S) scores, and PANSS Marder factor scores and subscales, and responder rate at week 13 were evaluated. Safety was also assessed. RESULTS: The PANSS total score (P<0.0001, least-squares mean change from baseline to week 13: PP, -3.5; placebo, +6.2), CGI-S score (P<0.0001), and PANSS Marder factor scores (P≤0.0025) were significantly improved at week 13 in the PP group versus placebo. More treatment responders (≥30% decrease in PANSS total score) were in the PP group (22.8%) versus placebo (8.5%). Insomnia (PP 17.0% versus placebo 15.2%), injection site pain (13.2% versus 6.7%), nasopharyngitis (12.6% versus 6.1%), psychiatric symptoms (11.3% versus 26.2%), and extrapyramidal symptoms (10.1% versus 4.9%) were the most frequently occurring treatment-emergent adverse events. CONCLUSION: PP is efficacious for Asian patients with schizophrenia at the dosing regimen approved in other countries, with a similar safety and tolerability profile.

Efficacy and safety of oral tapentadol extended release in Japanese and Korean patients with moderate to severe, chronic malignant tumor-related pain.

OBJECTIVE: This phase 3 study evaluated the efficacy and safety of tapentadol extended release (ER) compared with oxycodone controlled release (CR) for the management of moderate to severe, chronic malignant tumor-related cancer pain. RESEARCH DESIGN AND METHODS: This randomized, double-blind, active-controlled study included Japanese and Korean patients with moderate to severe, chronic malignant tumor-related pain. Patients were randomized (1:1) to receive oral tapentadol ER (25-200 mg bid) or oral oxycodone HCl CR (5-40 mg bid) for 4 weeks of double-blind treatment. ClinicalTrials.gov identifier: NCT01165281. MAIN OUTCOME MEASURES: This study was designed to evaluate the non-inferiority of the efficacy provided by tapentadol ER versus oxycodone CR, based on the mean change in average pain intensity (11 point numerical rating scale) from baseline to the last 3 days of study drug administration. Treatment-emergent adverse events (TEAEs) were recorded throughout the study. RESULTS: Of the 374 patients who were screened, 343 were randomized and 236 completed treatment. The least-squares mean difference in the change in pain intensity from baseline to the last 3 days of study treatment between tapentadol ER and oxycodone CR was -0.06 (95% confidence interval [CI], -0.506 to 0.383). The upper limit of the 95% CI was <1 (the predefined threshold value for non-inferiority), indicating that tapentadol ER provided analgesic efficacy that was non-inferior to that of oxycodone CR. The percentage of patients reporting at least one TEAE was similar in the tapentadol ER (87.5% [147/168]) and oxycodone CR (90.1% [155/172]) treatment groups, but the incidence of gastrointestinal TEAEs was lower in the tapentadol ER group (55.4% [93/168]) than in the oxycodone CR group (67.4% [116/172]). CONCLUSIONS: Tapentadol ER (25-200 mg bid) provides analgesic efficacy that is non-inferior to that provided by oxycodone HCl CR (5-40 mg bid) for the management of moderate to severe, chronic malignant tumor-related pain, and is well tolerated overall, with a better gastrointestinal tolerability profile than oxycodone CR.