Fluticasone propionate/salmeterolThe propionate de fluticasone salmeterol of fluticasone and propionate de fluticasone salmeterol Advair Diskus, Advair HFA is used to treat difficulty breathing, wheezing, shortness of breath, coughing, and chest tightness caused by asthma. The combination of fluticasone and salmeterol Advair Diskus is also used to prevent and treat wheezing, shortness of breath, coughing, and chest tightness caused by chronic obstructive pulmonary disease COPD; a group of lung diseases that includes chronic bronchitis and emphysema. The combination of fluticasone and salmeterol Advair Diskus is used in adults and children 4 years of age and older. The combination of fluticasone and salmeterol Advair HFA is used in children 12 years of age and older. Fluticasone is in a class of medications called steroids. It works by reducing swelling in the airways. Tren 75 is in a class of medications called long-acting beta-agonists LABAs.
Safety of Adding Salmeterol to Fluticasone Propionate in Children with Asthma | NEJM
Long-acting beta-agonists LABAs have been shown to increase the risk of asthma-related death among adults and the risk of asthma-related hospitalization among children. It is unknown whether the concomitant use of inhaled glucocorticoids with LABAs mitigates those risks. This trial prospectively evaluated the safety of the LABA salmeterol, added to fluticasone propionate, in a fixed-dose combination in children. We randomly assigned, in a 1: The primary safety end point was the first serious asthma-related event death, endotracheal intubation, or hospitalization , as assessed in a time-to-event analysis.
The main efficacy end point was the first severe asthma exacerbation that led to treatment with systemic glucocorticoids, as assessed in a time-to-event analysis. Among the patients, 27 patients in the fluticasone—salmeterol group and 21 in the fluticasone-alone group had a serious asthma-related event all were hospitalizations ; the hazard ratio with fluticasone—salmeterol versus fluticasone alone was 1.
A total of patients 8. In this trial involving children with asthma, salmeterol in a fixed-dose combination with fluticasone was associated with the risk of a serious asthma-related event that was similar to the risk with fluticasone alone. The safety of inhaled beta-agonists in patients with asthma has been debated since the s. Clinical-trial experience regarding the safety of LABAs in children 4 to 11 years of age is limited. The secondary objective was to assess whether the combination was superior to fluticasone alone in terms of the risk of severe asthma exacerbations.
We conducted this international, randomized, double-blind, active-comparator, week trial from November through November at trial centers in 32 countries Fig. The trial protocol , including the statistical analysis plan, is available at NEJM.
A pediatric steering committee reviewed performance standards, a pediatric adjudication committee, whose members were unaware of the treatment assignments, determined the relatedness of end points to asthma, and an independent data and safety monitoring committee reviewed safety data every 6 months, with one planned interim statistical analysis after approximately half the expected 43 events occurred see the Supplementary Appendix. Scientific oversight was provided by employees of the sponsor GlaxoSmithKline who were collectively responsible for the trial design and conduct.
The initial draft of the manuscript was written by the first and second authors, and all the authors collaborated to prepare the final content for submission. Editorial support was provided by two professional writers, paid by the sponsor. All the authors had full access to the data and vouch for the accuracy and completeness of all data and analyses and for the fidelity of this report to the protocol.
All the authors made the decision to submit the manuscript for publication. Ethical approval was obtained from the relevant ethics committees and institutional review boards. The trial was conducted in accordance with Good Clinical Practice guidelines and the provisions of the Declaration of Helsinki. Key inclusion criteria were an age of 4 to 11 years, consistent use of asthma medication during the 4 weeks before enrollment, the Childhood Asthma Control Test C-ACT 13 score on a scale from 0 to 27, with higher scores indicating better control of asthma 13 ; minimally important difference, 1.
Patients were excluded if they had a history of life-threatening asthma or unstable asthma see the Supplementary Appendix. Children whose asthma was controlled by inhaled glucocorticoids and a LABA were enrolled on the basis of the U. The parent or legal guardian provided written informed consent. Assent by patients was given as appropriate. Patients were randomly assigned, in a 1: Treatment was administered twice daily with the use of Diskus devices GlaxoSmithKline that were identical for all regimens to maintain blinding.
Treatment was administered in a double-blind manner with respect to the use of salmeterol but not with respect to the dose of fluticasone propionate. Rescue therapy with albuterol also known as salbutamol was supplied to all patients by means of a metered-dose inhaler. The primary end point was the first serious asthma-related event a composite end point that included death, endotracheal intubation, and hospitalization , as assessed in a time-to-event analysis.
All intubations and deaths were fully adjudicated. All hospitalizations were screened by one committee member, and those that were deemed to be potentially related to asthma were fully adjudicated.
All nonserious adverse events that led to the discontinuation of treatment and all serious adverse events were documented. The vital status of all the patients who received at least one dose of treatment was assessed at the end of the 6-month trial period. Height was measured with the use of standard clinical-office procedures. The main objective with respect to efficacy was to determine whether fluticasone—salmeterol was superior to fluticasone alone in terms of the first severe asthma exacerbation.
Asthma exacerbations were recorded independently of adverse events, and withdrawal from the trial was at the discretion of the investigator. Secondary efficacy end points included the number of rescue therapy—free days and the number of asthma-control days. The primary safety end point was assessed by a stratified Cox proportional-hazards regression model, with terms for randomized treatment fluticasone—salmeterol or fluticasone alone and randomization stratum.
The noninferiority margin was based on the event rate observed in the meta-analysis of LABA-containing products conducted in 8 and also factored in the sample size and time period that were required to complete the trial. The main efficacy objective — to determine whether fluticasone—salmeterol was superior to fluticasone alone in terms of the first severe asthma exacerbation — was tested with the use of a Cox proportional-hazards regression model.
The trial was not powered to allow the formal statistical comparison or evaluation of fluticasone—salmeterol versus fluticasone alone in subgroups. In calculating the sample size for the primary safety end point, we assumed a rate of 0. The sample size was adjusted to accommodate one interim statistical analysis, which was to be conducted when approximately half the expected number of composite end points had occurred. The Haybittle—Peto method was used for managing the alpha-spending function over the interim analysis and the final analysis.
The intention-to-treat population, which included all the patients who underwent randomization and received at least one dose of trial medication, was used for the analysis of the primary end point. Events were included in the analysis during the entire 6-month trial period even if the treatment was discontinued early or until 7 days after the last dose of treatment, whichever was the longer interval from randomization. A modified intention-to-treat population was used for efficacy analyses, which included only data collected up to 7 days after each patient stopped the trial medication.
Four efficacy subgroups were determined on the basis of asthma control at baseline, exacerbation history, and previous asthma therapy Table S2 in the Supplementary Appendix. The intention-to-treat population included patients in the fluticasone—salmeterol group and in the fluticasone-alone group Figure 1. The characteristics of age, sex, race, baseline C-ACT score, and season of enrollment season of enrollment was analyzed post hoc were similar in the two overall treatment groups Table 1 , and Table S3 in the Supplementary Appendix.
The end point was assessed in the intention-to-treat population, which included all the patients who had undergone randomization and received at least one dose of fluticasone—salmeterol or fluticasone alone. The inset shows the same data on an expanded y axis. I bars indicate standard errors. Of the patients in the intention-to-treat population, 48 had a serious asthma-related event 27 patients in the fluticasone—salmeterol group and 21 in the fluticasone-alone group Table 2.
Only asthma-related hospitalizations were reported; there were no deaths or asthma-related endotracheal intubations in either treatment group Table 2.
The hazard ratio for a serious asthma-related event fluticasone—salmeterol vs. The Kaplan—Meier curves for the first event of the composite end point in the time-to-event analysis are shown in Figure 2. A total of 34 children 1. A total of 56 patients 1. The growth velocity was 2. The hazard ratio in the time-to-event analysis of the first severe asthma exacerbation with fluticasone—salmeterol versus fluticasone alone was 0.
Among black patients, 6. There was no apparent between-group difference in the number of patients who had a severe exacerbation in each of the age groups 4 to 6 years and 7 to 11 years Table 3.
For further insight into the efficacy of the LABA, we compared four prespecified subgroups that included Among patients in subgroup 1, who entered the trial with asthma controlled by combined inhaled glucocorticoid and LABA therapy, fewer patients who continued to take combination therapy had a severe exacerbation than those who had LABA withdrawn i. In subgroup 2, patients entered the trial with asthma that was uncontrolled by low-dose glucocorticoid and LABA therapy and had their dose of inhaled glucocorticoid increased.
Among patients in subgroup 4, who entered the trial with asthma that was controlled by inhaled glucocorticoid treatment only and who had had two or more exacerbations in the previous year, The mean percentage of rescue therapy—free days was similar in the fluticasone—salmeterol group and the fluticasone-alone group The C-ACT score showed that The observed end points fell within the prespecified noninferiority margin with respect to the risk of serious asthma-related events associated with salmeterol delivered in a fixed-dose combination with fluticasone propionate, as compared with equipotent doses of fluticasone alone.
The safety findings in this trial concur with those of previous meta-analyses that compared a fixed-dose combination of a LABA with inhaled glucocorticoids and with the results of the AUSTRI trial, which involved 11, adolescents and adults and which was similar in design to the current trial. Asthma-related deaths are uncommon in children, and no association with LABAs has been reported previously.
The hospitalization rate in our trial was approximately 1. National Surveillance of Asthma among children 5 to 14 years of age. These safety comparisons were not powered to detect noninferiority and the event rates were numerically consistent with data in the AUSTRI trial, including data from adolescents.
The entry criteria in our trial were selected primarily for the safety analysis. More than half the patients entered the study with a C-ACT score that showed asthma control, and there was no pretreatment run-in phase to establish baseline medication requirements. Given the variability in the baseline characteristics, efficacy subgroups were prespecified to address differences in asthma control and previous medication use.
Of the overall trial population, This finding suggests the need to understand better the appropriate clinical variables that need to be assessed before patients step down from combination therapy. Patients in subgroup 3 had uncontrolled asthma at baseline and had differing baseline medications, and the addition of a LABA had no significant effect.
In subgroup 4, the number of children who had a severe exacerbation was not significantly lower among children whose asthma was controlled with the use of low- or medium-dose inhaled glucocorticoid monotherapy and who had salmeterol added than among those who continued glucocorticoid monotherapy; this finding supports present asthma guidelines that do not recommend adjunctive therapy for patients whose asthma is adequately controlled with the use of inhaled glucocorticoids. The evidence supporting the role of LABAs in children whose asthma is uncontrolled by low-dose inhaled glucocorticoids is limited by the fact that few clinical trials involving children have had efficacy as a primary end point.
Two studies that included children 4 to 11 years of age whose asthma was inadequately controlled by inhaled glucocorticoids showed an improvement in lung function and a resolution or abatement of symptoms with the addition of a LABA. The limitations of this trial include the short 6-month duration and the infrequent occurrence of serious asthma-related events.
Other limitations include the following: The trial was designed with FDA guidance to assess a composite end point of serious asthma-related events. However, only asthma-related hospitalizations were observed. Second, it is not known whether the results of this trial are applicable to other combinations of inhaled glucocorticoids and LABAs.
Third, potential concomitant risk factors such as allergen sensitivity were not addressed in this analysis. Fourth, the adherence to the medication regimen was higher than that seen in clinical practice; however, adherence is important when testing the risk associated with a drug to ensure that patients have maximal exposure to the drug. Finally, height data did not include growth velocity at baseline, a stadiometer was not used, and the data were not limited to prepubescent children.
Disclosure forms provided by the authors are available with the full text of this article at NEJM. Yun Kirby, and Dr. Pascoe are employees of and hold stock in GlaxoSmithKline. Prillaman are former employees of and hold stock in GlaxoSmithKline; Mr.