Early Changes in eDiary COPD Symptoms Predict Clinically Relevant Treatment Response at 12 Weeks: Analysis from the CRYSTAL Study

COPD. 2018 Apr;15(2):185-191. doi: 10.1080/15412555.2018.1445213. Epub 2018 Apr 16.


Early detection of treatment response is important in the long-term treatment and management of patients with chronic obstructive pulmonary disease (COPD). This analysis evaluated whether early improvement in symptoms, recorded in the first 7 or 14 days via an electronic diary (eDiary) compared with baseline, can predict clinically meaningful treatment responders at 12 weeks. CRYSTAL was a 12-week, randomized, open-label study that demonstrated the increased effectiveness of indacaterol/glycopyrronium (IND/GLY) or glycopyrronium (GLY), after a direct switch from on-going baseline therapies, in patients with symptomatic COPD and moderate airflow obstruction. The co-primary endpoints were trough forced expiratory volume in 1 second (FEV1) and transition dyspnea index (TDI) at Week 12. Patients' symptom status was recorded daily in an eDiary. Of 4,389 patients randomized, 3,936 and 3,855 reported symptoms on Days 7 and 14, respectively. Patients who reported an early decrease in symptoms on Day 7 or 14 were more likely to achieve the minimal clinically important difference of ≥100 mL in trough FEV1 or ≥ 1 point in TDI at Week 12. Using stepwise multivariate regression models we identified as best predictors of FEV1 responders the decrease in wheeze on Day 7, and nighttime symptoms and wheeze on Day 14; best predictors of TDI responders were decrease in nighttime symptoms and wheeze on Day 7, and nighttime symptoms, sputum and wheeze on Day 14. Early symptom improvement at Day 7 or 14, especially wheeze and nighttime symptoms, may identify patients with clinically important improvement in lung function and dyspnea at Week 12.

Keywords: CRYSTAL; Chronic obstructive pulmonary disease; eDiary; early bronchodilator response; electronic diary; forced expiratory volume in 1 second; transition dyspnea index.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Bronchodilator Agents / therapeutic use*
  • Drug Combinations
  • Dyspnea / etiology
  • Dyspnea / physiopathology
  • Female
  • Forced Expiratory Volume
  • Glycopyrrolate / therapeutic use*
  • Humans
  • Indans / therapeutic use*
  • Logistic Models
  • Male
  • Middle Aged
  • Multivariate Analysis
  • Patient Reported Outcome Measures*
  • Prognosis
  • Pulmonary Disease, Chronic Obstructive / complications
  • Pulmonary Disease, Chronic Obstructive / drug therapy*
  • Pulmonary Disease, Chronic Obstructive / physiopathology
  • Quinolones / therapeutic use*
  • Surveys and Questionnaires
  • Time Factors
  • Treatment Outcome


  • Bronchodilator Agents
  • Drug Combinations
  • Indans
  • Quinolones
  • indacaterol-glycopyrronium combination
  • Glycopyrrolate