Salmeterol xinafoate is a long-acting, highly selective β2-adrenergic agonist providing bronchodilatation for a median duration of 12 hours and protecting against a variety of bronchoconstrictory stimuli for a similar time interval. Salmeterol is available as an aerosol and a dry powder inhaler approved down to the age of 4 years. Because younger children have difficulty in properly using a metered dose inhaler, a powder inhaler, which is breath-activated, would be an advantage particularly in this population. The purpose of this study was to evaluate the efficacy and safety of salmeterol powder versus placebo in children 4 to 11 years of age with chronic, persistent asthma.
Male and female patients ages 4 to 11 years with asthma as defined by American Thoracic Society (ATS) criteria who required daily maintenance therapy for at least 6 months were eligible. In addition entry criteria included either peak expiratory flow (PEF) (in younger children) or forced expiratory volume in 1 second (FEV1) between 50% to 80% of predicted and 15% reversibility with albuterol. Treatment with antiinflammatory agents (ie, disodium cromolyn, nedocromil, or inhaled corticosteroids) was permitted throughout the study if the medication had been taken for at least 3 months before the study.
This was a multicenter, double-blind, placebo-controlled study. During a 1- to 2-week run-in period the patients received their usual medications and a placebo powder twice a day and rescue albuterol as needed, while keeping a diary of signs and symptoms, PEF, and medication use. Patients qualified for randomization on the basis of albuterol need, symptoms, and daily compliance. At randomization, the patient received either salmeterol powder in a nonpressurized breath activated delivery device or placebo. Patients were evaluated by signs and symptoms of asthma, PEF, and albuterol use by diary card as well as 12-hour pulmonary function tests after study medication in the research center over a period of 12 weeks. The primary efficacy variable was PEF or FEV1 measured over 12 hours. Safety variables included vital signs, electrocardiogram, 12-hour Holter monitoring, and incidence of patient withdrawal from the study.
Two hundred seven patients, 102 on salmeterol and 105 on placebo, were randomized. On day 1 and week 12, both the PEF and FEV1were significantly (P < .01) higher on drug than placebo over the 12-hour post-dosing period. In addition, overall reduction in rescue albuterol and mean asthma score were also significantly greater (P < .01) in the salmeterol group compared with placebo. The frequency of adverse events was similar in both groups.
Salmeterol powder (50 μg bid) is effective and safe in producing bronchodilatation and reducing signs and symptoms in children with chronic persistent asthma. Over a 12-week period there was no evidence of tachyphylaxis.
This is a useful study since delivery of inhaled medication, particularly in very young children, can be problematic. Current modalities in this population include metered dose inhalers, which are difficult to coordinate and require a spacer, and nebulizers, which are expensive and time-consuming for chronic usage. Compliance with the dry powder inhaler mechanism in this study appears to be very good with the children easily learning the technique. In addition, the study found efficacy and no evidence of tachyphylaxis for bronchodilatation over a 12-week period, which is similar to findings with older children and adults. The issue of tachyphylaxis to the protection from bronchoconstrictory stimuli, particularly exercise, was not addressed here, but continues to be an important issue. The major question with salmeterol, however, is not the delivery system, but where it best fits in the current guidelines for asthma therapy. Its optimal use appears to be not as monotherapy, but rather as an addition to antiinflammatory therapy when the latter has not provided optimal therapy.