Immunogenicity and safety of the diphtheria, pertussis, tetanus and inactivated poliovirus vaccine when co-administered with the human rotavirus vaccine (Rotarix) in healthy Japanese infants: a phase IV randomized study.

Rotavirus infections have been reported to account for 40-50% of all hospitalized acute gastroenteritis cases in young children (<5 years) in Japan. Since 2011, Rotarix containing the live attenuated human rotavirus RIX4414 strain (HRV) has been licensed in Japan for infants. Vaccination against rotavirus is optional in Japan whereas administration of diphtheria, pertussis, tetanus, and inactivated poliovirus (DPT-IPV) vaccine is part of the national routine immunization program. In this open-label, randomized, controlled, multicenter study, we evaluated the immunogenicity and safety of the DPT-IPV vaccine (Squarekids) administered concomitantly or staggered with the liquid HRV (Rotarix) vaccine in healthy Japanese infants. A total of 292 infants aged 6-12 weeks were randomly assigned to receive DPT-IPV vaccine and HRV vaccine co-administered (n = 147) or staggered (n = 145). Immune responses to DPT-IPV vaccine were evaluated by measuring the post-vaccination serum antibody titers/concentrations to each antigen at one month following the third dose of DPT-IPV vaccine. Seroprotection/seropositivity against each of the diphtheria, pertussis (pertussis toxin and filamentous hemagglutinin), tetanus, and poliovirus type 1, 2 and 3 antigens was 92.8% or higher in both groups. In terms of immunogenicity, DPT-IPV vaccine co-administered with HRV vaccine was shown to be non-inferior to DPT-IPV vaccine with a staggered administration. The safety profile was comparable in the two vaccine groups with no vaccine-related serious adverse events, no deaths and no cases of intussusception. These results support co-administration of HRV vaccine with DPT-IPV vaccine in Japan. ClinicalTrials.gov NCT02907216.

Investigation of safety and efficacy of the new more thermostable formulation of Flolan (epoprostenol) in Japanese patients with pulmonary arterial hypertension (PAH)-An open-label, single-arm study.

OBJECTIVE: This study was conducted to evaluate the safety and efficacy of a new more thermostable Flolan (epoprostenol) solution prepared with the reformulated pH 12.0 diluent in Japanese patients with pulmonary arterial hypertension (PAH) receiving higher doses of Flolan than those typically administered in Western countries. METHODS: This open-label, single-arm study was conducted in 10 Japanese PAH patients. During the run-in period, patients were intravenously infused with Flolan (45 ng/kg/min or higher doses) solution prepared with the existing pH 10.5 diluent. The patients were then switched to a new more thermostable Flolan solution prepared with the reformulated pH 12.0 diluent and observed for a 4-week treatment period. As a primary endpoint, safety after switching to the new Flolan solution was evaluated. Secondary endpoints included hemodynamics and the necessity for dose adjustment of Flolan in these patients. RESULTS: All 10 patients completed the study period. Observed adverse events were nausea and hepatic function abnormal in 1 patient each, and both events were mild. No patients required dose adjustment due to the change from baseline in mean pulmonary artery pressure (mPAP) measured 3 hrs after switching to Flolan solution prepared with the reformulated diluent. No major changes from baseline in mPAP, pulmonary vascular resistance, or right atrial pressure were observed at 24 hrs and at 4 weeks after switching to the Flolan solution prepared with pH 12.0 diluent. Although some patients showed increases in cardiac output (CO) from baseline at 24 hrs and 4 weeks, no patients required dose reduction as a result of an increase in CO. CONCLUSION: Neither safety/efficacy concerns nor any dose adjustments of Flolan after switching to a more thermostable Flolan solution prepared with the reformulated pH 12.0 diluent could be required in Japanese patients with PAH receiving higher doses of Flolan. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02705807.

Long-term (52 weeks) safety and tolerability of umeclidinium in Japanese patients with chronic obstructive pulmonary disease.

Objective Umeclidinium bromide (UMEC) 62.5 µg is a long-acting muscarinic antagonist (LAMA) that is administered once daily via inhalation for chronic obstructive pulmonary disease (COPD) treatment. The objective of this study was to evaluate the safety and tolerability of long-term treatment with UMEC 125 µg in Japanese patients with COPD. Methods This was a 52 week, multicenter, open-label study to evaluate the safety and tolerability of UMEC 125 µg once daily delivered via a novel dry powder inhaler (nDPI) in Japanese patients with COPD. The primary endpoint was the incidence and severity of all adverse events (AEs) throughout the 52 week treatment period. Clinical trial registration number ClinicalTrials.gov identifier is NCT01702363. Results A total of 153 patients were enrolled in the study. Of these, 131 patients started treatment with UMEC 125 µg, and 111 patients (85%) completed the study. AEs did not differ greatly in incidence over the various time periods (Weeks 0 to 12, 13 to 24, 25 to 36, and 37 to 52 of treatment) and did not increase with continued treatment. The incidence of drug-related AEs associated with the pharmacological effects of LAMAs (including constipation, blurred vision, and thirst) was low. Serious adverse events (SAEs) during the treatment period were reported in 17 patients (13%). SAEs reported in more than one patient were COPD exacerbation and pneumonia (3 patients each, 2%). One SAE of angina pectoris was considered to be drug related. No fatalities were reported during this study. Conclusions No new AEs were identified beyond those attributable to the pharmacological effects of LAMAs. UMEC 125 µg was well tolerated over 52 weeks of treatment in Japanese patients with COPD.

Prognostic signature of protocadherin 10 methylation in curatively resected pathological stage I non-small-cell lung cancer.

Although curative resection is the current treatment of choice for localized non-small-cell lung cancer (NSCLC), patients show a wide spectrum of survival even after complete resection of pathological stage I NSCLC. Thus, identifying molecular biomarkers that help to accurately select patients at high risk of relapse is an important key to improving the treatment strategy. The purpose of this study was to evaluate the prognostic signature of protocadherin 10 (PCDH10) promoter methylation in curatively resected pathological stage I NSCLC. Using methylation-specific polymerase chain reaction assays, methylation of PCDH10 promoter was assessed in cancer tissues of 109 patients who underwent curative resection of pathological stage I NSCLC. Associations between PCDH10 methylation status and disease outcome was analyzed. PCDH10 promoter methylation was detected in 46/109 patients (42.2%). Patients with methylated PCDH10 showed significantly worse recurrence-free, overall, and disease-specific survival compared with those without methylation (P < 0.0001, P = 0.0004, P = 0.0002, respectively). Multivariate Cox proportional hazard regression analysis revealed that adjusted hazard ratios of methylated PCDH10 were 5.159 for recurrence-free, 1.817 for overall, and 5.478 for disease-specific survival (P = 0.0005, P = 0.1475, P = 0.0109, respectively). The pattern of recurrence was not significantly different between patients with and without PCDH10 methylation (P = 0.5074). PCDH10 methylation is a potential biomarker that predicts a poor prognosis after curative resection of pathological stage I NSCLC. Assessment of PCDH10 methylation status might assist in patient stratification for determining an appropriate adjuvant treatment and follow-up strategy.