Sustained 24-hour efficacy of once daily indacaterol (300 μg) in patients with chronic obstructive pulmonary disease: A randomized, crossover study

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Abstract

Purpose

Indacaterol is a novel, once daily, inhaled ultra-long-acting β2-agonist for the treatment of chronic obstructive pulmonary disease (COPD). Here we compared the 24-h spirometry profile of once daily indacaterol 300 μg with that of placebo and twice daily salmeterol 50 μg in patients with COPD.

Methods

This randomized, multicenter, placebo-controlled, crossover study comprised three 14-day treatment periods (with 14-day washouts). Patients (male/female ≥40 years) with moderate-to-severe COPD were randomized to receive double-blind indacaterol 300 μg or placebo once daily, or open-label salmeterol 50 μg twice daily. The primary outcome measure was 24-h post-dose (trough) FEV1 (mean of FEV1 at 23 h 10 min and 23 h 45 min post-indacaterol dose) after 14 days. FEV1 was assessed at multiple time points on Days 1 and 14 of each treatment period. Safety and tolerability were also monitored.

Results

Of 68 randomized patients, 61 completed. Trough FEV1 (primary endpoint) on Day 14 for indacaterol was 200 mL higher than placebo (p < 0.001), exceeding the prespecified minimum clinically important difference (120 mL), and was 90 mL higher than for salmeterol (p = 0.011). After Day 1, trough FEV1 for indacaterol was 150 mL higher than placebo (p < 0.001). Indacaterol provided superior bronchodilation compared with placebo (p < 0.001) across the full 24-h assessment period on Days 1 and 14. In addition, on both days, indacaterol provided superior FEV1 compared with salmeterol (p < 0.05) at many post-baseline time points, including 5 min post-dose. All treatments were well tolerated.

Conclusions

Once daily indacaterol 300 μg produced effective sustained 24-h bronchodilation from the first dose, an efficacy profile superior to placebo and twice daily salmeterol. Given its effective bronchodilation with once daily dosing, indacaterol is likely to be a useful treatment option for patients with moderate-to-severe COPD.

Introduction

Chronic obstructive pulmonary disease (COPD) is a major (and increasing) cause of morbidity and mortality worldwide [1]. The condition is characterized by progressive airflow limitation and air trapping, resulting in hyperinflation. This hyperinflation reduces inspiratory capacity resulting in dyspnea and limitations in exercise capacity [2].

COPD treatment guidelines, including those from the Global Initiative for Chronic Obstructive Lung Disease (GOLD) [2], advocate the use of inhaled bronchodilators, including β2-agonists, at all COPD stages to improve expiratory flow and emptying of the lungs, thereby reducing hyperinflation at rest and during exercise [2]. Regular treatment with long-acting bronchodilators in symptomatic COPD patients has been shown to be more effective and convenient than treatment with short-acting bronchodilators [2]. Currently available inhaled long-acting β2-agonists (LABAs), such as salmeterol and formoterol, induce bronchodilation that lasts for approximately 12 h and are therefore administered twice daily [3], [4], [5], [6].

Indacaterol is a novel, inhaled, ultra-LABA [7] for the treatment of COPD. In clinical trials, indacaterol has demonstrated 24-h bronchodilation with once daily dosing, with a good overall safety and tolerability profile [8], [9]. The majority of studies conducted thus far with indacaterol have incorporated relatively few spirometric assessments between 12 and 22 h post-dose. This study was therefore conducted to further characterize the 24-h lung spirometric profile of indacaterol 300 μg once daily in patients with moderate-to-severe COPD by incorporating multiple spirometric assessments across the full 24-h dosing interval.

Section snippets

Methods

This was a Phase III, randomized, multicenter, double-blind, placebo-controlled, crossover study conducted at specialized respiratory care centers in Belgium, Spain, and the US (ClinicalTrials.gov registration no.: NCT00622635) [10]. The study was approved by the institutional review board or the independent ethics committee of each participating study center and was conducted in accordance with the ethical principles embodied in the Declaration of Helsinki (1989) and applicable local

Patient disposition, demographics, and baseline characteristics

This study was conducted at 11 centers in 3 countries (6 in the USA, 3 in Belgium, and 2 in Spain). Out of 101 patients screened, 68 were randomized, and 61 (89.7%) completed the study. The most common reason for premature discontinuation was AE(s) (four patients), followed by withdrawal of consent (two patients) and abnormal test result(s) (one patient). Discontinuations were higher during treatment with salmeterol (n = 4) compared with indacaterol (n = 1) or placebo (n = 2).

The baseline

Discussion

The majority of studies conducted so far with once daily indacaterol have incorporated relatively few spirometric assessments between 12 and 22 h post-dose. This has generally been done to permit patients to rest overnight and avoid the requirement for them to remain in the study center for a full 24-h period. This was the first study to evaluate the spirometric profile of indacaterol 300 μg once daily in patients with COPD across the full 24-h dosing interval. In particular, the time points at

Conclusion

Indacaterol 300 μg once daily produced effective bronchodilation from the first dose, with efficacy compared with placebo that was sustained over 24-h. The efficacy of indacaterol was greater than that of open-label salmeterol administered twice daily. Indacaterol was generally well tolerated with a good overall safety profile. Indacaterol is therefore a useful alternative to the established bronchodilator therapies in patients with moderate-to-severe COPD. The sustained 24-h profile of

Disclosure statement

Amir Iqbal, David Young, Roger Owen, Mark Higgins and Benjamin Kramer are employees of the study sponsor, Novartis. Craig LaForce has received fees for speaking for Novartis. Joseph Aumann and Luis de Teresa Parreño have no actual or potential conflict of interest. All authors contributed to the development of the manuscript, and approved the decision to submit the manuscript for publication.

Funding

This study was funded by Novartis Pharma AG, Basel, Switzerland. The sponsor (represented by AI, DY, RO, MH and BK) was responsible for the design and analysis of the study, and for the writing of the study report. CLF, JA and LdTP were involved in the collection of data.

Acknowledgements

The authors thank the patients who took part and the staff at the participating clinical centers, and express special thanks for the conduct of the study to the principal investigators at the participating centers. The authors acknowledge Lakshmi Kasthurirangan, professional medical writer (Novartis) for assistance in the preparation of this manuscript.

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