Efficacy and Safety of Esaxerenone in Hypertensive Patients with Left Ventricular Hypertrophy (ESES-LVH) Study: A Multicenter, Open-Label, Prospective, Interventional Study.

INTRODUCTION: In contrast to the antihypertensive effect of esaxerenone, there is little evidence of its cardioprotective effect. We investigated the efficacy and safety of esaxerenone in patients with uncontrolled hypertension and left ventricular hypertrophy taking a renin-angiotensin system inhibitor (RASi) or calcium-channel blocker (CCB). METHODS: This was a multicenter, open-label, exploratory study with a 24-week treatment period. Esaxerenone was orally administered at an initial dose of 2.5 mg/day (maximum dose: 5 mg/day). The primary endpoints were the change in morning home systolic blood pressure (BP)/diastolic BP and change and percentage change in left ventricular mass index (LVMI) from baseline to end of treatment (EOT). Key secondary endpoints included change from baseline in bedtime home and office BP, achievement rate of target BP, and safety. RESULTS: In total, 60 patients were enrolled. Morning home systolic/diastolic BP was significantly decreased from baseline to EOT in the total population (- 11.5/ - 4.7 mmHg, p < 0.001) and in both the RASi and CCB subcohorts (all p < 0.01). Significant reductions in bedtime home and office BP were shown in the total population and both subcohorts. LVMI was also significantly decreased from baseline to EOT in the total population (- 9.9 g/m2, - 8.5%, both p < 0.001) and both subcohorts (all p < 0.05). The incidences of treatment-emergent adverse events (TEAEs) and drug-related TEAEs were 35.0% and 3.3%, respectively; most were mild or moderate. No new safety concerns were identified. CONCLUSION: Esaxerenone showed favorable antihypertensive and cardioprotective effects and safety in hypertensive patients with cardiac hypertrophy. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCTs071190043).

Efficacy and safety of add-on mirogabalin to conventional therapy for the treatment of peripheral neuropathic pain after thoracic surgery: the multicenter, randomized, open-label ADMIT-NeP study.

BACKGROUND: For chronic pain after thoracic surgery, optimal timing of its diagnosis and effective treatment remains unresolved, although several treatment options are currently available. We examined the efficacy and safety of mirogabalin, in combination with conventional pain therapy (nonsteroidal anti-inflammatory drugs and/or acetaminophen), for treating peripheral neuropathic pain (NeP) after thoracic surgery. METHODS: In this multicenter, randomized, open-label, parallel-group study, patients with peripheral NeP were randomly assigned 1:1 to mirogabalin as add-on to conventional therapy or conventional treatment alone. RESULTS: Of 131 patients of consent obtained, 128 were randomized (mirogabalin add-on group, 63 patients; conventional treatment group, 65 patients). The least squares mean changes (95% confidence interval [CI]) in Visual Analogue Scale (VAS) score for pain intensity at rest from baseline to Week 8 (primary endpoint) were - 51.3 (- 54.9, - 47.7) mm in the mirogabalin add-on group and - 47.7 (- 51.2, - 44.2) mm in the conventional group (between-group difference: - 3.6 [95% CI: - 8.7, 1.5], P = 0.161). However, in patients with Self-administered Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) score (used for the screening of NeP) ≥ 12 at baseline, the greater the S-LANSS score at baseline, the greater the decrease in VAS score in the mirogabalin add-on group, while no such trend was observed in the conventional treatment group (post hoc analysis). This between-group difference in trends was statistically significant (interaction P value = 0.014). Chronic pain was recorded in 7.9% vs. 16.9% of patients (P = 0.171) at Week 12 in the mirogabalin add-on vs. conventional treatment groups, respectively. Regarding activities of daily living (ADL) and quality of life (QOL), changes in Pain Disability Assessment Scale score and the EQ-5D-5L index value from baseline to Week 8 showed significant improvement in the mirogabalin add-on group vs. conventional treatment group (P < 0.001). The most common adverse events (AEs) in the mirogabalin add-on group were dizziness (12.7%), somnolence (7.9%), and urticaria (3.2%). Most AEs were mild or moderate in severity. CONCLUSIONS: Addition of mirogabalin to conventional therapy did not result in significant improvement in pain intensity based on VAS scores, but did result in significant improvement in ADL and QOL in patients with peripheral NeP after thoracic surgery. TRIAL REGISTRATION: Japan Registry of Clinical Trials jRCTs071200053 (registered 17/11/2020).

Efficacy and safety of mirogabalin for chemotherapy-induced peripheral neuropathy: a prospective single-arm trial (MiroCIP study).

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a painful, dose-limiting adverse effect of commonly used chemotherapeutic agents. The purpose of this exploratory study was to evaluate the efficacy and safety of mirogabalin in patients with moderate to severe CIPN during chemotherapy and the effects of 12 weeks' intervention on chemotherapy completion and CIPN severity. METHODS: Patients experiencing moderate to severe CIPN while undergoing oxaliplatin- or taxane-containing chemotherapy for colorectal, gastric, non-small-cell lung, or breast cancer received mirogabalin at between 5 and 15 mg twice daily. The primary endpoint was change in numeric rating scale (NRS) score for pain from baseline to week 12. Secondary endpoints included NRS scores for tingling and sleep, completion of chemotherapy, severity of CIPN, and quality of life (QOL) scores. The safety endpoint was incidence of adverse events. RESULTS: Of 58 patients who consented to participation, 52 were eligible and constituted the full analysis set and safety analysis set. From baseline to week 12 (last observation carried forward [LOCF]), NRS score decreased by 30.9%: mean change (95% confidence interval [CI]), - 1.7 (- 2.4 to - 1.0) (p < 0.001). Patients with baseline NRS of ≥ 6 experienced a 44.0% reduction in score from baseline to week 12 (LOCF): mean change (95% CI), - 3.3 (- 5.0 to - 1.5) (p = 0.002). Chemotherapy was discontinued in 18 (34.6%) patients; CIPN led to discontinuation in only 2 (3.8%). There was no notable worsening of CIPN severity in terms of Common Terminology Criteria for Adverse Events grade or Modified Total Neuropathy Score-reduced, although use of pain medications during chemotherapy might cause worsening of CIPN due to underestimation of subjective symptoms. QOL score based on the EuroQol five-dimensional descriptive system did not worsen during the 12 weeks. Thirty-one percent of patients experienced adverse drug reactions, and the most common event was somnolence (13.5%). Serious adverse events and death occurred in 3 patients and 1 patient, respectively; however, they were unrelated to mirogabalin treatment. CONCLUSIONS: Intervention with mirogabalin during chemotherapy may be effective and safe for cancer patients with moderate to severe CIPN. It can contribute to completion of chemotherapy without worsening of CIPN. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCTs031210101, registered 20/5/2021).

Treatment with trastuzumab deruxtecan in patients with HER2-positive breast cancer and brain metastases and/or leptomeningeal disease (ROSET-BM).

Therapeutic options for breast cancer patients with brain metastases (BM)/leptomeningeal carcinomatosis (LMC) are limited. Here, we report on the effectiveness and safety of trastuzumab deruxtecan (T-DXd) in human epidermal growth factor receptor 2-positive breast cancer patients with BM. Data were analyzed for 104 patients administered T-DXd. Overall response rate (ORR), progression-free survival (PFS), overall survival (OS), intracranial (IC)-ORR, and IC-PFS were evaluated. ORR by investigator assessment was 55.7% (total population). Median PFS was 16.1 months; 12-month OS rate was 74.9% (total population). Median time-to-treatment failure was 9.7 months. In 51 patients with BM imaging, IC-ORR and median IC-PFS by independent central review were 62.7% and 16.1 months, respectively. In 19 LMC patients, 12-month PFS and OS rates were 60.7% and 87.1%, respectively. T-DXd showed effectiveness regarding IC-ORR, IC-PFS, PFS, and OS in breast cancer patients with BM/active BM, and sustained systemic and central nervous system disease control in LMC patients.Trial Registration: UMIN000044995.

Efficacy and Safety of Esaxerenone in Hypertensive Patients with Diabetes Mellitus Undergoing Treatment with Sodium-Glucose Cotransporter 2 Inhibitors (EAGLE-DH).

INTRODUCTION: The EAGLE-DH study assessed the efficacy and safety of esaxerenone in hypertensive patients with diabetes mellitus receiving sodium-glucose cotransporter 2 (SGLT2) inhibitors. METHODS: In this multicenter, open-label, prospective, interventional study, esaxerenone was started at 1.25 or 2.5 mg/day and could be gradually increased to 5 mg/day on the basis of blood pressure (BP) and serum potassium levels. Oral hypoglycemic or antihypertensive medications prior to obtaining consent was continued. Data were evaluated in the total population and creatinine-based estimated glomerular filtration rate (eGFR) subcohorts (eGFR ≥ 60 mL/min/1.73 m2 [G1-G2 subcohort] and 30 to < 60 mL/min/1.73 m2 [G3 subcohort]). RESULTS: In total, 93 patients were evaluated (G1-G2, n = 49; G3, n = 44). Morning home systolic/diastolic BP values (SBP/DBP) were significantly reduced from baseline to week 12 (- 11.8 ± 10.8/- 5.1 ± 6.3 mmHg, both P < 0.001) and week 24 (- 12.9 ± 10.5/- 5.7 ± 6.3 mmHg, both P < 0.001). Similar results were observed in both eGFR subcohorts. The urinary albumin-to-creatinine ratio significantly decreased from baseline to week 24 in the total population (geometric percentage change, - 49.1%, P < 0.001) and in both eGFR subcohorts. The incidences of treatment-emergent adverse events (TEAEs) and drug-related TEAEs were 45.2% and 12.9%, respectively; most were mild or moderate. Serum potassium levels increased over the first 2 weeks of esaxerenone treatment, gradually decreased by week 12, and remained constant to week 24. One patient in the G1-G2 subcohort had serum potassium levels ≥ 5.5 mEq/L. No patients had serum potassium ≥ 6.0 mEq/L. CONCLUSION: Esaxerenone effectively lowered BP, was safe, and showed renoprotective effects in hypertensive patients with diabetes mellitus receiving treatment with SGLT2 inhibitors. Esaxerenone and SGLT2 inhibitors did not interfere with either drug's efficacy and may reduce the frequency of serum potassium elevations, suggesting they are a compatible combination. CLINICAL TRIAL REGISTRATION: jRCTs031200273.

Nighttime home blood pressure lowering effect of esaxerenone in patients with uncontrolled nocturnal hypertension: the EARLY-NH study.

There is limited evidence on the blood pressure (BP)-lowering effect of esaxerenone on home BP, including nighttime BP. Using two newly developed nocturnal home BP monitoring devices (brachial and wrist), this multicenter, open-label, prospective study investigated the nighttime home BP-lowering effect of esaxerenone in patients with uncontrolled nocturnal hypertension being treated with an angiotensin receptor blocker (ARB) or calcium-channel blocker (CCB). In total, 101 patients were enrolled. During the 12-week study period, change in nighttime home systolic/diastolic BP from baseline to end of treatment measured by the brachial device was -12.9/-5.4 mmHg in the total population and -16.2/-6.6 and -10.0/-4.4 mmHg in the ARB and CCB subcohorts, respectively (all p < 0.001). For the wrist device, the change was -11.7/-5.4 mmHg in the total population and -14.6/-6.2 and -8.3/-4.5 mmHg in each subcohort, respectively (all p < 0.001). Similar significant reductions were shown for morning and bedtime home BP and office BP. Urinary albumin-to-creatinine ratio, N-terminal pro-brain natriuretic peptide, and cardio-ankle vascular index improved in the total population and each subcohort. Incidences of treatment-emergent adverse events (TEAEs) and drug-related TEAEs were 38.6% and 16.8%, respectively; most were mild or moderate. The most frequent drug-related TEAEs were associated with serum potassium elevation (hyperkalemia, 9.9%; blood potassium increased, 3.0%); however, no new safety concerns were raised. Esaxerenone was effective in lowering nighttime home BP as well as morning and bedtime home BP and office BP, safe, and showed organ-protective effects in patients with uncontrolled nocturnal hypertension. Caution is warranted regarding elevated serum potassium levels. This study investigated the effect of esaxerenone on nighttime home BP and organ damage (UACR and NT-proBNP) in patients with uncontrolled nocturnal hypertension despite treatment with an ARB or CCB. Our results show that safe 24-h BP control and organ protection are possible with esaxerenone.

Steady-State Pharmacokinetics of Intravenous Hydromorphone in Japanese Patients With Renal Impairment and Cancer Pain.

Background: The opioid analgesic hydromorphone has a low renal excretion ratio; however, exposure after oral administration is several times higher in those with moderate or severe renal impairment. Objectives: We evaluated the impact of renal impairment on the steady-state pharmacokinetics of intravenously administered hydromorphone in patients with cancer being treated for pain. Design: This was an open-label, prospective, parallel-comparison, interventional clinical pharmacology study. Setting/Subjects: This study was conducted at one hospital in Japan. Using creatinine clearance (CLcr) values, patients were grouped according to kidney function: CLcr ≥90 mL/min (normal), 60-<90 mL/min (mild impairment), 30-<60 mL/min (moderate impairment), or <30 mL/min (severe impairment). Measurements: Hydromorphone was administered by constant infusion to patients at the same constant dose rate as at the time of enrollment. Hydromorphone and its glucuronide metabolite concentrations in plasma and urine were measured by liquid chromatography-mass spectrometry. Pharmacokinetic parameters at steady state were assessed using noncompartmental analysis. Results: Thirty-two patients were enrolled (normal, n = 3; mild, n = 10; moderate, n = 15; and severe, n = 4). Adjusted geometric mean ratios for hydromorphone steady-state clearance (CLss) for patients with impaired versus normal renal function were 0.69 (90% confidence interval [CI], 0.41-1.14), 0.52 (90% CI, 0.31-0.84), and 0.55 (90% CI, 0.30-1.02) for mild, moderate, or severe impairment, respectively. Exposures to the metabolite hydromorphone-3-glucuronide generally increased with renal impairment. No adverse event was reported. Conclusion: Hydromorphone CLss in patients with impaired renal function (moderate and severe) was decreased ∼50% of that of normal renal function.

Relationship between the dose titration and adherence of mirogabalin in patients with peripheral neuropathic pain depending on renal function: a nationwide electronic medical record database study.

BACKGROUND: Mirogabalin has been attracting attention for treating peripheral neuropathic pain. The package insert recommends that mirogabalin should be titrated depending on renal function. Here, we investigated the relationship between dose titration patterns and adherence, and persistence of mirogabalin treatment. RESEARCH DESIGN AND METHODS: Peripheral neuropathic pain patients who initiated mirogabalin between March 2020 and May 2021 were identified using an electronic medical record database. The dose titration pattern was described according to degrees of renal function. Regression analyses were performed to compare adherence and persistence between the patients with and without titration. RESULTS: Of the 4,138 identified patients, 1,696 (41.0%) titrated the dose within 45 days and were more adherent than those without titration (Adjusted odds ratio: 1.75, 95% CI 1.21, 2.54). Of the total 952 patients with renal function parameters, 229 (24.1%) titrated to the effective dose within 45 days and were less likely to discontinue than those without titration (Adjusted hazard ratio: 0.57, 95% CI 0.40, 0.81). CONCLUSION: Mirogabalin dose titration was associated with better adherence and persistence. It is important for mirogabalin treatment to determine the initial prescription dose based on renal function and subsequent dose titration according to the package insert. TRIAL REGISTRATION: UMIN000047313.

Efficacy and Safety of Esaxerenone in Hypertensive Patients with Diabetic Kidney Disease: A Multicenter, Open-Label, Prospective Study.

INTRODUCTION: Clinical data of esaxerenone in hypertensive patients with diabetic kidney disease (DKD) are lacking. We evaluated the efficacy and safety of esaxerenone in patients with DKD and an inadequate response to blood pressure (BP)-lowering treatment. METHODS: In this multicenter, open-label, prospective study, patients were divided into urinary albumin-to-creatinine ratio subcohorts (UACR < 30, 30 to < 300, and 300 to < 1000 mg/gCr). Esaxerenone was initiated at 1.25 mg/day and followed by incremental dose escalation based on BP and serum potassium level monitoring. The treatment period was 12 weeks. The primary endpoint was change in morning home systolic BP/diastolic BP (SBP/DBP) from baseline to end of treatment (EOT). Secondary endpoints included achievement rate of target BP, change in UACR from baseline, and safety. RESULTS: In total, 113 patients were enrolled. Morning home SBP/DBP significantly decreased from baseline to EOT in the total population (- 11.6/- 5.2 mmHg, both p < 0.001) and in all UACR subcohorts (all p < 0.001). The target BP achievement rate was 38.5%. Significant reductions in bedtime home and office BPs were also shown in the total population and all UACR subcohorts. UACR significantly improved from baseline to EOT in the total (- 50.9%, p < 0.001) and all UACR subcohorts (all p < 0.001). Incidence of serum potassium elevation as drug-related treatment emergent adverse events was 2.7%. The change from baseline in estimated glomerular filtration rate (eGFR) was - 4.8 mL/min/1.73 m2. CONCLUSION: Esaxerenone demonstrated a BP-lowering effect and improved albuminuria. The effects were consistent regardless of the severity of albuminuria without clinically relevant serum potassium elevation and eGFR reduction. CLINICAL TRIAL REGISTRATION: jRCTs06119002.

Efficacy and Safety of Add-on Mirogabalin to NSAIDs in Lumbar Spinal Stenosis with Peripheral Neuropathic Pain: A Randomized, Open-Label Study.

INTRODUCTION: In Japan, conservative therapy for patients with lumbar spinal stenosis (LSS) includes non-steroidal anti-inflammatory drugs (NSAIDs), prostaglandin E1, tramadol, physical/exercise therapy, and nerve blocks. Mirogabalin, a selective oral α2δ ligand, is approved for treating peripheral neuropathic pain, though data regarding visual analog scores (VAS) for pain in patients with LSS are limited. We investigated the efficacy and safety of mirogabalin as an add-on treatment in patients with LSS taking NSAIDs compared with patients taking NSAIDs only. METHODS: This multicenter, randomized, open-label study (MiroTAS) was conducted at 32 centers in Japan between June 2020 and October 2021. Patients were randomly assigned to mirogabalin and NSAIDs or NSAIDs alone in a 1:1 ratio. NSAIDs were administered according to their Japanese package inserts; mirogabalin was administered based on renal function [creatinine clearance (CrCL) ≥ 60 mL/min, 5 mg twice daily (BID) in Weeks 1-2, 10 mg BID in Weeks 3-4, and 15 or 10 mg BID after Week 5; CrCL 30 to < 60 mL/min, 2.5 mg BID Weeks 1-2, 5 mg BID Weeks 3-4, and 7.5 or 5 mg BID after Week 5]. The primary endpoint was the change in VAS score for leg pain from baseline to Week 12. Secondary endpoints were quality of life, evaluated using the EuroQol five-dimensional descriptive system (EQ-5D-5L) (at baseline and Week 12) and Patient Global Impression of Change (PGIC) (at Week 12), and safety. Change in VAS score at Week 12 was calculated using a linear mixed model for repeated measures. The safety endpoints were treatment-emergent adverse events (TEAEs) and adverse drug reactions. RESULTS: In total, 220 patients who met the eligibility criteria were enrolled. In the mirogabalin and NSAIDs and NSAIDs groups, mean ages (67.8 vs. 70.9 years), proportions of female patients (54.5% vs. 49.0%), mean body weights (63.9 vs. 62.0 kg), mean CrCL values (81.5 vs. 70.7 mL/min), proportions of patients with CrCL 30 to < 60 mL/min (27.3% vs. 33.7%), mean VAS scores (63.8 vs. 62.8 mm), and proportions of patients with VAS score ≥ 60 (53.6% vs. 52.9%) at enrollment were similar. The median durations of LSS were 9.0 and 11.0 months and the spine pain DETECT questionnaire (SPDQ) scores were 6.8 and 7.8, respectively. The least square (LS) mean change in VAS score from baseline to Week 12 was - 24.1 mm in the mirogabalin and NSAIDs group and - 14.2 mm in the NSAIDs group (both P < 0.0001 vs. baseline). The difference in LS mean was - 9.9 [95% confidence interval (CI), - 18.0, - 1.8] (P = 0.0174). The improvement in EQ-5D-5L score at Week 12 was significantly greater in the mirogabalin and NSAIDs group versus the NSAIDs group [mean difference, 0.0529 (95% CI, 0.0036, 0.1022), P = 0.0357]. At Week 12, the proportions of patients with PGIC scores ≤ 3 and ≤ 2 were higher in the mirogabalin and NSAIDs group vs. the NSAIDs group (76.2% vs. 50.0%, P = 0.0006, and 47.6% vs. 32.4%, P = 0.0523). In the mirogabalin and NSAIDs group, the incidences of TEAEs and adverse drug reactions were 60.9% and 57.3%, respectively, and the most common TEAEs were somnolence (30.0%) and dizziness (25.5%). CONCLUSIONS: The addition of mirogabalin to NSAIDs improved VAS, EQ-5D-5L, and PGIC. The main TEAEs were somnolence and dizziness. The addition of mirogabalin to NSAIDs improved peripheral neuropathic pain associated with LSS and raised no new safety concerns. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCTs021200007).

Rationale and Design of the Efficacy and Safety of Esaxerenone in Hypertensive Patients With Left Ventricular Hypertrophy (ESES-LVH) Study　- Protocol for a Multicenter, Open-Label, Exploratory Interventional Study.

Background: The complication of left ventricular (LV) hypertrophy (LVH) is associated with increased incidence of major cardiovascular events. Hypertension is an independent risk factor among several factors contributing to the development of LVH, and thus appropriate treatment of both hypertension and LVH reduces the risk of developing heart failure. Mineralocorticoid-receptor blockers (MRBs) have been reported to improve the prognosis of LVH, but use of currently available MRBs is limited by adverse events. Esaxerenone is a novel selective nonsteroidal MRB recently approved for treatment of hypertension. Although the renoprotective effect of esaxerenone has been demonstrated in both preclinical and clinical studies, little data is available in terms of its cardioprotective effects. Methods and Results: This multicenter, open-label, exploratory interventional study was designed to evaluate the safety and efficacy of esaxerenone in combination with renin-angiotensin system (RAS) inhibitors or calcium-channel blockers (CCBs). Eligible criteria are hypertensive patients with LVH, and target blood pressure (BP) not reached with an RAS inhibitor or a CCB. The primary endpoints are change from baseline in seated home BP (early morning systolic/diastolic BPs), and change and %change from baseline in the LV mass index at the end of treatment. Conclusions: This study will provide the first clinical evidence of the antihypertensive effect and safety of esaxerenone in hypertensive patients with LVH.

A large-scale database study for the prescription status of a new voltage-gated Ca2+ channel α2δ ligand, mirogabalin, in Japan.

BACKGROUND: A new voltage-gated Ca2+ channel α2δ ligand, mirogabalin, was first approved for treating peripheral neuropathic pain in Japan in 2019. This is the first report on the prescription status of mirogabalin using a large-scale prescription database. RESEARCH DESIGN AND METHODS: The authors analyzed the prescription data of 12,924 patients prescribed mirogabalin between 1 June and 31 August 2020. The endpoints were the number of patients prescribed, prescription days, prescription doses, dose changes, co-prescription patterns, medication possession ratio (MPR), and treatment discontinuation rates (TDRs). RESULTS: Mirogabalin was newly prescribed to 7,914 patients in the 3-month study period. Most patients were prescribed mirogabalin at about 10 mg/day during the study period, and 30.9% of patients were prescribed ≥ 20 mg/day on Day 90 after the first prescription. The most frequently prescribed concomitant drug was celecoxib. The MPR (80 to 110%) was 86.2%, indicating good treatment adherence. The cumulative TDRs during ≤ 7 Days, Days 31-60, and 61-90 were 14.0%, 70.0%, and 77.9%, respectively. CONCLUSIONS: Mirogabalin was prescribed to a considerable number of patients. These results may be useful for optimizing mirogabalin use for patients with peripheral neuropathic pain in daily clinical practice. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000042592.

Mirogabalin treatment of postoperative neuropathic pain after thoracic surgery: study protocol for a multicenter, randomized, open-label, parallel-group, interventional trial.

BACKGROUND: Intercostal nerve damage due to thoracotomy or thoracoscopic manipulation is a major contributor to chronic postsurgical pain after pulmonary resection. Chronic postsurgical pain may last for months or years and can negatively impair physical functioning and daily activities. Global consensus on severe postoperative pain management is lacking, and chronic pain incidence after thoracic surgery remains high. Many patients report neuropathic pain, which can be difficult to treat with currently available therapies. The efficacy and safety of mirogabalin have been demonstrated for other types of neuropathic pain; thus, this study was planned to investigate the efficacy and safety of mirogabalin to treat neuropathic pain after thoracic surgery. METHODS: In this multicenter, randomized, open-label, parallel-group, interventional study, patients who are diagnosed with neuropathic pain following removal of a chest drain after lung resection will receive conventional therapy (non-steroidal anti-inflammatory drugs and/or acetaminophen) with or without the addition of a clinical dose of mirogabalin for 8 weeks. For patient stratification, a visual analog scale pain intensity score at baseline of <60 vs. ≥60 mm will be used. Treatment efficacy and safety with and without the addition of mirogabalin will be assessed using a questionnaire evaluating postoperative changes in pain severity and activity. The primary study endpoint is the change in pain intensity from baseline to Week 8, measured by the visual analog scale. Additionally, the presence of chronic pain at 12 weeks after enrollment in each treatment group will be recorded. DISCUSSION: This protocol has been reviewed and approved by the Clinical Research Review Board of Nagasaki University. Study data will be published in the Japan Registry of Clinical Trials database and peer-reviewed journals. Mirogabalin is already approved for the treatment of other types of neuropathic pain. It is anticipated that this study will provide data to elucidate the impact of mirogabalin treatment, in combination with conventional therapy, to benefit patients with neuropathic pain following thoracic surgery. TRIAL REGISTRATION: Japan Registry of Clinical Trials Identifier: jRCTs071200053.

The safety and efficacy of the long-acting neuraminidase inhibitor laninamivir octanoate hydrate for Inhalation Suspension Set in children under the age of 5 in a post-marketing surveillance.

INTRODUCTION: We conducted a post-marketing surveillance of laninamivir octanoate hydrate for Inhalation Suspension Set in patients under the age of 5 infected with the influenza virus to evaluate safety and efficacy of the drug. METHODS: Subjects enrolled by the centralized enrollment system were administered laninamivir once using a nebulizer based on the package insert. RESULTS: Safety was evaluated in 1104 patients. The incidence of ADRs was 1.00% (11/1104). Compared to the incidence of ADRs of 2.04% (9/441) in the clinical trials for development, no increase in the frequency of ADRs was noted. Serious ADRs were noted in 3 patients (5 cases): 2 cases of convulsive attack, each 1 case of muscular weakness, a depressed level of consciousness, and pain in extremities. Excluding 2 patients with unknown outcomes, all of the patients recovered or their symptoms were alleviated. To detect risk factors for the occurrence of ADRs, 16 attributes were examined, and none of them were found to be significant. Efficacy was evaluated in 881 patients. The median time (95% CI) to fever resolution was 37.0 (33.0-39.0) h in type A virus (785 patients), 45.0 (34.0-56.0) h in type B virus (95 patients), and 22.0 h (1 patient) in the mixed type. This was similar to the time to fever resolution in the clinical trials. CONCLUSION: The results of this surveillance verified that there are no noticeable problems with the safety or efficacy of laninamivir for children under the age of 5 infected with the influenza A and B viruses.

A Cross-Sectional Web Survey of Satisfaction with Treatment for Pain in Participants with Suspected Diabetic Peripheral Neuropathic Pain in Both Feet.

INTRODUCTION: Diabetic peripheral neuropathic pain (DPNP), a symptom of diabetic polyneuropathy (DPN), is underdiagnosed in people with diabetes. To date, no studies have determined the relationship between diagnosis of DPN and satisfaction with treatment for pain. Additionally, the factors that influence satisfaction with treatment for pain remain unknown. This questionnaire study was conducted to understand satisfaction with treatment for pain among participants with diabetes who experienced bilateral pain or numbness in their feet. METHODS: This cross-sectional, observational, web-based questionnaire study for participants with diabetes and suspected DPNP was conducted in Japan. Potential respondents were registered in the INTAGE Disease Panel or the Rakuten Insight Disease Panel. The primary endpoint was the number and percentage of participants who were satisfied with their DPNP treatment. Secondary endpoints included participant opinions regarding treatment-related efficacy, side effects, and economic burden, and factors affecting satisfaction with treatment. RESULTS: The questionnaire was accessed by 7565 potential participants; 777 met the eligibility criteria (final analysis set). Satisfaction with treatment for bilateral foot pain was low (satisfied, 27.9%; neither satisfied nor unsatisfied, 42.2%; unsatisfied, 23.4%; very unsatisfied, 6.4%). Participants were somewhat more satisfied with treatment side effects than with treatment efficacy and economic burden. Satisfaction with treatment mainly differed by improvement in actions in daily life, improvement in quality of life, and communication with doctors. The diagnostic testing rate for DPN was low, and diagnosis was more common in participants who complained of symptoms of pain and numbness (any visit) versus those who did not. CONCLUSION: Participants with diabetes who experience bilateral foot pain or numbness reported a low level of satisfaction with treatment for pain.

People with diabetes may develop diabetic polyneuropathy and experience diabetic peripheral neuropathic pain, which is often felt as pain or numbness below the knee. This study aimed to learn whether participants with diabetes who had pain or numbness in both feet were satisfied with the pain treatment they received. Factors affecting satisfaction with treatment were also evaluated. Potential participants with diabetes identified from two commercial databases (INTAGE Disease Panel or Rakuten Insight Disease Panel) of patients with various diseases living in Japan were asked to respond to our web survey. Besides satisfaction with treatment for pain, participants were asked about how well their treatment was working, treatment side effects, how treatment affected them financially, and what factors affected their satisfaction with treatment. The main finding was that only 27.9% of participants were satisfied with their treatment for foot pain and numbness. Generally, participants were more satisfied with treatment side effects than they were with how well the treatment worked, and how treatment affected them financially. Participants were more satisfied if they had an improved ability to perform everyday activities or experienced an improvement in quality of life with treatment. Participants were also more satisfied if they communicated well with their physician. The rate of diagnostic tests was low; however, participants were more likely to receive a diagnostic test when they complained of pain or numbness than when they did not. On the basis of these findings, we think improvements in the treatment of foot pain or numbness in those with diabetes are needed.

An exploratory assessment of the applicability of direct-to-consumer genetic testing to translational research in Japan.

OBJECTIVE: In order to assess the applicability of a direct-to-consumer (DTC) genetic testing to translational research for obtaining new knowledge on relationships between drug target genes and diseases, we examined possibility of these data by associating SNPs and disease related phenotype information collected from healthy individuals. RESULTS: A total of 12,598 saliva samples were collected from the customers of commercial service for SNPs analysis and web survey were conducted to collect phenotype information. The collected dataset revealed similarity to the Japanese data but distinguished differences to other populations of all dataset of the 1000 Genomes Project. After confirmation of a well-known relationship between ALDH2 and alcohol-sensitivity, Phenome-Wide Association Study (PheWAS) was performed to find association between pre-selected drug target genes and all the phenotypes. Association was found between GRIN2B and multiple phenotypes related to depression, which is considered reliable based on previous reports on the biological function of GRIN2B protein and its relationship with depression. These results suggest possibility of using SNPs and phenotype information collected from healthy individuals as a translational research tool for drug discovery to find relationship between a gene and a disease if it is possible to extract individuals in pre-disease states by properly designed questionnaire.

Safety and effectiveness of edoxaban in Japanese patients with nonvalvular atrial fibrillation: Final report of a two-year postmarketing surveillance study (ETNA-AF-Japan).

BACKGROUND: Direct oral anticoagulants (DOACs) are the recommended first-line therapy for ischemic stroke prevention in patients with nonvalvular atrial fibrillation (NVAF). However, the safety and effectiveness of edoxaban for this indication requires monitoring over the long term in real-world settings. METHODS: ETNA-AF-Japan (trial no. UMIN000017011) was a prospective, multicenter observational study (part of postmarketing surveillance in Japan). NVAF patients due to receive edoxaban to prevent ischemic stroke were enrolled between 13 April 2015 and 30 September 2017. RESULTS: A total of 11 569 patients were enrolled. For the 11 111 patients (female, 40.6%) whose data comprised the safety analysis set, age, body weight, creatinine clearance (CLcr), and CHADS2 score were 74.2 ± 10.0 years, 60.0 ± 12.7 kg, 63.9 ± 25.8 mL/min, and 2.2 ± 1.3, respectively (mean ± SD). The majority (86.3%) received edoxaban in accordance with package insert information. The mean duration of treatment was 561.9 ± 261.2 days. The annual incidence (95% confidence interval) of all bleeding events and major bleeding events was 5.60% (5.25%-5.98%) and 1.02% (0.88%-1.18%), respectively. The annual incidence of ischemic stroke (excluding transient ischemic attack, TIA) or systemic embolism was 1.08% (0.93%-1.25%). Multivariate analysis showed low body weight, low CLcr, history of gastrointestinal bleeding, anemia, and use of an antiplatelet agent to be associated with major bleeding, and history of ischemic stroke or TIA, vascular disease, and antiplatelet agent use to be associated with ischemic stroke (excluding TIA) or systemic embolism. CONCLUSIONS: These results provide real-world evidence for the long-term good safety and effectiveness profile of edoxaban in Japanese NVAF patients under clinical practice.

Switching From Pregabalin to Mirogabalin in Patients with Peripheral Neuropathic Pain: A Multi-Center, Prospective, Single-Arm, Open-Label Study (MIROP Study).

INTRODUCTION: Mirogabalin, which is a selective ligand of the α2δ subunit of voltage-gated Ca2+ channels, was recently approved in Japan for peripheral neuropathic pain. The α2δ ligands, including mirogabalin and pregabalin, are associated with significant risk of adverse events (AEs) such as somnolence or dizziness, leading to poor compliance and subsequent inefficacy. Safety and efficacy data for switching patients from pregabalin to mirogabalin are scarce. METHODS: This prospective, single-arm, open-label study involving ten participating centers in Japan recruited patients aged ≥ 20 years with peripheral neuropathic pain [visual analog scale (VAS) score ≥ 40 mm]. Where necessary, patients underwent a 1-week tapering period to reduce their pregabalin dose, after which pregabalin was stopped and mirogabalin dose was increased using a step-wise dose titration. Patients underwent dose increases after the first and second weeks if there were no tolerability issues, followed by the effective doses until the end of the study (4 weeks). The primary endpoint was the incidence of somnolence, dizziness, and peripheral edema; secondary endpoints included changes in VAS score. AEs were monitored for safety. RESULTS: Of 157 patients who provided informed consent, 152 patients were enrolled; 136 (89.5%) patients completed the study. The overall incidences of somnolence, dizziness, and peripheral edema were 41.4, 15.8, and 2.6%, respectively. Most patients (> 70%) experienced mild AEs, and one patient experienced a severe AE (dizziness). Most patients (> 70%) were able to achieve dose titration to an effective dose. Overall mean VAS score significantly decreased (Δ15.7 mm, p < 0.0001) by the end of the study. CONCLUSIONS: Mirogabalin switching from pregabalin is well tolerated and effective in pain management for peripheral neuropathic pain using a step-wise titration. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCTs031190113).

A Cross-sectional Survey of Patients with Suspected Diabetic Peripheral Neuropathic Pain in Japan.

Objective The burden of diabetic peripheral neuropathic pain (DPNP) is poorly understood. The present study reported on the current status of DPNP in Japan, to improve our understanding of this condition among healthcare providers and inform future clinical research on its prevalence, diagnosis, and management. Methods A cross-sectional, observational study (UMIN000037023) was conducted via a web-based survey. The primary endpoints were the frequency of patients with bilateral foot symptoms, consulting a doctor, understanding DPNP, and reporting problems in daily life, as well as the treatment awareness of patients. Patients Adults ≥20 years old who were registered in the Rakuten Insight Disease Panel and receiving anti-diabetic therapy in Japan were included. Results Bilateral foot pain symptoms were reported by 1,768/7,754 (22.8%) respondents, most commonly intense numbness (13.0%). Of those with symptoms, 55.3% consulted a doctor; the most common reason for not seeking consultation was feeling that symptoms were insufficiently severe to bother their doctor (89.4%). Nearly 60% reported understanding the causes of their symptoms, with diabetes-associated neurologic deficits (58.8%) most commonly identified. About one-quarter reported daily life problems, including an inability to walk for long periods (58.3%) and feeling anxious (58.1%). Treatment awareness was reported by 18.2%; oral medications were commonly recognized (64.6%). Conclusion In Japan, 22.8% of patients with diabetes have bilateral foot pain symptoms; some experience problems in their daily life without understanding the causes of their symptoms. This supports the importance of actions to increase awareness and minimize DPNP-associated impairment of daily life in patients with diabetes.