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

ABSTRACT

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:

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

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Declaration of interest statement

Konstantinos Kostikas (KK) is an employee and shareholder of Novartis Pharma AG. KK has previously received honoraria for speeches and consulting services from AstraZeneca, Chiesi, ELPEN and Takeda and received honoraria for speeches from Boehringer Ingelheim outside the submitted work. Maryam Aalamian-Mattheis (MA-M) is an employee of Novartis Pharma AG. Veronica Anna Pagano (VAP) and Xavier Nunez (XN) were statisticians for this subgroup analysis of CRYSTAL study and work at TFS. Robert Fogel (RF) is an employee and shareholder of Novartis Pharmaceutical Corporation. Francesco Patalano (FP) and Andreas Clemens (AC) are employees and shareholders of Novartis Pharma AG.

Acknowledgments

All authors have contributed substantially in data interpretation, development and revision of manuscript draft, who provided their consent and approval for publishing this manuscript. Writing and editorial assistance for this manuscript was provided by Claire Field (Novartis Pharmaceuticals & Novartis Global Service Center, Dublin) and Santanu Bhadra (Novartis Healthcare Pvt. Ltd., India).

Additional information

Funding

The study was supported and funded by Novartis.