title: Safety of Adding Salmeterol to Fluticasone Propionate in Children with Asthma.
abstract: 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 1:1 ratio, children 4 to 11 years of age who required daily asthma medications and had a history of asthma exacerbations in the previous year to receive fluticasone propionate plus salmeterol or fluticasone alone for 26 weeks. 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 statistical design specified that noninferiority would be shown if the upper boundary of the 95% confidence interval of the hazard ratio for the primary safety end point was less than 2.675. 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 6208 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 1.28 (95% confidence interval [CI], 0.73 to 2.27), which showed the noninferiority of fluticasone-salmeterol (P=0.006). A total of 265 patients (8.5%) in the fluticasone-salmeterol group and 309 (10.0%) in the fluticasone-alone group had a severe asthma exacerbation (hazard ratio, 0.86; 95% CI, 0.73 to 1.01).
  
  
  
  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. (Funded by GlaxoSmithKline; VESTRI ClinicalTrials.gov number, NCT01462344 .).
authors: From Respiratory Clinical Development (D.A.S., A.M.Y., L.A.L., I.H.R., K.S.B., S.Y.K., S.J.P.) and Research and Development, Clinical Platforms and Sciences, Clinical Statistics (K.M.K.), GlaxoSmithKline, Research Triangle Park, Rho, Chapel Hill (H.M.), and Biostatistics, Parexel International, Durham (B.A.P.) - all in North Carolina; the Department of Pediatrics, Breathing Institute, Pediatric Pulmonary Section, Children's Hospital Colorado and University of Colorado School of Medicine, Aurora (S.J.S., A.H.L.); the Department of Pediatrics, Center Lillebælt, Fredericia and Kolding Hospital, Odense, Denmark (S.P.); and the Department of Allergy and Research and Evaluation, Kaiser Permanente Research, San Diego, CA (R.S.Z.).
authors: David A
authors: DA
authors: Stempel
authors: From Respiratory Clinical Development (D.A.S., A.M.Y., L.A.L., I.H.R., K.S.B., S.Y.K., S.J.P.) and Research and Development, Clinical Platforms and Sciences, Clinical Statistics (K.M.K.), GlaxoSmithKline, Research Triangle Park, Rho, Chapel Hill (H.M.), and Biostatistics, Parexel International, Durham (B.A.P.) - all in North Carolina; the Department of Pediatrics, Breathing Institute, Pediatric Pulmonary Section, Children's Hospital Colorado and University of Colorado School of Medicine, Aurora (S.J.S., A.H.L.); the Department of Pediatrics, Center Lillebælt, Fredericia and Kolding Hospital, Odense, Denmark (S.P.); and the Department of Allergy and Research and Evaluation, Kaiser Permanente Research, San Diego, CA (R.S.Z.).
authors: Stanley J
authors: SJ
authors: Szefler
authors: From Respiratory Clinical Development (D.A.S., A.M.Y., L.A.L., I.H.R., K.S.B., S.Y.K., S.J.P.) and Research and Development, Clinical Platforms and Sciences, Clinical Statistics (K.M.K.), GlaxoSmithKline, Research Triangle Park, Rho, Chapel Hill (H.M.), and Biostatistics, Parexel International, Durham (B.A.P.) - all in North Carolina; the Department of Pediatrics, Breathing Institute, Pediatric Pulmonary Section, Children's Hospital Colorado and University of Colorado School of Medicine, Aurora (S.J.S., A.H.L.); the Department of Pediatrics, Center Lillebælt, Fredericia and Kolding Hospital, Odense, Denmark (S.P.); and the Department of Allergy and Research and Evaluation, Kaiser Permanente Research, San Diego, CA (R.S.Z.).
authors: Søren
authors: S
authors: Pedersen
authors: From Respiratory Clinical Development (D.A.S., A.M.Y., L.A.L., I.H.R., K.S.B., S.Y.K., S.J.P.) and Research and Development, Clinical Platforms and Sciences, Clinical Statistics (K.M.K.), GlaxoSmithKline, Research Triangle Park, Rho, Chapel Hill (H.M.), and Biostatistics, Parexel International, Durham (B.A.P.) - all in North Carolina; the Department of Pediatrics, Breathing Institute, Pediatric Pulmonary Section, Children's Hospital Colorado and University of Colorado School of Medicine, Aurora (S.J.S., A.H.L.); the Department of Pediatrics, Center Lillebælt, Fredericia and Kolding Hospital, Odense, Denmark (S.P.); and the Department of Allergy and Research and Evaluation, Kaiser Permanente Research, San Diego, CA (R.S.Z.).
authors: Robert S
authors: RS
authors: Zeiger
authors: From Respiratory Clinical Development (D.A.S., A.M.Y., L.A.L., I.H.R., K.S.B., S.Y.K., S.J.P.) and Research and Development, Clinical Platforms and Sciences, Clinical Statistics (K.M.K.), GlaxoSmithKline, Research Triangle Park, Rho, Chapel Hill (H.M.), and Biostatistics, Parexel International, Durham (B.A.P.) - all in North Carolina; the Department of Pediatrics, Breathing Institute, Pediatric Pulmonary Section, Children's Hospital Colorado and University of Colorado School of Medicine, Aurora (S.J.S., A.H.L.); the Department of Pediatrics, Center Lillebælt, Fredericia and Kolding Hospital, Odense, Denmark (S.P.); and the Department of Allergy and Research and Evaluation, Kaiser Permanente Research, San Diego, CA (R.S.Z.).
authors: Anne M
authors: AM
authors: Yeakey
authors: From Respiratory Clinical Development (D.A.S., A.M.Y., L.A.L., I.H.R., K.S.B., S.Y.K., S.J.P.) and Research and Development, Clinical Platforms and Sciences, Clinical Statistics (K.M.K.), GlaxoSmithKline, Research Triangle Park, Rho, Chapel Hill (H.M.), and Biostatistics, Parexel International, Durham (B.A.P.) - all in North Carolina; the Department of Pediatrics, Breathing Institute, Pediatric Pulmonary Section, Children's Hospital Colorado and University of Colorado School of Medicine, Aurora (S.J.S., A.H.L.); the Department of Pediatrics, Center Lillebælt, Fredericia and Kolding Hospital, Odense, Denmark (S.P.); and the Department of Allergy and Research and Evaluation, Kaiser Permanente Research, San Diego, CA (R.S.Z.).
authors: Laurie A
authors: LA
authors: Lee
authors: From Respiratory Clinical Development (D.A.S., A.M.Y., L.A.L., I.H.R., K.S.B., S.Y.K., S.J.P.) and Research and Development, Clinical Platforms and Sciences, Clinical Statistics (K.M.K.), GlaxoSmithKline, Research Triangle Park, Rho, Chapel Hill (H.M.), and Biostatistics, Parexel International, Durham (B.A.P.) - all in North Carolina; the Department of Pediatrics, Breathing Institute, Pediatric Pulmonary Section, Children's Hospital Colorado and University of Colorado School of Medicine, Aurora (S.J.S., A.H.L.); the Department of Pediatrics, Center Lillebælt, Fredericia and Kolding Hospital, Odense, Denmark (S.P.); and the Department of Allergy and Research and Evaluation, Kaiser Permanente Research, San Diego, CA (R.S.Z.).
authors: Andrew H
authors: AH
authors: Liu
authors: From Respiratory Clinical Development (D.A.S., A.M.Y., L.A.L., I.H.R., K.S.B., S.Y.K., S.J.P.) and Research and Development, Clinical Platforms and Sciences, Clinical Statistics (K.M.K.), GlaxoSmithKline, Research Triangle Park, Rho, Chapel Hill (H.M.), and Biostatistics, Parexel International, Durham (B.A.P.) - all in North Carolina; the Department of Pediatrics, Breathing Institute, Pediatric Pulmonary Section, Children's Hospital Colorado and University of Colorado School of Medicine, Aurora (S.J.S., A.H.L.); the Department of Pediatrics, Center Lillebælt, Fredericia and Kolding Hospital, Odense, Denmark (S.P.); and the Department of Allergy and Research and Evaluation, Kaiser Permanente Research, San Diego, CA (R.S.Z.).
authors: Herman
authors: H
authors: Mitchell
authors: From Respiratory Clinical Development (D.A.S., A.M.Y., L.A.L., I.H.R., K.S.B., S.Y.K., S.J.P.) and Research and Development, Clinical Platforms and Sciences, Clinical Statistics (K.M.K.), GlaxoSmithKline, Research Triangle Park, Rho, Chapel Hill (H.M.), and Biostatistics, Parexel International, Durham (B.A.P.) - all in North Carolina; the Department of Pediatrics, Breathing Institute, Pediatric Pulmonary Section, Children's Hospital Colorado and University of Colorado School of Medicine, Aurora (S.J.S., A.H.L.); the Department of Pediatrics, Center Lillebælt, Fredericia and Kolding Hospital, Odense, Denmark (S.P.); and the Department of Allergy and Research and Evaluation, Kaiser Permanente Research, San Diego, CA (R.S.Z.).
authors: Kenneth M
authors: KM
authors: Kral
authors: From Respiratory Clinical Development (D.A.S., A.M.Y., L.A.L., I.H.R., K.S.B., S.Y.K., S.J.P.) and Research and Development, Clinical Platforms and Sciences, Clinical Statistics (K.M.K.), GlaxoSmithKline, Research Triangle Park, Rho, Chapel Hill (H.M.), and Biostatistics, Parexel International, Durham (B.A.P.) - all in North Carolina; the Department of Pediatrics, Breathing Institute, Pediatric Pulmonary Section, Children's Hospital Colorado and University of Colorado School of Medicine, Aurora (S.J.S., A.H.L.); the Department of Pediatrics, Center Lillebælt, Fredericia and Kolding Hospital, Odense, Denmark (S.P.); and the Department of Allergy and Research and Evaluation, Kaiser Permanente Research, San Diego, CA (R.S.Z.).
authors: Ibrahim H
authors: IH
authors: Raphiou
authors: From Respiratory Clinical Development (D.A.S., A.M.Y., L.A.L., I.H.R., K.S.B., S.Y.K., S.J.P.) and Research and Development, Clinical Platforms and Sciences, Clinical Statistics (K.M.K.), GlaxoSmithKline, Research Triangle Park, Rho, Chapel Hill (H.M.), and Biostatistics, Parexel International, Durham (B.A.P.) - all in North Carolina; the Department of Pediatrics, Breathing Institute, Pediatric Pulmonary Section, Children's Hospital Colorado and University of Colorado School of Medicine, Aurora (S.J.S., A.H.L.); the Department of Pediatrics, Center Lillebælt, Fredericia and Kolding Hospital, Odense, Denmark (S.P.); and the Department of Allergy and Research and Evaluation, Kaiser Permanente Research, San Diego, CA (R.S.Z.).
authors: Barbara A
authors: BA
authors: Prillaman
authors: From Respiratory Clinical Development (D.A.S., A.M.Y., L.A.L., I.H.R., K.S.B., S.Y.K., S.J.P.) and Research and Development, Clinical Platforms and Sciences, Clinical Statistics (K.M.K.), GlaxoSmithKline, Research Triangle Park, Rho, Chapel Hill (H.M.), and Biostatistics, Parexel International, Durham (B.A.P.) - all in North Carolina; the Department of Pediatrics, Breathing Institute, Pediatric Pulmonary Section, Children's Hospital Colorado and University of Colorado School of Medicine, Aurora (S.J.S., A.H.L.); the Department of Pediatrics, Center Lillebælt, Fredericia and Kolding Hospital, Odense, Denmark (S.P.); and the Department of Allergy and Research and Evaluation, Kaiser Permanente Research, San Diego, CA (R.S.Z.).
authors: Kathleen S
authors: KS
authors: Buaron
authors: From Respiratory Clinical Development (D.A.S., A.M.Y., L.A.L., I.H.R., K.S.B., S.Y.K., S.J.P.) and Research and Development, Clinical Platforms and Sciences, Clinical Statistics (K.M.K.), GlaxoSmithKline, Research Triangle Park, Rho, Chapel Hill (H.M.), and Biostatistics, Parexel International, Durham (B.A.P.) - all in North Carolina; the Department of Pediatrics, Breathing Institute, Pediatric Pulmonary Section, Children's Hospital Colorado and University of Colorado School of Medicine, Aurora (S.J.S., A.H.L.); the Department of Pediatrics, Center Lillebælt, Fredericia and Kolding Hospital, Odense, Denmark (S.P.); and the Department of Allergy and Research and Evaluation, Kaiser Permanente Research, San Diego, CA (R.S.Z.).
authors: Suyong
authors: S
authors: Yun Kirby
authors: From Respiratory Clinical Development (D.A.S., A.M.Y., L.A.L., I.H.R., K.S.B., S.Y.K., S.J.P.) and Research and Development, Clinical Platforms and Sciences, Clinical Statistics (K.M.K.), GlaxoSmithKline, Research Triangle Park, Rho, Chapel Hill (H.M.), and Biostatistics, Parexel International, Durham (B.A.P.) - all in North Carolina; the Department of Pediatrics, Breathing Institute, Pediatric Pulmonary Section, Children's Hospital Colorado and University of Colorado School of Medicine, Aurora (S.J.S., A.H.L.); the Department of Pediatrics, Center Lillebælt, Fredericia and Kolding Hospital, Odense, Denmark (S.P.); and the Department of Allergy and Research and Evaluation, Kaiser Permanente Research, San Diego, CA (R.S.Z.).
authors: Steven J
authors: SJ
authors: Pascoe
mesh_terms: D000280:Administration, Inhalation; D058665:Adrenergic beta-1 Receptor Agonists / Q000008:administration & dosage / Q000009:adverse effects; D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage / Q000009:adverse effects; D001249:Asthma / Q000188:drug therapy*; D001993:Bronchodilator Agents / Q000008:administration & dosage* / Q000009:adverse effects; D002648:Child; D002675:Child, Preschool; D003692:Delayed-Action Preparations; D004311:Double-Blind Method; D005260:Female; D000068298:Fluticasone / Q000008:administration & dosage* / Q000009:adverse effects; D000068297:Fluticasone-Salmeterol Drug Combination / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D008297:Male; D036501:Metered Dose Inhalers; D016016:Proportional Hazards Models
chemical_list: D058665:Adrenergic beta-1 Receptor Agonists; D058666:Adrenergic beta-2 Receptor Agonists; D001993:Bronchodilator Agents; D003692:Delayed-Action Preparations; D000068297:Fluticasone-Salmeterol Drug Combination; D000068298:Fluticasone