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BACKGROUND & AIMS: SERENE UC (Study of a Novel Approach to Induction and Maintenance Dosing With Adalimumab in Patients With Moderate to Severe Ulcerative Colitis) evaluated the efficacy of higher adalimumab induction and maintenance dose regimens in patients with ulcerative colitis. METHODS: This phase 3, double-blind, randomized trial included induction and maintenance studies, with a main study (ex-Japan) and Japan substudy. Eligible patients (18-75 years, full Mayo score 6-12, centrally read endoscopy subscore 2-3) were randomized 3:2 to higher induction regimen (adalimumab 160 mg at weeks 0, 1, 2, and 3) or standard induction regimen (160 mg at week 0 and 80 mg at week 2); all received 40 mg at weeks 4 and 6. At week 8, all patients were rerandomized 2:2:1 (main study) to 40 mg every week (ew), 40 mg every other week (eow), or exploratory therapeutic drug monitoring; or 1:1 (Japan substudy) to 40 mg ew or 40 mg eow maintenance regimens. RESULTS: In the main study, 13.3% vs 10.9% of patients receiving the higher induction regimen vs standard induction regimen achieved clinical remission (full Mayo score ≤2 with no subscore >1) at week 8 (induction primary end point; P = .265); among week-8 responders, 39.5% vs 29.0% receiving 40 mg ew vs 40 mg eow achieved clinical remission at week 52 (maintenance primary end point; P = .069). In the integrated (main + Japan) population, 41.1% vs 30.1% of week-8 responders receiving 40 mg ew vs 40 mg eow achieved clinical remission at week 52 (nominal P = .045). Safety profiles were comparable between dosing regimens. CONCLUSION: Although primary end points were not met, a >10% absolute difference in clinical remission was demonstrated with higher adalimumab maintenance dosing. Higher dosing regimens were generally well tolerated and consistent with the known safety profile of adalimumab in ulcerative colitis. CLINICALTRIALS: gov, Number: NCT002209456. ispartof: GASTROENTEROLOGY vol:162 issue:7 pages:1891-1910 ispartof: location:United States status: published

Shu Hashimoto,1 Hisataro Ikeuchi,2 Shujiro Murata,2 Tetsuji Kitawaki,2 Kimitoshi Ikeda,2 Donald Banerji3 1Division of Respiratory Medicine, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan; 2Novartis Pharma KK, Minato-ku, Tokyo, Japan; 3Novartis Pharmaceuticals Corporation, EastHanover, NJ, USA Background: COPD-related deaths are increasing in Japan, with ~5.3 million people at risk.Methods: The SHINE was a 26-week, multicenter, randomized, double-blind, parallel-group study that evaluated safety and efficacy of indacaterol (IND)/glycopyrronium (GLY) 110/50µg once daily (od) compared with GLY 50µg od, IND 150µg od, open-label tiotropium (TIO) 18µg od, and placebo. The primary end point was trough forced expiratory volume in 1second (FEV1) at Week 26. Other key end points included peak FEV1, area under the curve for FEV1 from 5minutes to 4hours (FEV1 AUC5min–4h), Transition Dyspnea Index focal score, St George’s Respiratory Questionnaire total score, and safety. Here, we present efficacy and safety of IND/GLY in the Japanese subgroup.Results: Of 2,144 patients from the SHINE study, 182 (8.5%) were Japanese and randomized to IND/GLY (n=42), IND (n=41), GLY (n=40), TIO (n=40), or placebo (n=19). Improvement in trough FEV1 from baseline was 190mL with IND/GLY and treatment differences versus IND (90mL), GLY (100mL), TIO (90mL), and placebo (280mL) along with a rapid onset of action at Week 26. IND/GLY showed an improvement in FEV1 AUC5min–4h versus all comparators (all P

Background To better evaluate the efficacy and safety of the indacaterol/glycopyrronium (IND/GLY) fixed-dose combination versus tiotropium in Japanese patients, a pooled data analysis was conducted from the SHINE and ARISE studies, which were part of the IND/GLY clinical trial program. Methods Japanese patients with moderate-to-severe COPD were included in the analysis. Efficacy in terms of pre-dose forced expiratory volume in one second (FEV 1 ) at Week 12 and Week 24/26 (ARISE/SHINE) and FEV 1 at 30min and 60min post-dose at Day 1, Week 12, and Week 24/26 was evaluated. Health status using the St. George׳s Respiratory Questionnaire (SGRQ) score, rescue medication use (number of puffs/day), safety, and tolerability were also assessed. Results In total, 340 patients (IND/GLY, n =161; IND, n =41; GLY, n =40; tiotropium, n =79; and placebo, n =19) were included in the analysis that focused on comparing IND/GLY versus tiotropium since they were included in both studies. At Week 12 and Week 24/26, pre-dose FEV 1 was significantly improved with IND/GLY compared with tiotropium (treatment differences=70mL and 80mL, respectively; both P ≤0.001). FEV 1 at 30min and 60min post-dose, the SGRQ total score, and rescue medication use were more statistically significant with IND/GLY than with tiotropium for all assessed time-points. The overall incidence of adverse events (AEs) and serious AEs was similar between the IND/GLY- and tiotropium-treated groups. Conclusions Compared to tiotropium, IND/GLY provided significant improvements in lung function, health status, and rescue medication use, while having a good safety profile in Japanese patients with moderate-to-severe COPD.

In recent years, multi-regional trials have received increasing attention by pharmaceutical companies carrying out global drug development programs. In Japan, new drugs are often approved several years after market release in other countries. The recently published guidance on 'Basic Principles on Global Clinical Trials' addresses specifically this time lag. A multi-regional trial has at least two main objectives. First, it is necessary to show a significant benefit in effect of a new drug in the entire population. Second, one needs to demonstrate that the results for a particular region are consistent with those from the entire population. In this paper, we discuss the methods proposed in the Japanese regulatory guidance document and derive closed form expressions for the resulting probabilities, which require the evaluation of multivariate normal or t probabilities. In addition, we propose an alternative method with better operating characteristics than the current approaches. Moreover, we examine the performance of our suggested method by simulating the probability of achieving the objectives and calculating the false-positive error rate.

Background We have previously demonstrated that addition of omalizumab to standard therapy improved asthma control by significantly improving lung function and reducing asthma exacerbations in Japanese patients with moderate-to-severe asthma. The aim of this study was to evaluate the effects of omalizumab on long-term disease control in Japanese patients with moderate-to-severe persistent asthma. Methods An open-label, 48-week study was conducted in 133 Japanese patients with moderate-to-severe persistent asthma. Omalizumab was administered subcutaneously every 2 or 4 weeks based on serum IgE level and body weight in each patient. Results Treatment with omalizumab significantly improved lung function. A subgroup of patients with inadequately controlled severe persistent asthma, despite high dose inhaled corticosteroids and other multiple controller therapies, which corresponds to the Japanese label (label population), showed greater improvements in morning PEF and FEV1 than the whole study population (full Analysis Set). Serum free IgE levels decreased to below the target and were maintained during the treatment period in almost all patients. The majority of adverse events were mild-to-moderate in severity and there was no trend toward an increase in incidence of adverse events with increase in duration of omalizumab. In addition, the profile of adverse events in this study was similar to that in a 16-week, placebo-controlled study which the present authors had conducted previously in Japan. There were no anaphylactic reactions and no anti-omalizumab antibodies were detected. Conclusions Long-term treatment with omalizumab is effective and well tolerated in Japanese patients with moderate-to-severe persistent asthma.