<p>Efficacy and Safety of Budesonide/Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler Formulated Using Co-Suspension Delivery Technology in Japanese Patients with COPD: A Subgroup Analysis of the KRONOS Study</p>

Abstract

Background: KRONOS, a Phase III, multicenter, randomized, double-blind study (NCT02497001) conducted in Canada, China, Japan, and the USA, assessed the efficacy and safety of budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI), a triple fixed-dose combination therapy, relative to dual therapies in patients with moderate-to-very severe COPD. Here we present findings from the Japanese subgroup of KRONOS. Methods: Patients received BGF MDI 320/18/9.6μg, glycopyrrolate/formoterol fumarate (GFF) MDI 18/9.6μg, budesonide/formoterol fumarate (BFF) MDI 320/9.6μg, or budesonide/formoterol fumarate dry powder inhaler (BUD/FORM DPI) 400/12μg twice-daily for 24 weeks. The primary endpoint was the change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV 1 ) over Weeks 12-24. Symptoms, quality of life, exacerbations, and safety were also assessed. Results: In total, 416 Japanese patients (21.9% of the global KRONOS population) were randomized and treated with BGF MDI (n=139), GFF MDI (n=138), BFF MDI (n=70), or BUD/FORM DPI (n=69). Nominally significant improvements in the change from baseline in morning pre-dose trough FEV 1 over Weeks 12-24 were observed for BGF MDI vs GFF MDI (least squares mean [LSM] difference 37 mL, 95% confidence interval [CI] 3, 72; P=0.0337) and BFF MDI (67 mL; 95% CI 25, 109; P=0.0020). Treatment with BGF MDI led to a nominally significant reduction in the rate of moderate/severe exacerbations vs GFF MDI (rate ratio 0.40, 95% CI 0.19, 0.83; P=0.0142). Compared with dual therapies, numerical improvements were observed with BGF MDI for Transition Dyspnea Index focal score and the change from baseline in Evaluating Respiratory Symptoms in COPD total score (P≤0.3899). All treatments were generally well tolerated. Conclusion: BGF MDI nominally significantly improved lung function and numerically improved symptoms vs GFF MDI and BFF MDI. BGF MDI nominally significantly reduced exacerbations vs GFF MDI in Japanese patients with COPD. Efficacy and safety findings were generally comparable to those in the global KRONOS population.

<p>Long-Term Safety and Efficacy of Budesonide/Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler Formulated Using Co-Suspension Delivery Technology in Japanese Patients with COPD</p>

“…All treatments were well tolerated, and there was no evidence that the profile or frequency of individual TEAEs differed based on the duration of exposure within or across treatment groups. Safety and efficacy results over 52 weeks were generally in agreement with findings from the global population and the Japanese subgroup of KRONOS over 24 weeks, 3,10 and support the long-term tolerability of BGF MDI in Japanese patients with moderateto-very severe COPD.…”

“…Full demographic characteristics of the Japanese safety population have been published. 10 In brief, the majority of Japanese patients were male (94.2%) with a mean age of 69.5 years. Eighty percent of patients had not experienced a COPD exacerbation in the previous year, and only 31.5% were receiving an ICS at study entry.…”

“…KRONOS included 416 patients enrolled in Japan, and efficacy and safety findings in the Japanese subgroup were generally comparable to the overall population. 10 To further characterize the risk/benefit profile of triple therapy in Japanese patients, we evaluated the long-term safety and efficacy of BGF MDI over 52 weeks in patients from Japan with moderate-to-very severe COPD who participated in a 28-week extension of the 24-week KRONOS study.…”

Narrative review of current COPD status in Japan

“…We assessed the use of these inhalers among individuals prior to enrolment in pharmaceutical interventional studies that were conducted worldwide, including the United States, Europe, and Asia. Figure 4 compares the uses of ICS-containing (A) and LAMAcontaining (B) regimens in a subgroup analysis of Japanese COPD patients to those in the complete datasets of COPD patients worldwide (41)(42)(43)(44)(45)(46)(47)(48). ICS use was less frequent, and LAMA use was more frequent in Japan.…”

“…Another report showed that the percentage of COPD patients using home-based LTOT to all patients using home based LTOT has been approximately 50% over time (53). In a single center prospective study, of 101 COPD patients who showed mild hypoxaemia (PaO 2 <80 Torr) at the baseline evaluation, 10 (10%) developed KRONOS (45,46), and SHINE (47,48) studies were conducted all over the world, including in the United States, Europe, Asia, and Japan.…”