A phase I, randomized, placebo-controlled study of molnupiravir in healthy Japanese to support special approval in Japan to treat COVID-19.

Molnupiravir (MK-4482) is an oral prodrug of the antiviral ribonucleoside analog, N-hydroxycytidine (NHC), which has activity against RNA viruses, including severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). We conducted a phase I safety and pharmacokinetic study of molnupiravir in healthy Japanese adult participants. A sample size larger than typically used in pharmacokinetic studies was implemented to collect additional safety data in the Japanese population to support special approval for emergency use in Japan. Single doses of molnupiravir up to 1600 mg and multiple doses of 400 and 800 mg administered every 12 h (q12h) for 5.5 days were generally well-tolerated. NHC appeared rapidly in plasma and reached maximum concentration (Cmax ), with a median time to Cmax (Tmax ) between 1.00 and 2.00 h. Area under the concentration versus time curve from zero to infinity (AUC0-inf ), area under the concentration versus time curve from zero to 12 h (AUC0-12 ), and Cmax of plasma NHC increased approximately dose proportionally. With q12h dosing, the geometric mean (GM) accumulation ratios for NHC AUC0-12 and Cmax were ~1 for 400 and 800 mg. Pharmacokinetics of NHC triphosphate (NHC-TP), the active metabolite of NHC was assessed in peripheral blood mononuclear cells and also demonstrated roughly dose proportional pharmacokinetics. The GM accumulation ratios for NHC-TP AUC0-12 and Cmax were ~2.5 for 400 and 800 mg. Following administration with food, only a modest reduction (24%) in plasma NHC Cmax with comparable AUC0-inf was seen, supporting administration without regard to food.

Pembrolizumab plus chemotherapy in Japanese patients with persistent, recurrent or metastatic cervical cancer: Results from KEYNOTE-826.

Pembrolizumab plus chemotherapy with or without bevacizumab demonstrated prolonged progression-free survival (PFS) and overall survival (OS) versus chemotherapy in patients with persistent, recurrent, or metastatic cervical cancer in the phase 3, randomized, double-blind, placebo-controlled KEYNOTE-826 study. We report outcomes in patients enrolled in Japan. Patients received pembrolizumab 200 mg or placebo Q3W for up to 35 cycles plus chemotherapy (paclitaxel 175 mg/m2 + cisplatin 50 mg/m2 or carboplatin AUC 5) with or without bevacizumab 15 mg/kg. Dual primary endpoints were PFS per RECIST v1.1 by investigator assessment and OS in the global population; these were evaluated in patients with tumors with PD-L1 combined positive score (CPS) ≥1, all-comers, and PD-L1 CPS ≥10. Fifty-seven patients from Japan were randomized (pembrolizumab plus chemotherapy, n = 35; placebo plus chemotherapy, n = 22). Pembrolizumab plus chemotherapy improved PFS versus placebo plus chemotherapy in patients with PD-L1 CPS ≥1 (n = 51; hazard ratio [HR; 95% CI], 0.36 [0.16-0.77]), all-comers (n = 57; 0.45 [0.22-0.90]), and patients with PD-L1 CPS ≥10 (n = 25; 0.36 [0.12-1.07]). HRs (95% CI) for OS were 0.38 (0.14-1.01), 0.41 (0.17-1.00), and 0.37 (0.10-1.30), respectively. Incidence of grade 3-5 AEs was 94% in the pembrolizumab group and 100% in the placebo group. Consistent with findings in the global KEYNOTE-826 study, pembrolizumab plus chemotherapy with or without bevacizumab may prolong survival versus placebo plus chemotherapy with or without bevacizumab and had a manageable safety profile in Japanese patients with persistent, recurrent, or metastatic cervical cancer.

Efficacy and safety of nintedanib in Japanese patients with progressive fibrosing interstitial lung diseases: Subgroup analysis of the randomised, double-blind, placebo-controlled, phase 3 INBUILD trial.

BACKGROUND: The efficacy of nintedanib in progressive fibrosing interstitial lung diseases (ILDs) was demonstrated in the randomised, double-blind, placebo-controlled INBUILD trial. This subgroup analysis evaluated the efficacy and safety of nintedanib in the Japanese population. METHODS: Patients with progressive fibrosing ILDs (evaluated by physicians within 24 months of screening) were randomised (1:1) to twice-daily 150-mg nintedanib or placebo; treatment continued until the last patient completed 52 weeks. The primary endpoint was the annual rate of decline in forced vital capacity (FVC) over 52 weeks. Time-to-first acute ILD exacerbation or death and time-to-death up until the last patient had completed the week 52 visit were evaluated. This subgroup analysis included 108 Japanese patients. RESULTS: The adjusted annual rates of FVC decline (mL/year) over 52 weeks for Japanese patients were -148.31 (nintedanib) and -240.36 (placebo), adjusted difference: 92.05 (95% CI: -10.69-194.80) and for non-Japanese patients were -67.41 (nintedanib) and -177.65 (placebo), adjusted difference: 110.24 (95% CI: 64.97-155.52). No heterogeneity in treatment effect between Japanese and non-Japanese subgroups was observed (treatment-by-subgroup interaction, p = 0.75). The risks of "acute exacerbation or death" (hazard ratio, 0.30 [95% CI: 0.10-0.91]) and mortality (hazard ratio, 0.54 [95% CI: 0.14-2.11]) in Japanese patients were numerically lower for nintedanib than placebo. There were no new or unexpected safety findings. CONCLUSIONS: In Japanese patients, nintedanib slowed ILD progression, evidenced by a reduction in the annual rate of decline in FVC vs placebo. The efficacy and safety of nintedanib in Japanese patients were consistent with the overall INBUILD population. CLINICALTRIALS.GOV: NCT02999178 (21-Dec-2016).

Nintedanib in patients with systemic sclerosis-associated interstitial lung disease: A Japanese population analysis of the SENSCIS trial.

OBJECTIVE: We examined the efficacy and safety of nintedanib in Japanese patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) in the global Safety and Efficacy of Nintedanib in Systemic Sclerosis (SENSCIS) trial. METHODS: Randomised patients received oral nintedanib 150 mg (N = 34) twice daily or placebo (N = 36) until the last patient reached 52 weeks of treatment (up to 100 weeks). Data were analysed using a subgroup analysis model with Japanese and non-Japanese patients as subgroup variables. RESULTS: In Japanese patients, the adjusted annual rate of forced vital capacity (FVC) decline over 52 weeks was -86.2 mL/year (nintedanib) and -90.9 mL/year (placebo); treatment difference, 4.67 mL/year (95% confidence interval, -103.28, 112.63). Treatment effect heterogeneity between Japanese and non-Japanese patients was not detected (treatment-by-visit-by-subgroup interaction; p = .49). FVC decline was smaller for nintedanib versus placebo through 100 weeks in Japanese patients. The most commonly reported adverse events with nintedanib were gastrointestinal and liver disorder events; most were mild-to-moderate in severity. CONCLUSION: In both Japanese and non-Japanese patients with SSc-ILD, nintedanib slowed the progression of ILD, with no heterogeneity detected between the subgroups. The safety profile for nintedanib in Japanese patients was similar to that observed in patients with idiopathic pulmonary fibrosis (ClinicalTrials.gov: NCT02597933).

Restricted mean survival time as a summary measure of time-to-event outcome.

Many clinical research studies evaluate a time-to-event outcome, illustrate survival functions, and conventionally report estimated hazard ratios to express the magnitude of the treatment effect when comparing between groups. However, it may not be straightforward to interpret the hazard ratio clinically and statistically when the proportional hazards assumption is invalid. In some recent papers published in clinical journals, the use of restricted mean survival time (RMST) or τ-year mean survival time is discussed as one of the alternative summary measures for the time-to-event outcome. The RMST is defined as the expected value of time to event limited to a specific time point corresponding to the area under the survival curve up to the specific time point. This article summarizes the necessary information to conduct statistical analysis using the RMST, including the definition and statistical properties of the RMST, adjusted analysis methods, sample size calculation, information fraction for the RMST difference, and clinical and statistical meaning and interpretation. Additionally, we discuss how to set the specific time point to define the RMST from two main points of view. We also provide developed SAS codes to determine the sample size required to detect an expected RMST difference with appropriate power and reconstruct individual survival data to estimate an RMST reference value from a reported survival curve.

Pharmacokinetics of Single Doses of BI 425809 in Healthy Chinese and Japanese Subjects: A Randomized Study.

PURPOSE: This study's primary goal was to evaluate the safety profile, tolerability, pharmacokinetics, and dose proportionality of BI 425809, a potent and selective inhibitor of glycine transporter 1, in healthy Chinese and Japanese subjects. METHODS: This single center, double-blind, single-rising dose study conducted in Korea randomly assigned (3:1) subjects within each ethnic subgroup (Chinese and Japanese) to receive a single dose of BI 425809 (10, 25, or 50 mg) or placebo. The primary end point was number (%) of subjects with drug-related adverse events (AEs). Secondary end points included AUC, Cmax, tmax, and t½ for BI 425809 in plasma. The CL/F and volume of distribution (Vz/F) were also measured. FINDINGS: Of the 49 subjects enrolled into the study (24 Chinese, 25 Japanese), 36 were randomly assigned to receive BI 425809 (12 per dose group) and 13 to receive placebo. All subjects were analyzed for the primary end point and completed the study. Overall, 4 of 49 subjects (8.2%) reported ≥1 AE (placebo: n = 1, BI 425809: n = 3). One drug-related AE of moderate somnolence was reported by a Japanese subject who received placebo. In both subgroups, slightly lower than dose-proportional increases in exposure (AUC and Cmax) were observed with increasing dose. In addition, median tmax was 3.5-4.0 h, with a geometric mean t½ of 29.0-41.2 h. CL/F was similar between Chinese and Japanese subjects and increased with increasing dose (10-50 mg: 68.1-111 mL/min). Vz/F was 209-315 L and similar between the subgroups. IMPLICATIONS: BI 425809 was generally well tolerated in healthy Chinese and Japanese subjects with no significant findings for tolerability. No apparent difference in the pharmacokinetic variables of BI 425809 was observed between Chinese and Japanese subjects. The safety profile results and pharmacokinetic exposure levels are consistent with previous trials in Caucasian subjects. ClinicalTrials.gov identifier: NCT02383888.

The efficacy and long-term safety of a triple combination of 80 mg telmisartan, 5 mg amlodipine and 12.5 mg hydrochlorothiazide in Japanese patients with essential hypertension: a randomized, double-blind study with open-label extension.

The aim of this study was to compare 80 mg telmisartan/5 mg amlodipine/12.5 mg hydrochlorothiazide (T80/A5/H12.5) with 80 mg telmisartan/12.5 mg hydrochlorothiazide (T80/H12.5) to determine their relative blood pressure (BP) lowering effects in essential hypertensive patients with inadequate control and to evaluate the long-term safety of T80/A5/H12.5 in a 52-week extension period. Patients (n=132) were randomly assigned to receive double-blind treatment with T80/A5/H12.5 or T80/H12.5 for 8 weeks after a 6-week run-in-period of T80/H12.5. All 126 patients who completed the double-blind period entered the 52-week open-label extension and received T80/A5/H12.5. The adjusted mean changes from the reference baseline of the trough-seated systolic and diastolic BP (SBP/DBP) at week 8 were significantly larger in the T80/A5/H12.5 group (-10.6/-8.8 mm Hg) than in the T80/H12.5 group (-2.3/-1.3 mm Hg) (P<0.0001). The BP-lowering effect of T80/A5/H12.5 was maintained over the 52-week extension period. The adverse events (AEs) during both treatment periods were generally mild. Drug-related AEs were reported in one patient in each group in the double-blind period and in five patients exposed to T80/A5/H12.5 in the double-blind and/or open-label extension period. T80/A5/H12.5 therapy was clinically and statistically superior to T80/H12.5 therapy for the reduction of BP in patients with essential hypertension uncontrolled with T80/H12.5, and its BP-lowering effect was maintained in the long term. T80/A5/H12.5 was generally well-tolerated.

Open-label phase 2 study of faldaprevir, deleobuvir and ribavirin in Japanese treatment-naive patients with chronic hepatitis C virus genotype 1 infection.

AIM: The safety and efficacy of the NS3/4A protease inhibitor faldaprevir in combination with the non-nucleoside NS5B polymerase inhibitor deleobuvir and ribavirin in Japanese treatment-naive patients with chronic genotype 1 hepatitis C virus (HCV) infection was evaluated. METHODS: In this multicenter, open-label phase 2 study, patients were assigned to 8 weeks of treatment with 80 mg (group 1) or 120 mg (group 2) faldaprevir once daily (q.d.) in combination with deleobuvir 600 mg twice daily and weight-based ribavirin. This was followed by a 24-week treatment with faldaprevir 120 mg q.d. in combination with peginterferon-α-2a and ribavirin. The primary objective was safety; virological response at weeks 4 and 8 was a secondary endpoint. RESULTS: Twelve and 13 patients were treated in group 1 and 2, respectively; all were infected with HCV genotype 1b. All patients experienced a drug-related adverse event (AE). The frequency of individual events was generally numerically greater in group 2 than 1. The most common AEs were nausea (66.7%, group 1; 76.9%, group 2) and vomiting (33.3%, group 1; 61.5%, group 2). Virological response at weeks 4 and 8 was achieved by 11 (91.7%) patients in group 1; in group 2, 12 (92.3%) patients achieved virological response at week 4 and all at week 8. All patients who achieved the week 8 endpoint achieved sustained virological response at week 12. CONCLUSION: Faldaprevir 80 or 120 mg q.d. in combination with deleobuvir and ribavirin was tolerable and had similar efficacy in Japanese patients with HCV genotype 1 infection. ClinicalTrials.gov: NCT01528735.