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

Int J Chron Obstruct Pulmon Dis. 2019 Dec 23;14:2993-3002. doi: 10.2147/COPD.S220861. eCollection 2019.


Background: Budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI) is a triple fixed-dose combination for COPD. The long-term safety of triple therapy for COPD has not been investigated in Japanese patients. In this 28-week extension study (NCT03262012), we investigated the long-term safety and tolerability of BGF MDI in Japanese patients with moderate-to-very severe COPD who completed the 24-week Phase III randomized, double-blind, multicenter KRONOS study (NCT02497001).

Materials and methods: Patients randomized to BGF MDI 320/18/9.6 μg, glycopyrrolate/formoterol fumarate (GFF) MDI 18/9.6 μg, budesonide/formoterol fumarate (BFF) MDI 320/9.6 μg, or budesonide/formoterol fumarate dry powder inhaler (BUD/FORM DPI) 400/12 μg twice-daily in KRONOS continued treatment for up to 28 additional weeks. Safety was evaluated over 52 weeks via adverse event (AE) monitoring, electrocardiograms, clinical laboratory testing, and vital sign measurements.

Results: The safety population included 416 patients who received BGF MDI (n=139), GFF MDI (n=138), BFF MDI (n=70), or BUD/FORM DPI (n=69). Treatment-emergent AE (TEAE) rates were similar across treatment groups (range: 82.6-82.9%). The most frequent TEAEs overall were nasopharyngitis (32.2%) and bronchitis (9.9%). The incidence of major adverse cardiovascular events was low across groups (range: 0.0-2.9%). Over 52 weeks, the incidence of confirmed pneumonia was 9.4% (BGF MDI), 3.6% (GFF MDI), 5.7% (BFF MDI), and 2.9% (BUD/FORM DPI); in the 28-week extension period, rates were comparable across groups (range: 2.9-5.7%). Six deaths were reported (0.7-2.2% per group); none were considered treatment-related. No clinically meaningful trends were observed in electrocardiograms, laboratory parameters, or vital signs over time in any of the treatment groups.

Conclusion: All treatments were well tolerated over 52 weeks, and the safety profile of BGF MDI was generally comparable to dual long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) and inhaled corticosteroid (ICS)/LABA therapies. These findings support the long-term tolerability of BGF MDI in Japanese patients with COPD.

Keywords: ICS/LAMA/LABA; Japan; co-suspension delivery technology; inhaled corticosteroid; long-acting muscarinic antagonist; long-acting β2-agonist.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Bronchodilator Agents / administration & dosage
  • Budesonide / administration & dosage*
  • Double-Blind Method
  • Drug Combinations
  • Drug Monitoring / methods
  • Drug Tolerance
  • Female
  • Formoterol Fumarate / administration & dosage*
  • Glycopyrrolate / administration & dosage*
  • Humans
  • Japan
  • Male
  • Metered Dose Inhalers*
  • Middle Aged
  • Pulmonary Disease, Chronic Obstructive* / drug therapy
  • Pulmonary Disease, Chronic Obstructive* / physiopathology
  • Respiratory Function Tests / methods
  • Severity of Illness Index
  • Time
  • Treatment Outcome


  • Bronchodilator Agents
  • Drug Combinations
  • Budesonide
  • Glycopyrrolate
  • Formoterol Fumarate

Associated data

  • ClinicalTrials.gov/NCT02497001

Grant support

The KRONOS study was supported by AstraZeneca.