Indacaterol, a novel inhaled β₂-agonist, provides sustained 24-h bronchodilation in asthma

Design

The present study was a multicentre, randomised, double-blind, placebo-controlled, crossover, dose-ranging study. Patients were randomised to one of five crossover treatment sequences (Latin square design) to inhale a single dose of indacaterol 50, 100, 200 or 400 µg or placebo from a hydrofluoroalkane (HFA) pressurised metered-dose inhaler (pMDI), with a 5–14 day washout between treatment periods. At all treatment visits, patients were under continuous medical supervision from the first pre-dose evaluation until 26 h after administration of the study medication. Study medication was administered between 17:00 and 19:00 h and patients were allowed to sleep for 7 h, approximately between 00:00–07:00 h.

The study received institutional review board approval and all patients gave informed written consent prior to the start of the study. The study was conducted according to Good Clinical Practice guidelines and in accordance with the Declaration of Helsinki (1964 and subsequent revisions).

Inclusion and exclusion criteria

Inclusion criteria were: 1) males and females aged 18–65 yrs; 2) a diagnosis of intermittent or persistent asthma 11; 3) use of daily treatment with an inhaled β₂-agonist, with or without an inhaled corticosteroid (ICS; ≤1,600 µg of beclometasone dipropionate or equivalent); 4) a stable regimen for ≥1 month prior to screening; 5) a forced expiratory volume in one second (FEV₁) at screening 60–85% of the predicted normal value 12 in the absence of short-acting β₂-agonist (SABA) and LABA use for ≥6 and ≥48 h prior, respectively; and 6) FEV₁ reversibility ≥15% over their baseline value within 30 min after inhalation of 400 µg (four inhalations) of salbutamol in the afternoon or evening of the screening visit.

Exclusion criteria were: 1) the presence of relevant pulmonary disease; 2) use of tobacco products within 6 months before screening or a smoking history of >10 pack-yrs; 3) hospitalisation or emergency room treatment for acute asthma in the 3 months prior to screening or between screening and the start of the treatment period; 4) a respiratory tract infection within 1 month prior to screening; 5) abnormal blood glucose levels; and 6) corrected QT (QTc) interval at screening >430 or 450 ms for males and females, respectively, or a history of prolonged QTc interval.

Study treatment

Patients received a single dose of indacaterol 50, 100, 200 or 400 µg or placebo on each of five separate visits. The range of doses was chosen on the basis of results from an earlier study 10. The study drug was administered by one inhalation from each of two HFA pMDIs (delivering indacaterol 50 or 200 µg or placebo).

Inhaled salbutamol was only permitted as rescue medication and was not to be taken within 6 h prior to the start of a treatment period. If rescue salbutamol was needed during this period, the visit was rescheduled. Patients taking ICS (≤1,600 µg of beclometasone dipropionate or equivalent) continued to do so throughout the study. Inhaled LABAs were allowed between treatment periods at recommended daily doses, providing the dose remained fixed throughout the study, but had to be discontinued 48 h prior to screening or study drug administration.

Treatments not permitted included fixed combinations of β₂-agonists and ICS, parenteral or oral corticosteroids, theophylline or other xanthines, leukotriene antagonists, and oral or inhaled anticholinergics.

Assessments

Spirometry was conducted according to American Thoracic Society standards 13 at all visits: pre-dose and 5, 10, 20, 30 and 60 min post-dose; hourly from 2–6 h post-dose; every 2 h from 13–19 h post-dose; and hourly from 20–26 h post-dose. The primary efficacy comparisons were the per cent changes in FEV₁ between indacaterol and placebo at 30 min and at 21 h post-dose.

Secondary efficacy comparisons with placebo (both per cent and absolute change) included the standardised areas under the curve (AUC) for FEV₁ 0–6 h, 13–24 h and 0–24 h post-dose. A summary table for FEV₁ at all time-points is also provided together with ANCOVAs assessing treatment ratios in FEV₁ at each post-dose time-point.

Safety was assessed by monitoring and recording all adverse events, serious adverse events, haematology, blood chemistry, urinalysis, vital signs, ECGs, spirometry and physical examination.

Statistical analyses

All efficacy variables were analysed for the intention-to-treat population, which included all randomised patients. All safety variables were analysed for the safety population, which included all randomised patients who received at least one dose of study medication.

The primary comparisons were performed using an ANCOVA model for log(FEV₁), with patient as a random effect, period and treatment as fixed effects and log(baseline FEV₁) as covariate. If patients took rescue medication prior to the 30-min post-dose evaluation, this value was excluded from the analysis. If a patient took rescue medication or withdrew 13–21 h post-dose, the 21-h value was derived using last observation carried forward. However, the 21-h measurement was used in the analysis if it was lower than the last pre-rescue measurement. If a patient withdrew from the study prior to the 13-h post-dose evaluation, the 21-h value was not derived. For either time-point, data missing for any other reason were imputed using linear interpolation.

ANCOVAs, similar to those used for the primary comparisons, were used for each of the AUC comparisons with no adjustment for multiplicity.

Sample size calculation

An improvement of 12% in FEV₁ compared with placebo was defined as clinically relevant 13. Assuming a within-patient variance of 0.011 for log(FEV₁), a sample size of 35 was required to detect an increase of 12% in FEV₁. This sample size would provide an overall one-sided error rate of 2.1% and an overall power of 95.5%. It was expected that ∼43 patients should be recruited in order for 35 to complete the study.

Establishing optimal dose

The optimal dose was identified using three pre-specified criteria. First, at both 30 min and 21 h post-dose, an effective dose was defined as a dose that was superior to placebo for FEV₁ at the 2.5% one-sided significance level, with an upper limit of the 95% confidence interval (CI) for the treatment/placebo ratio of >1.12, which corresponds to a clinically relevant increase of 12% improvement over placebo. Secondly, efficacy was to be determined from an estimation of the treatment difference between each pair of active doses. Thirdly, the safety of each dose would be considered.

Patients

The present study was carried out at three locations. A total of 50 patients were screened and 42 were randomised, all receiving at least one dose of study medication. Their demographics are shown in table 1⇓. More than half of the patients had at least one concomitant disease at the start of the study, most frequently related to allergic rhinoconjunctivitis, and 24 (57%) were using ICS.

In total, 40 (95%) patients completed all five treatments in the study. One patient discontinued due to protocol violation (out of range FEV₁ at pre-dose spirometry), and one, who later reported a previous history of a minor abnormality in a liver function test, due to mildly elevated bilirubin levels (suspected Gilbert's syndrome).

Efficacy

Indacaterol 50, 200 and 400 µg were superior to placebo for FEV₁ at both 30 min and 21 h post-dose; indacaterol 100 µg was superior to placebo at 30 min, but not at 21 h post-dose (fig. 1⇓). Indacaterol 400 µg was the most effective dose, although the difference from the other indacaterol doses was not always statistically superior. The upper boundary of the 95% CI for the ratio with placebo exceeded 1.12 (corresponding to an increase of 12% over placebo) for indacaterol 200 and 400 µg at both time-points (fig. 1⇓). Therefore, both the 200 and 400 µg doses met the first set of pre-specified criteria for clinical efficacy.

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Fig. 1—

Estimates of per cent increases for forced expiratory volume in one second (FEV₁) of treatment groups compared with placebo and associated 95% confidence intervals at 30 min and 21 h post-dose. ○: 50 µg versus placebo; ▒: 100 µg versus placebo; ▓: 200 µg versus placebo; •: 400 µg versus placebo. p-Values were 0.003, 0.003, <0.001 and <0.001 for 50, 100, 200 and 400 μg, respectively, at 30 min post-dose and 0.011, 0.080, 0.002 and <0.001 for 50, 100, 200 and 400 μg, respectively, at 21 h post-dose.

FEV₁ at each post-dose time-point is shown both as a summary table (table 2⇓) and with ANCOVAs assessing treatment ratios (table 3⇓). All indacaterol doses demonstrated higher mean FEV₁ values over the 26-h assessment period compared with placebo (fig. 2⇓, table 3⇓). At the (first) 5-min time-point, significant improvements relative to placebo (p<0.05) were obtained for indacaterol 200 and 400 µg (table 3⇓), and these were sustained at each subsequent time-point up to and including 25 h (200 μg) and 26 h (400 μg). Indacaterol 400 µg was statistically superior (p<0.05) to the other indacaterol doses at most time-points (fig. 2⇓). The highest mean differences in FEV₁ from placebo were reached at 2–3 h post-dose.

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Fig. 2—

The 26-h profile of mean forced expiratory volume in one second (FEV₁). Indacaterol 400 µg was superior to placebo (p<0.05) at all post-dose time-points; 200 µg superior to placebo (p<0.05) from 5 min to 25 h post-dose (inclusive); 100 µg superior to placebo (p<0.05) from 10 min to 6 h, 15–19 h and 22–23 h post-dose (inclusive); 50 µg superior to placebo (p<0.05) from 10 min to 6 h and 15–25 h post-dose (inclusive). ░: Sleep; ▪: indacaterol 400 μg (n = 41); □: indacaterol 200 μg (n = 41); •: indacaterol 100 μg (n = 41); ○: indacaterol 50 μg (n = 41); ▴: placebo (n = 40). *: p<0.05 versus indacaterol 200 µg; ^#: p<0.05 versus indacaterol 100 µg; ^¶: p<0.05 versus indacaterol 50 µg.

Analysis of standardised AUC for FEV₁ at 0–6, 13–24 and 0–24 h (table 4⇓) demonstrated that all doses of indacaterol were superior to placebo (p<0.05), with the exception of the 100 µg dose at 13–24 h. FEV₁ AUC for indacaterol 400 µg was statistically superior to all other doses (p<0.05) at 0–6 h and 0–24 h, and was superior to indacaterol 100 µg at 13–24 h (p<0.05).

Safety and tolerability

All doses of indacaterol were well tolerated, with no serious adverse events experienced in any treatment sequence. The overall number of adverse events appeared to be dose-related (table 5⇓). The most common adverse events were headache and cough, all episodes of which were mild to moderate apart from one severe headache with indacaterol 400 µg. There were no asthma-related adverse events.

Haematological and biochemical measurements fell within the normal ranges and, with one exception, there were no clinically significant differences between treatments. One patient who had abnormally high values of creatinine kinase at the screening visit also had marked increases 6 h post-dose whilst receiving indacaterol 100 µg, although the values returned to normal 13–26 h post-dose. The incidence of newly occurring biochemical abnormalities was low, with no clinically meaningful differences across treatments. There were minimal changes in mean potassium and glucose levels 6 h post-dose, with no statistically significant or clinically meaningful differences between treatments (table 6⇓).

There were no clinically significant differences in vital signs, including cardiac frequency and blood pressure, or ECG abnormalities between treatments. For all treatments, the QTc interval decreased from pre-dose to 15 min post-dose, with only minor changes at 6 and 24 h post-dose. There were no clinically meaningful or statistically significant differences in mean QTc interval between indacaterol and placebo. No QTc interval increases >60 ms from pre- to post-dose were observed.