title: Efficacy and safety of ipratropium bromide/albuterol compared with albuterol in patients with moderate-to-severe asthma: a randomized controlled trial.
abstract: BACKGROUND
  Many patients with asthma require frequent rescue medication for acute symptoms despite appropriate controller therapies. Thus, determining the most effective relief regimen is important in the management of more severe asthma. This study's objective was to evaluate whether ipratropium bromide/albuterol metered-dose inhaler (CVT-MDI) provides more effective acute relief of bronchospasm in moderate-to-severe asthma than albuterol hydrofluoroalkaline (ALB-HFA) alone after 4 weeks.
  
  
  METHODS
  In this double-blind, crossover study, patients who had been diagnosed with asthma for ≥1 year were randomized to two sequences of study medication "as needed" for symptom relief (1-7 day washout before second 4-week treatment period): CVT-MDI/ALB-HFA or ALB-HFA/CVT-MDI. On days 1 and 29 of each sequence, 6-hour serial spirometry was performed after administration of the study drug. Co-primary endpoints were FEV1 area under the curve (AUC0-6) and peak (post-dose) forced expiratory volume in 1 s (FEV1) response (change from test day baseline) after 4 weeks. The effects of "as needed" treatment with ALB-HFA/CVT-MDI were analyzed using mixed effect model repeated measures (MMRM).
  
  
  RESULTS
  A total of 226 patients, ≥18 years old, with inadequately controlled, moderate-to-severe asthma were randomized. The study met both co-primary endpoints demonstrating a statistically significant treatment benefit of CVT-MDI versus ALB-HFA. FEV1 AUC0-6h response was 167 ml for ALB-HFA, 252 ml for CVT-MDI (p <0.0001); peak FEV1 response was 357 ml for ALB-HFA, 434 ml for CVT-MDI (p <0.0001). Adverse events were comparable across groups.
  
  
  CONCLUSIONS
  CVT-MDI significantly improved acute bronchodilation over ALB-HFA alone after 4 weeks of "as-needed" use for symptom relief, with a similar safety profile. This suggests additive bronchodilator effects of β2-agonist and anticholinergic treatment in moderate-to-severe, symptomatic asthma.
  
  
  BACKGROUND
  ClinicalTrials.gov No.: NCT00818454 ; Registered November 16, 2009.
authors.affiliation: Division of Pulmonary Diseases & Critical Care Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: James F
authors.initials: JF
authors.lastname: Donohue
authors.affiliation: Pulmonary and Critical Care Division, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Wise
authors.affiliation: Department of Medicine, University of Wisconsin, Wisconsin, WI, USA.
authors.forename: William W
authors.initials: WW
authors.lastname: Busse
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Garfinkel
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA.
authors.forename: Valentina B
authors.initials: VB
authors.lastname: Zubek
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA.|Previously of Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA.
authors.forename: Mo
authors.initials: M
authors.lastname: Ghafouri
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA.
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Manuel
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA.
authors.forename: Rozsa
authors.initials: R
authors.lastname: Schlenker-Herceg
authors.affiliation: Wake Forest School of Medicine, Center for Genomics and Personalized Medicine, Winston-Salem, NC, 27157, USA. ebleeck@wakehealth.edu.
authors.forename: Eugene R
authors.initials: ER
authors.lastname: Bleecker
mesh_terms: D000280:Administration, Inhalation; D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage; D000420:Albuterol / Q000008:administration & dosage*; D001249:Asthma / Q000188:drug therapy* / Q000503:physiopathology; D001993:Bronchodilator Agents / Q000008:administration & dosage; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D009241:Ipratropium / Q000008:administration & dosage*; D008297:Male; D036501:Metered Dose Inhalers; D008875:Middle Aged; D012189:Retrospective Studies; D013147:Spirometry; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D001993:Bronchodilator Agents; D009241:Ipratropium; D000420:Albuterol
keywords: Acute symptom relief; Albuterol hydrofluoroalkaline; Anticholinergic/β2-agonist; As-needed; Bronchodilation; Ipratropium bromide; Ipratropium bromide/albuterol metered-dose inhaler; Moderate-to-severe asthma; Randomized controlled trial