Safety and tolerability of indacaterol in asthma: A randomized, placebo-controlled 28-day study

Indacaterol is a novel once-a-day and fast-acting β2-agonist in development for the treatment (Pulmonology Research Institute) of asthma and chronic obstructive pulmonary disease (COPD). Preclinical data suggest that, for a given degree of bronchodilator activity, indacaterol has a greater cardiovascular safety margin than formoterol or salmeterol.5 In-vivo guinea pig studies with indacaterol have demonstrated a sustained bronchodilator and bronchoprotective effect, and a rapid onset of action (comparable to salbutamol and formoterol).

Inhaled β2-agonists are the most effective bronchodilators for the prevention and relief of bronchoconstriction associated with asthma, and therefore have an important role in managing asthma symptoms.  Long-acting β2-agonists, such as salmeterol and formoterol, have 12-h durations of action, and their recommended use is in combination with inhaled corticosteroids (ICS) in patients with moderate or severe persistent asthma.

The aim of the current study was to assess the safety and tolerability of indacaterol 200, 400 and 600 μg compared with placebo, dosed once daily over 28 days in patients with asthma. The 200 μg dose was selected as a potentially therapeutic dose based on the results of a previous Phase I study.6 Particular attention was paid to the predictable pharmacological effects of a β2-agonist on serum potassium, blood glucose, heart rate, blood pressure, QTc, and occurrence of tremor, headache and

Patients were randomized using a validated automated system in the ratio 1:1:1:1 to receive indacaterol 200, 400 or 600 μg or placebo once daily by inhalation from hydrofluoroalkane (HFA) metered dose inhalers (pMDIs). To ensure blinding, indacaterol and placebo devices were identical in appearance.

Inhaled salbutamol was permitted as rescue medication. Patients who had been using long-acting β2-agonists prior to the study were instructed to use salbutamol on a regular basis for the duration of the run-in phase and as needed during the randomized treatment phase. The steroid component of combination (inhaled corticosteroid and β2-agonist) therapy was replaced with the equivalent monotherapy inhaled corticosteroid. Those patients on “monotherapy” inhaled corticosteroid continued on the pre-study steroid regimen. Patients could use nasal corticosteroids, antihistamines, cromones, ketotifen and leukotriene antagonists, provided that treatment had been stable for 1 month prior to the study. Desensitization therapy for rhinitis was permitted, provided that treatment had been stable for the previous 3 months.

The safety and tolerability of indacaterol, a novel once-daily β2-agonist bronchodilator with a fast onset of action, were assessed in 156 asthma patients in a multicentre, randomized, double-blind, placebo-controlled study. Patients received indacaterol 200, 400 or 600 μg or placebo once daily for 28 days. Adverse events (AEs), laboratory assessments, vital signs, electrocardiograms, spirometry and physical examinations were monitored. Indacaterol pharmacokinetics were assessed.

There was no evidence of dose-related increases in AE incidence or clinically significant hypokalaemia or hyperglycaemia in indacaterol-treated patients. Mean pulse rate changes were minor in any group, with maximum 1-h post-dose changes from baseline of −3.7, −3.3 and −2.2 bpm for indacaterol 200, 400 and 600 μg, respectively, and −2.9 bpm for placebo. Mean QTc interval was similar between groups; change from baseline >60 ms occurred in only two patients. Mean FEV1 increased after the first indacaterol dose; baseline-adjusted pre-dose (trough) values remained ⩾166 mL higher than placebo at all subsequent visits, supporting a 24-h bronchodilator effect. Pre-dose (but not post-dose) serum indacaterol concentrations indicated a slight trend for accumulation.

Once-daily indacaterol 200–600 μg has a favourable therapeutic index. It is well tolerated, and is not associated with any adverse cardiac or metabolic effects, while providing effective 24-h bronchodilation.



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