The effect of indacaterol/glycopyrronium versus tiotropium or salmeterol/fluticasone on the prevention of clinically important deterioration in COPD

Abstract

Background

Endpoints that evaluate deterioration rather than improvement of disease may have clinical utility in COPD. In this analysis, we compared the effects of different maintenance treatments on the prevention of clinically important deterioration (CID) in moderate-to-severe COPD patients.

Methods

Data were analyzed from three 26-week studies comparing indacaterol/glycopyrronium (IND/GLY) with tiotropium (TIO) or salmeterol/fluticasone (SFC). Two definitions of CID were used; each was a composite of three outcome measures typically associated with COPD. Definition 1 (D1) comprised a ≥100 mL decrease in forced expiratory volume in 1 second (FEV₁), a ≥4-unit increase in St George’s Respiratory Questionnaire, and a moderate-to-severe COPD exacerbation. In Definition 2 (D2), a ≥1-unit decrease in transition dyspnea index replaced FEV₁.

Results

Using D1, IND/GLY significantly reduced the risk of first or sustained CID versus either TIO (hazard ratio 0.72 [0.61, 0.86], P=0.0003 and 0.73 [0.61, 0.89], P=0.001) or SFC (0.67 [0.57, 0.80] and 0.63 [0.52, 0.77], both P<0.0001). With D2, IND/GLY significantly reduced the risk of first, but not sustained, CID versus TIO (0.80 [0.64 to 0.99], P=0.0359 and 0.85 [0.66, 1.10], P=0.2208) and both first and sustained CID versus SFC (0.73 [0.61, 0.88], P=0.001 and 0.72 [0.58, 0.90], P=0.0036).

Conclusion

These data confirm the utility of the CID endpoint as a means of monitoring COPD worsening in patients with moderate-to-severe COPD. Using the CID measure, we demonstrated that dual bronchodilation with IND/GLY significantly reduced the risk of CID versus either long-acting muscarinic antagonist or long-acting β₂-agonist/inhaled corticosteroid treatment, providing further evidence for the benefit of dual bronchodilation in this patient population.

Keywords:

• IND/GLY
• deterioration
• COPD

Supplementary materials

Component analyses

In order to verify the main analysis results and to test the validity of using a composite endpoint, the time to first or sustained clinically important deterioration (CID) for each of the separate components of the composite endpoint were examined.

Kaplan–Meier curves for time-to-event data were generated for both data sets to illustrate patients’ times to CIDs or sustained CIDs, and hazard ratios with 95% confidence intervals, and P-values for treatment comparisons were analyzed using the Cox proportional hazard model. Covariates included in the model were treatment group, gender, age group, baseline COPD severity, ex-smoker (yes/no), and eosinophil count at baseline (>300 or ≤300 cells/µL). In addition, the log rank tests were used to compare the curves for treatment comparisons, and the P-values are presented alongside Kaplan–Meier curves. For time to CID and sustained CID analyses, patients without an event who remained on treatment were censored at the study end date; those who had discontinued were censored at their last study contact date.

The data are shown in Figures S1 and S2 for time to first event (ie, a CID of each separate component), and in Figure S3 for time to sustained CID. Apart from time to first exacerbation in SHINE¹ and time to first transition dyspnea index deterioration in LANTERN/ILLUMINATE,^2,3 indacaterol/glycopyrronium (IND/GLY) versus either comparator significantly delayed the time to first CID for each of the separate components of the composite endpoint. The strongest driver of CID in each of the analysis populations was lung function, with time to first forced expiratory volume in 1 second CID event significantly longer in IND/GLY-treated patients versus tiotropium (TIO)- or salmeterol/fluticasone (SFC)-treated patients (both P<0.0001; Figures S1 and S2, respectively). IND/GLY also significantly delayed the time to sustained CID versus TIO in the SHINE population (Figures S3A). A numerical benefit versus SFC was observed in LANTERN/ILLUMINATE, although this did not translate into statistical significance (Figures S3B).

Figure S1 Kaplan–Meier curves (with numbers of subjects at risk and 95% CIs) of time to first CID: IND/GLY versus TIO: SHINE¹: (A) time to first exacerbation, (B) time to first FEV₁ ≤ −100, (C) time to first SGRQ ≥4, (D) time to first TDI ≤ −1.

Abbreviations: CI, confidence interval; HR, hazard ratio; CID, clinically important deterioration; IND/GLY, indacaterol/glycopyrronium; TDI, Transition Dyspnea Index; TIO, tiotropium; FEV₁, forced expiratory volume in 1 second; SGRQ, St George’s Respiratory Questionnaire; trtp, treatment.

Figure S2 Kaplan–Meier curves (with numbers of subjects at risk and 95% CIs) of time to first CID: IND/GLY versus SFC: LANTERN/ILLUMINATE^2,3: (A) time to first exacerbation, (B) time to first FEV₁ ≤ −100, (C) time to first SGRQ ≥4, (D) time to first TDI ≤ −1.

Abbreviations: CI, confidence interval; HR, hazard ratio; CID, clinically important deterioration; IND/GLY, indacaterol/glycopyrronium; SFC, salmeterol/fluticasone; SGRQ, St George’s Respiratory Questionnaire; TDI, Transition Dyspnea Index; trtp, treatment.

Figure S3 Kaplan–Meier curves (with numbers of subjects at risk and 95% CIs) on the component of sustained CID for (A) IND/GLY versus TIO (SHINE¹) and (B) IND/GLY versus SFC (LANTERN/ILLUMINATE^2,3).

Abbreviations: CI, confidence interval; HR, hazard ratio; CID, clinically important deterioration; IND/GLY, indacaterol/glycopyrronium; TIO, tiotropium; SFC, salmeterol/fluticasone; trtp, treatment.

References

• BatemanEDFergusonGTBarnesNDual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE studyEur Respir J20134261484149423722616
   PubMed Web of Science ®Google Scholar
• ZhongNWangCZhouXLANTERN: a randomized study of QVA149 versus salmeterol/fluticasone combination in patients with COPDInt J Chron Obstruct Pulmon Dis2015101015102626082625
   PubMed Web of Science ®Google Scholar
• VogelmeierCFBatemanEDPallanteJEfficacy and safety of once-daily QVA149 compared with twice-daily salmeterol-fluticasone in patients with chronic obstructive pulmonary disease (ILLUMI NATE): a randomised, double-blind, parallel group studyLancet Respir Med201311516024321804
   PubMed Web of Science ®Google Scholar

Acknowledgments

This analysis was sponsored by Novartis Pharma AG (Basel, Switzerland). Medical writing assistance was provided by Colette O’Sullivan, PhD, of Scriva Medical Communications Ltd, a professional medical writer funded by Novartis.

Disclosure

The authors take full responsibility for the scope, direction, content, and editorial decisions relating to the manuscript, and were involved at all stages of development and approved the submitted manuscript. The authors received no compensation related to the development of the manuscript.

ARA has acted as a consultant and served on advisory boards for Novartis Pharma AG, AstraZeneca, Boehringer Ingelheim, GSK, and Sunovion.

CFV has acted as a consultant and served on advisory boards for Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi; received grants and personal fees from GlaxoSmithKline, grants and personal fees from Grifols, Mundipharma, Novartis, Takeda, Cipla, and Berlin Chemie/Menarini.

KK is an employee and shareholder of Novartis Pharma AG. Previously he has received honoraria for educational activities and lectures from AstraZeneca, Boehringer Ingelheim, Chiesi, ELPEN, GSK, Novartis, and Takeda, and has participated on advisory boards arranged by AstraZeneca, Chiesi, ELPEN, Novartis, and Takeda.

KM, SF, GB, SS, DB and RF are employees and shareholders of Novartis Pharma AG or Novartis Pharmaceuticals Corporation.

The authors have no other conflicts of interest to report in this work.