Letermovir safety and efficacy for cytomegalovirus prophylaxis in adult Japanese kidney transplant recipients: a multicenter, open-label, noncomparative Phase 3 study.

BACKGROUND: Letermovir is approved for cytomegalovirus (CMV) prophylaxis in adult allogeneic hematopoietic cell transplantation recipients worldwide and is also approved in the United States for CMV prophylaxis in adult high-risk (D+/R-) kidney transplant recipients (KTRs). The safety and efficacy of letermovir for CMV prophylaxis in adult Japanese KTRs are reported here. METHODS: In this Phase 3, single-arm, open-label study, adult Japanese KTRs with CMV serostatuses D+/R-, D+/R+, and D-/R+ received letermovir 480 mg daily orally within 7 days post-transplant through Week 28. Participants were followed through Week 52. The primary objective was to evaluate letermovir safety and tolerability. Efficacy was a secondary objective, measured by CMV disease, CMV disease or infection requiring intervention, and quantifiable CMV DNAemia. All CMV disease cases were confirmed by an independent adjudication committee. RESULTS: Among 22 participants (12 were D+/R-) who received letermovir prophylaxis, 20 (90.9%) experienced ≥ 1 AE through Week 28. Most AEs were mild to moderate in severity; no deaths were reported. During the prophylaxis period through Week 28, one transient case of quantifiable CMV DNAemia was detected, but no CMV disease or infection requiring intervention was reported. Through Week 52, four D+/R- participants met the endpoint of CMV disease or infection requiring intervention, of whom two had committee-confirmed CMV syndrome; all recovered with CMV therapy. A total of 5 participants had quantifiable CMV DNAemia through Week 52. CONCLUSION: Letermovir was generally well tolerated, and the data support its use for the prevention of CMV disease/infection in adult Japanese KTRs. TRIAL REGISTRATION: ClinicalTrials.gov NCT04129398.

Investigations into the Potential of Using Open Source CFD to Analyze the Differences in Hemodynamic Parameters for Aortic Dissections (Healthy versus Stanford Type A and B).

BACKGROUND: The objective of this study was to develop a method to evaluate the effects of an aortic dissection on hemodynamic parameters by conducting a comparison with that of a healthy (nondissected) aorta. Open-source software will be implemented, no proprietary software/application will be used to ensure accessorily and repeatability, in all the data analysis and processing. Computed tomography (CT) images of aortic dissection are used for the model geometry segmentation. Boundary conditions from literature are implemented to computational fluid dynamics (CFD) to analyze the hemodynamic parameters. METHODS: A numerical simulation model was created by obtaining accurate 3-dimensional geometries of aortae from CT images. In this study, CT images of 8 cases of aortic dissection (Stanford type-A and type-B) and 3 cases of healthy aortae are used for the actual aorta model geometry segmentation. These models were exported into an open-source CFD software, OpenFOAM, where a simplified pulsating flow was simulated by controlling the flow pressure. Ten cycles of the pulsatile flow (0.50 sec/cycle) conditions, totaling 5 sec, were calculated. RESULTS: The pressure distribution, wall shear stress (WSS) and flow velocity streamlines within the aorta and the false lumen were calculated and visualized. It was found that the flow velocity and WSS had a high correlation in high WSS areas of the intermittent layer between the true and false lumen. Most of the Stanford type-A dissections in the study showed high WSS, over 38 Pa, at the systole phase. This indicates that the arterial walls in type-A dissections are more likely to be damaged with pulsatile flow. CONCLUSIONS: Using CFD to estimate localized high WSS areas may help in deciding to treat a type-A or B dissection with a stent graft to prevent a potential rupture.

Efficacy and safety of tedizolid for the treatment of ventilated gram-positive hospital-acquired or ventilator-associated bacterial pneumonia in Japanese patients: Results from a subgroup analysis of a phase 3, randomized, double-blind study comparing tedizolid and linezolid.

INTRODUCTION: The results from the phase 3 study that evaluated the efficacy and safety of tedizolid phosphate, an oxazolidinone drug, for the treatment of gram-positive ventilated hospital-acquired bacterial pneumonia (vHABP)/ventilator-associated bacterial pneumonia (VABP) compared with linezolid (VITAL study), have been previously reported. We conducted a subgroup analysis to report the data obtained from Japanese patients enrolled in this study. METHODS: Patients aged ≥18 years with vHABP/VABP likely to be caused by gram-positive cocci were randomized 1:1 to tedizolid phosphate 200 mg once daily for 7 days or linezolid 600 mg twice daily for 10 days. In both treatment groups, patients with concurrent gram-positive bacteremia were treated for 14 days. Primary efficacy endpoints were day 28 all-cause mortality (ACM) and investigator-assessed clinical response at test-of-cure (TOC) in the intention-to-treat population. Safety outcomes included assessment of treatment-emergent adverse events. RESULTS: Fifty-three Japanese patients were randomized at received study drug (tedizolid, n = 28; linezolid, n = 25). Demographics and characteristics were generally similar between treatment groups. Rates of day 28 ACM were 10.7% and 20.0% with tedizolid and linezolid, respectively (difference, 9.3%; 95% CI, -10.1 to 28.7). Rates of investigator-assessed clinical cure at TOC were 78.6% and 72.0% with tedizolid and linezolid, respectively (difference, 6.6%; 95% CI, -16.7 to 29.8). Tedizolid phosphate was generally well tolerated and no new safety concerns were observed in the Japanese subgroup. CONCLUSION: The results from this subgroup analysis suggest generally favorable efficacy and safety of tedizolid in adult Japanese patients with vHABP/VABP. (ClinicalTrials.gov identifier: NCT02019420).

A randomized, placebo-controlled study to evaluate the efficacy and safety of adding omarigliptin to insulin therapy in Japanese patients with type 2 diabetes and inadequate glycaemic control.

AIM: To evaluate the efficacy and safety of adding the once-weekly oral dipeptidyl peptidase-4 inhibitor omarigliptin to treatment of Japanese patients with type 2 diabetes and inadequate glycaemic control on insulin monotherapy. MATERIALS AND METHODS: In a 52-week clinical trial, Japanese patients on insulin monotherapy were randomized to once-weekly omarigliptin 25 mg (N = 123) or placebo (N = 61) for a 16-week, double-blind, placebo-controlled period. After Week 16, patients continued or switched to omarigliptin for a 36-week open-label period. RESULTS: From a mean baseline of approximately 8.8%, the Week 16 least squares mean changes in HbA1c were -0.61% (omarigliptin) and 0.29% (placebo); the between-group difference was -0.90% (p < .001). At Week 52, the mean change from baseline in HbA1c was -0.57% in both the group on omarigliptin for 52 weeks and the group on omarigliptin for 36 weeks (switched from placebo at Week 16). During the first 16 weeks of treatment, the incidences of adverse events (AEs), serious AEs, drug-related AEs and discontinuation from trial medication because of an AE were similar in both groups. A slight increase in incidence of symptomatic hypoglycaemia was observed in the omarigliptin group (n = 13 [10.6%]) compared with placebo (n = 4 [6.6%]). No severe hypoglycaemia was reported during the study. No new safety signals emerged with treatment beyond Week 16 through Week 52. CONCLUSION: The addition of once-weekly omarigliptin to insulin therapy for up to 52 weeks was generally well tolerated and provided clinically meaningful improvement in glycaemic control throughout the trial period. ClinicalTrials.gov: NCT02906709.

Switch rates, time-to-switch, and switch patterns of antiretroviral therapy in people living with human immunodeficiency virus in Japan, in a hospital-claim database.

BACKGROUND: Regardless of chronic treatment with antiretroviral therapy (ART), the switching rate for ART regarding anchor drugs has not been articulated in real-world clinical-settings in Japan. We assessed switch rates and time-to-switch of ART regimens according to anchor drug classes (integrase strand transfer inhibitors (INSTI), non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI)) and common switching patterns of anchor drug classes in people living with human immunodeficiency virus (HIV) (PLWH) from 2008 to 2016. METHODS: This retrospective, observational study used data of 1694 PLWH drawn from a large-scale medical claims database. The median time-to-switch and switch rates of anchor drug class were estimated by Kaplan-Meier analysis. To estimate 95% confidence intervals for switch rates and median days, the Brookmeyer and Crowley method and Greenwood method were used respectively. The switching patterns were summarized based on the time of switching. The switch rates were compared between two anchor drug classes for each year using log-rank tests. RESULTS: We focused our results on 2011-2016 (n = 1613), during which most ART prescriptions were observed. A total of 268 patients switched anchor drug class from the first to a second regimen. The switch rate constantly increased over four years for NNRTIs (17.8-45.2%) and PIs (16.2-47.6%), with median time-to-switch of 1507 and 1567 days, respectively, while INSTI maintained a low switch rate (2.3-7.6%), precluding median-days calculation. The majority originally treated with NNRTI and PI switched to INSTI regardless of the switching timing after starting the first regimen (< 1 year: 91.7 and 97.5%, respectively, and ≥ 1 year: 100.0 and 97.5%, respectively). The risk of switching anchor drug classes was lower for INSTI than for other anchor drug classes in the first regimen even after adjusting for potential confounding factors. CONCLUSIONS: Patients with an ART regimen including INSTI as an anchor drug class maintained a low switch rate for long durations. The major switching strategies of anchor drug class for secondary treatment were from NNRTI or PI to INSTI. These results suggest that INSTI may be a durable anchor drug class for PLWH on ART although there are limitations inherent to the database.

A randomized, double-blind, placebo-controlled study of the effect of ezetimibe on glucose metabolism in subjects with type 2 diabetes mellitus and hypercholesterolemia.

BACKGROUND: Recent evidence points to an increased incidence of new-onset diabetes and a negative impact on glucose parameters with statin use. This study examined the safety of ezetimibe vs placebo for change from baseline to week 24 in HbA1c (primary endpoint), glycoalbumin, and fasting plasma glucose (secondary endpoints) in Japanese subjects with type 2 diabetes and hypercholesterolemia. METHODS: This was a randomized, double-blind, placebo-controlled, parallel-group, multi-site trial. Adults with type 2 diabetes and hypercholesterolemia whose LDL-C measured <140 mg/dl (subjects receiving lipid-lowering drugs) or <160 mg/dl (subjects not receiving lipid-lowering drugs) at the start of the screening phase, were randomized after a 5-week wash-out period to ezetimibe 10 mg or placebo (1:1) for 24 weeks. Changes in HbA1c, glycoalbumin and fasting plasma glucose from baseline to week 24 were evaluated. The non-inferiority margin was set at 0.5% for HbA1c. RESULTS: Overall, 152 subjects were randomized (75 to ezetimibe and 77 to placebo). From baseline to 24 weeks, HbA1c significantly increased in both the ezetimibe and placebo groups (between-treatment difference 0.08 [95% CI: -0.07 to 0.23]). Ezetimibe was statistically non-inferior to placebo. At 24 weeks, the mean change from baseline in glycoalbumin levels (between-treatment differences 0.00 [95% CI: -0.47, 0.47]) and fasting plasma glucose (between-treatment differences -4.8 [95% CI: -12.1, 2.1]) were similar in both treatment groups. CONCLUSIONS: These results suggest that ezetimibe 10 mg does not result in dysregulation of glucose metabolism in Japanese patients with type 2 diabetes and hypercholesterolemia over 24 weeks of treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01611883 .

Safety, Tolerability, and Immunogenicity of V160, a Conditionally Replication-Defective Cytomegalovirus Vaccine, in Healthy Japanese Men in a Randomized, Controlled Phase 1 Study.

Cytomegalovirus (CMV) infection can cause newborn morbidity and mortality; no pharmacological method of reducing CMV infection during pregnancy is currently available. In a phase 1 study in the United States, V160, a conditionally replication-defective CMV vaccine, was immunogenic and well tolerated. This placebo-controlled study (NCT03840174) investigated the safety and immunogenicity of a three-dose V160 vaccine administered over six months. A total of 18 healthy adult Japanese males (9 seronegative and 9 seropositive) were enrolled at a single center and randomized 2:1 to intramuscular V160 or placebo. In vitro, V160 induced high CMV-specific neutralizing antibody (NAb) titers (50% neutralization titer [NT50], 3651; 95% confidence interval [CI], 1688-7895) in the CMV-seronegative per-protocol immunogenicity (PPI) population one month after the third vaccine dose was administered compared with no change in the placebo arm (NT50, <94; 95% CI <94-115). The geometric mean titer ratio in the seronegative population versus baseline was 77.7 (95% CI, 23.9-252.4). CMV NAb titers in the CMV-seropositive PPI population were similar to baseline NAb titers observed in the CMV-seropositive population. V160 was well tolerated, and no vaccine viral DNA shedding was observed. In conclusion, the immunogenicity and safety profile of V160 in Japanese participants was consistent with other populations.

Safety, tolerability, and immunogenicity of a 21-valent pneumococcal conjugate vaccine, V116, in Japanese healthy adults: A Phase I study.

V116 is an investigational 21-valent pneumococcal conjugate vaccine (PCV) to address the burden of residual adult pneumococcal disease after the introduction of pediatric PCVs into national immunization programs (NIPs) and includes serotypes highly prevalent in adult invasive pneumococcal disease (IPD). This Phase I study assessed the safety, tolerability, and immunogenicity of V116 in Japanese adults. Participants ≥20 years of age were randomized to receive a single dose of V116 or 23-valent pneumococcal polysaccharide vaccine (PPSV23) at day 1. Outcomes were solicited injection-site and systemic adverse events (AEs) from day 1 to day 5, vaccine-related serious AEs from day 1 through day 30, and serotype-specific opsonophagocytic antibody (OPA) titers and immunoglobulin G (IgG) concentrations at day 30. Overall, 102 participants were randomized 1:1 to each group. Comparable proportions vaccinated with V116 and PPSV23 experienced ≥1 solicited injection-site AE and ≥1 solicited systemic AE. The most common injection-site AEs were injection-site pain (V116: 54.9%; PPSV23: 66.7%) and swelling (V116 and PPSV23: 13.7%), and the most common systemic AEs were myalgia (V116: 17.6%; PPSV23: 19.6%) and fatigue (V116: 13.7%; PPSV23: 9.8%). Solicited AEs were mostly mild and of ≤3 days duration. No vaccine-related serious AEs or deaths were reported. The OPA and IgG findings showed that the immunogenicity of V116 and PPSV23 were comparable for the 12 common serotypes and V116 was more immunogenic for the nine unique serotypes compared with PPSV23. V116 was well tolerated, with a safety profile similar to PPSV23, and induced functional antibodies against all 21 serotypes.

Characteristics of 2-drug regimen users living with HIV-1 in a real-world setting: A large-scale medical claim database analysis in Japan.

BACKGROUND: Regimen simplification to 2-drug antiretroviral therapy (2-ART) may address potential tolerability issues, increase adherence, and reduce toxicity and potential drug-drug-interactions among people living with HIV-1 (PLWH). However, real-world treatment patterns and characteristics of 2-ART users are unclear. METHODS: This retrospective observational cohort study employed a large-scale medical claim database of Japanese hospitals to extract data on 4,293 PLWH aged ≥18 years with diagnosis of HIV and treated with any ART regimens between April 2008 and April 2019. A 2-ART cohort was compared with a 3-drug antiretroviral therapy (3-ART) cohort in terms of population characteristics, comorbid conditions, and treatment patterns. Treatment switching rates were calculated for each cohort followed by sensitivity analysis to confirm the robustness of the findings. RESULTS: There were 94 individuals identified in the 2-ART cohort. Compared to the standard 3-ART cohort (n = 3,993), the 2-ART cohort was older (median age 53 [IQR 44-64] vs 42 years [IQR 35-50]), with a lower proportion of males (87.2% vs 93.8%), higher Charlson Comorbidity Index (CCI) (median score 6 [IQR 5-8] vs 5 [IQR 4-6]), more co-medications (median 6 [IQR 4-11] vs 3 [IQR 2-7]), and a higher percentage of AIDS-defining conditions (66.0% vs 42.8%). The most common 2-ART were protease inhibitor (PI) + integrase strand transfer inhibitor (INSTI) and non-nucleoside reverse transcriptase inhibitor (NNRTI) + INSTI (33.0% and 31.9%, respectively). Overall, most of the regimens were nucleoside reverse transcriptase inhibitor (NRTI)-sparing (71.3%), with a decreasing trend over time (76.2% to 70.2%). ART regimen switch occurred more often in the 2-ART cohort than in the 3-ART cohort (33.0% vs 21.2%). CONCLUSION: The profiles of individuals on 2-ART in Japan were demonstrated to be complex. Most were treated with NRTI-sparing regimens which may reflect an effort to reduce treatment-related toxicities.

A phase I study to evaluate safety, pharmacokinetics, and pharmacodynamics of respiratory syncytial virus neutralizing monoclonal antibody MK-1654 in healthy Japanese adults.

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection among all infants worldwide and remains a significant cause of morbidity and mortality. To address this unmet medical need, MK-1654, a half-life extended RSV neutralizing monoclonal antibody, is in clinical development for the prevention of RSV disease in infants. This was a phase I, randomized, placebo-controlled, single-site, double-blind trial of MK-1654 in 44 healthy Japanese adults. The safety, tolerability, pharmacokinetics, antidrug antibodies (ADAs), and serum neutralizing antibody (SNA) titers against RSV were evaluated for 1 year after a single intramuscular (i.m.) or intravenous (i.v.) dose of MK-1654 or placebo in five groups (100 mg i.m., 300 mg i.m., 300 mg i.v., 1000 mg i.v., or placebo). MK-1654 was generally well-tolerated in Japanese adults. There were no serious drug-related adverse events (AEs) reported in any MK-1654 recipient and no discontinuations due to any AEs in the study. The half-life of MK-1654 ranged from 76 to 91 days across dosing groups. Estimated bioavailability was 86% for 100 mg i.m. and 77% for 300 mg i.m. One participant out of 33 (3.0%) developed detectable ADA with no apparent associated AEs. The RSV SNA titers increased in a dose-dependent manner among participants who received MK-1654. These data support the development of MK-1654 for use in Japanese infants.

Evaluation of Montelukast for the Treatment of Children With Japanese Cedar Pollinosis Using an Artificial Exposure Chamber (OHIO Chamber).

Background: This study evaluated the efficacy of montelukast in reducing seasonal allergic rhinitis symptoms in Japanese children with Japanese cedar (JC) pollinosis induced in an artificial exposure chamber (OHIO Chamber). Methods: Pediatric patients aged 10 to 15 years sensitive to JC pollen entered a randomized, double-blind, single-site, crossover study. After confirmation of an allergic response to a JC pollen exposure for 3 hours in the OHIO Chamber during the screening period, subjects received either montelukast 5 mg chewable tablets or placebo for a 7-day treatment period, followed by a 3-hour pollen exposure in the chamber. After a 7-day washout period, subjects crossed over to the other treatment. Subjects were instructed to self-assess their nasal symptoms using 5-point scale for every 30 minutes. The primary end point was the change from baseline (just before entering the exposure chamber for each exposure) in total nasal symptom score (TNSS; the sum of nasal congestion, nasal discharge, and sneezing scores) over 3 hours of pollen exposure. Adverse events (AEs) were evaluated throughout the study. Results: A total of 220 subjects (median age, 12 years) received treatment. For TNSS, the between-group difference in the change (95% confidence interval) was -0.01 (-0.11 to 0.10); the change between placebo and montelukast 5 mg was not significant. TNSS in the screening and treatment periods after receiving placebo for 7 days was 1.58 and 1.31, respectively, suggesting a placebo response. On account of high placebo response, a post hoc analysis was conducted. The analysis in a subgroup of subjects who did not show placebo response demonstrated a difference in the efficacy between montelukast and placebo (nominal P < .037). The most common AE was positive urine protein (4.6% with montelukast vs 7.8% with placebo). Conclusions: Although montelukast was well tolerated, this study did not demonstrate a treatment difference between active drug and placebo in Japanese children exposed to JC pollen in the OHIO Chamber.Trial Registry: ClinicalTrials.gov, NCT01852812.

Efficacy and safety of asenapine in Asian patients with an acute exacerbation of schizophrenia: a multicentre, randomized, double-blind, 6-week, placebo-controlled study.

RATIONALE: Asenapine is a second generation anti-psychotic approved in the USA in 2009 for the treatment of schizophrenia, but its efficacy has not been proven in Asian patients. OBJECTIVES: The objectives of this study are to evaluate the efficacy and tolerability of asenapine in Asian patients experiencing an acute exacerbation of schizophrenia. METHODS: In this prospective, double-blind study, patients in Japan, Korea, and Taiwan were randomized (1:1:1) to asenapine 5 mg twice daily (bid), 10 mg bid or placebo for 6 weeks after a 3- to 7-day washout/screening period. The primary endpoint was the mean change in the positive and negative syndrome scale (PANSS) total score from baseline to day 42/treatment end. RESULTS: Of the 532 participants randomized, 530 received treatment. The primary endpoint was significantly greater with asenapine 5 and 10 mg bid than with placebo (-12.24 and -14.17 vs. -0.95; p < 0.0001). The results of secondary endpoints including PANSS negative subscale scores and PANSS responders at the end of treatment supported the results of the primary endpoint. There were no significant differences in the incidence of treatment-emergent adverse events reported with asenapine 5 and 10 mg bid and placebo (84.6, 80.7, and 81.6 %). There was a mean (± standard deviation) change in weight of -1.76 ± 2.45 kg for placebo, +0.42 ± 2.65 kg for asenapine 5 mg bid, and +0.81 ± 2.89 kg for asenapine 10 mg bid group. CONCLUSIONS: Asenapine was effective and generally well tolerated when used for the treatment of acute exacerbations of schizophrenia in Asian patients.

Montelukast in the treatment of perennial allergic rhinitis in paediatric Japanese patients; an open-label clinical trial.

Background: This study was conducted to evaluate the safety and tolerability, and population pharmacokinetics (PPK) of montelukast as well as efficacy in the treatment of perennial allergic rhinitis (PAR) in paediatric Japanese patients aged between 1 and 15 years. Methods: In this multi-centre, open-label trial, 87 paediatric Japanese patients with PAR received montelukast 4 mg oral granules (OG) for 4 weeks (1-5-year-olds, N = 15), 4 mg OG for 12 weeks (1-5-year-olds, N = 36), 5 mg chewable tablets (CT) for 12 weeks (6-9-year-olds, N = 18), or 5 mg CT for12 weeks (10-15-year-olds, N = 18). Clinical exams and laboratory assessments were conducted at study visits, and adverse events (AE) were monitored throughout the study up to 14 days after the last visit. Population pharmacokinetic approach was used to estimate AUC0-∞, Cmax, Tmax and apparent elimination half-life in each age group. Efficacy was assessed based on global evaluations by the subject's caregiver. Results: There were no serious AEs and one discontinuation due to an AE. The most common AEs in any of the treatment groups were nasopharyngitis, pharyngitis, and acute sinusitis. Montelukast exposure (AUC0-∞) was similar in the 1-5-year-old group and the 6-9-year-old group, but 19% lower in the 10-15-year-old group. Among all patients, the total proportion of patients whose global evaluation was "very much better" was 5.7% (week 2), 11.5% (week 4), and 16.9% (week 12) reflecting improvement in symptoms over time. Conclusion: Montelukast was generally well tolerated in Japanese children with PAR. AUC0-∞was similar in 1-5 and 6-9-year-olds, while a lower exposure was observed in the 10-15-year-old group likely due to differences in bodyweight. The exposure in Japanese paediatric patients was generally consistent with that in non-Japanese paediatric and adult patients. As assessed by the patients' caregivers, montelukast also demonstrated symptomatic improvement based on global evaluations of PAR.