The Prospective Natural History Study of Patients with Intractable Venous Malformation and Klippel-Trenaunay Syndrome to Guide Designing a Proof-of-Concept Clinical Trial for Novel Therapeutic Intervention.

Background: The natural history of venous malformation (VM) and Klippel-Trenaunay Syndrome (KTS) has not been quantitatively studied. To obtain benchmarks to guide designing clinical trials to assess safety and efficacy of novel drug candidates, the clinical course of the patients was followed for 6 months. Methods and Results: This is a multicenter prospective observational study evaluating the change rate in lesion volume from baseline with magnetic resonance images, as the primary endpoint. In addition, disease severities, performance status (PS), pain visual analog scale (VAS) score, quality of life (QoL), infections, and coagulation markers were also evaluated. Thirty-four patients (VM = 17, KTS = 17, 1-53 of age; median 15.9 years) with measurable lesion volume were analyzed. There was no statistically significant difference in the lesion volume between baseline and day 180, and the mean change rate (standard deviation) was 1.06 (0.28). There were no baseline characteristics that affected the change in lesion volume over 6 months. However, there were patients who showed more than 20% volume change and it was suggested that the lesion volume was largely impacted by local infection. There were no statistically significant changes in pain VAS score, severity, PS, QoL score, D-dimer, and platelet count over 6 months within all patients analyzed. Conclusion: The results showed the representative natural course of VM and KTS for a 6-month period with objective change of lesion volume and other factors, suggesting that it is scientifically reasonable to conduct a Phase 2 proof-of-concept study without a placebo arm, using the results of this study as the control. Clinical Trial Registration: NCT04285723, NCT04589650.

Double-Blind, Randomized, Placebo-Controlled Trial Evaluating the Efficacy and Safety of Eplerenone in Japanese Patients With Chronic Heart Failure (J-EMPHASIS-HF).

BACKGROUND: The mineralocorticoid receptor antagonist eplerenone improved clinical outcomes among patients with heart failure with reduced ejection faction (HFrEF) in the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure) study. However, similar efficacy and safety have not been established in Japanese patients. We evaluated the efficacy and safety of eplerenone in patients with HFrEF in a multicenter, randomized, double-blind placebo-controlled outcome study (ClinicalTrials.gov Identifier: NCT01115855). The aim of the study was to evaluate efficacy predefined as consistency of the primary endpoint with that of EMPHASIS-HF at a point estimate of <1 for the hazard ratio.Methods and Results:HFrEF patients with NYHA functional class II-IV and an EF ≤35% received eplerenone (n=111) or placebo (n=110) on top of standard therapy for at least 12 months. The primary endpoint was a composite of death from cardiovascular causes or hospitalization for HF. The primary endpoint occurred in 29.7% of patients in the eplerenone group vs. 32.7% in the placebo group [hazard ratio=0.85 (95% CI: 0.53-1.36)]. Hospitalization for any cause and changes in plasma BNP and LVEF were favorable with eplerenone. A total of 17 patients (15.3%) in the eplerenone group and 10 patients (9.1%) in the placebo group died. Adverse events, including hyperkalemia, were similar between the groups. CONCLUSIONS: Eplerenone was well-tolerated in Japanese patients with HFrEF and showed results consistent with those reported in the EMPHASIS-HF study.

Apixaban for the Treatment of Japanese Subjects With Acute Venous Thromboembolism (AMPLIFY-J Study).

BACKGROUND: Anticoagulation is recommended as standard of care for venous thromboembolism (VTE) (pulmonary embolism [PE]/deep vein thrombosis [DVT]), for which unfractionated heparin (UFH) and warfarin are used in Japan. In the multi-regional AMPLIFY study, a fixed-dose regimen of apixaban alone was non-inferior to conventional therapy for treatment of PE/DVT and was associated with significantly fewer bleeding events. METHODS AND RESULTS: Japan phase 3 study (AMPLIFY-J), randomized, active-controlled, open-label study in Japanese subjects with acute PE/DVT, was designed based on AMPLIFY. Key objectives were to investigate safety and efficacy of apixaban in symptomatic PE/DVT subjects during 24-week treatment. UFH/warfarin was used as control treatment. Apixaban was initiated at 10 mg twice daily for 7 days, followed by 5 mg twice daily for 23 weeks. All endpoints and imaging for thrombotic burden were assessed by an event adjudication committee. Eighty subjects were randomized, 33 subjects (41.3%) were aged <65 years. Proportion of major/clinically relevant non-major bleeding was lower in apixaban (7.5%) compared with well-controlled UFH/warfarin (28.2%; median TTR, 70.4%). [corrected]. Recurrent VTE occurred in no subjects in apixaban and in 1 subject in UFH/warfarin. Thrombotic burden results were similar in both groups. Proportions of subjects with adverse events was generally similar in both groups. CONCLUSIONS: Apixaban was well-tolerated and had a favorable safety profile. No clinically important efficacy difference compared with UFH/warfarin was observed.

Investigation of the Safety Profiles of Japanese Clinical Trials.

BACKGROUND: The increasing attrition rates of new drug research and development have become a global problem. To tackle this problem as well as the problem of "drug lag" in Japan, strategies utilizing multiregional clinical trials (MRCTs) are now being commonly applied. It is important to determine whether clinical data in a specific country and region have tendencies or patterns that will help us to consider an appropriate strategy for drug development in the specific region as well as worldwide. However, little has been studied on strategies and methods for drug development to pursue simultaneous development taking into account these characteristics. It would be valuable to determine and characterize the safety profile of Japanese clinical trial data. METHODS: To characterize the overall safety profile of Japanese data in terms of the frequency of adverse events (AEs), serious AEs, and discontinuation due to AEs compared with non-Japanese data, 73 pharmaceutical products recently approved in Japan were selected. Their clinical trial safety data, derived from comparable studies conducted in Japan and Western countries using the bridging strategy and MRCTs, were reviewed and analyzed. RESULTS: Japanese data are similar to non-Japanese data in terms of overall frequency of AEs; however, the sample size of Japanese patients in the bridging studies and MRCTs was generally smaller than that in non-Japanese data. CONCLUSIONS: The safety profile in Japanese clinical data was shown to be similar to that of non-Japanese data from the standpoint of overall frequency of AEs. This finding should be encouraging to pharmaceutical companies and the health authority in Japan to accelerate participation in MRCTs.

Investigation of Characteristics of Japanese Clinical Trials in Terms of Data Variability.

BACKGROUND: Because Asian countries have become involved in multiregional clinical trials, it is increasingly important to understand the characteristics of each country in terms of clinical trials to seek an appropriate strategy for worldwide drug development. Since variability of data is one of the important factors in clinical trials, variability of Japanese data, such as shown in coefficient of variation (CV) and standard deviation (SD) values, is an area of interest from which to consider an appropriate development strategy. METHODS: To characterize variability of Japanese data compared with non-Japanese data, the authors selected pharmaceutical products recently approved in Japan, reviewed their clinical trial data, and analyzed these data for efficacy response variables in Japan and Western countries. Twenty-nine products were selected for the examination. RESULTS: Japanese data are similar to non-Japanese data in terms of data variability, and the ratios of the Japanese to the non-Japanese values for CV and SD were within a relatively narrow range for most products. CONCLUSIONS: Japanese clinical trial data showed variability similar to that of non-Japanese data for most cases. It is expected that further studies to characterize specific regions in terms of clinical trial data will be conducted to consider an appropriate strategy for worldwide drug development.

Safety and efficacy of the oral direct factor xa inhibitor apixaban in Japanese patients with non-valvular atrial fibrillation. -The ARISTOTLE-J study-.

BACKGROUND: Guidelines recommend warfarin as the standard of care for patients with atrial fibrillation (AF) at moderate or high risk for stroke. This phase II study assessed the effects of 2 doses of the factor Xa inhibitor apixaban vs. warfarin in Japanese patients with non-valvular AF. The composite primary endpoint was major and clinically relevant non-major (CRNM) bleeding. METHODS AND RESULTS: Two hundred and twenty-two patients with AF and 1 or more additional risk factors for stroke were randomized (1:1:1) to double-blind apixaban 2.5 or 5mg b.i.d. or open-label warfarin (target international normalized ratio 2.0-3.0; 2.0-2.6 if age ≥ 70 years) for 12 weeks. The primary endpoint occurred in 1 patient (1.4%) in each apixaban group and 4 (5.3%) warfarin patients. There were no strokes, systemic emboli, myocardial infarctions, or deaths in either apixaban group. The warfarin group had 2 ischemic strokes and 1 subarachnoid hemorrhage, but there were no deaths. Major and CRNM bleeds each occurred with higher frequency in the warfarin group vs. either apixaban group. Most adverse events were mild or moderate. No patients had hepatic aminotransferase elevations greater than 3 times the upper limit of normal. CONCLUSIONS: In Japanese patients with AF, apixaban 2.5 and 5mg b.i.d. were well tolerated over 12 weeks. A global phase III trial, which includes Japanese patients, is ongoing (ClinicalTrials.gov Identifier NCT00787150).