title: Impact of acute antibiotic therapy on the pulmonary exacerbation endpoint in cystic fibrosis clinical trials.
abstract: BACKGROUND
  In a chronic disease setting such as cystic fibrosis (CF), antibiotics are often prescribed for emergent symptoms and it is unclear whether this affects endpoints in a clinical trial. Pulmonary exacerbations (PEs) are defined episodes of acute worsening and a key clinical efficacy measure in CF. Our hypothesis was that acute antibiotics given for illnesses not meeting the PE definition may alter estimates of treatment effect that do not account for this antibiotic use.
  
  
  METHODS
  A randomized, placebo-controlled trial of azithromycin (AZ) including 260 participants with CF was utilized for this study. PEs were defined using a priori criteria. Physician initiated antibiotic therapy (PIT) not meeting the PE endpoint was characterized and its impact on treatment effect assessed.
  
  
  RESULTS
  40% (104/260) of participants were prescribed 188 courses of PIT in the absence of a PE; 19% (25/129) of placebo and 10% (13/131) of AZ participants received ≥2 courses of PIT and never fulfilled the PE definition (9% difference, 95% confidence interval: 1%, 18%, p = 0.04). Accounting for PIT through use of a composite endpoint including time to PE or need for repeated PIT altered treatment effect estimates (a 56% reduction in the event rate comparing AZ to placebo [p < 0.0001] as compared to a 50% reduction not accounting for PIT [p = 0.003]).
  
  
  CONCLUSIONS
  PIT is common in CF and may impact treatment effect estimates. Optimization of the PE endpoint to include meaningful events necessitating treatment may improve our ability to conduct efficient trials by reducing the sample size 30-50%, ultimately enabling rapid evaluation of new therapies.
authors.affiliation: Department of Pediatrics and Biostatistics, University of Washington, Seattle, WA, USA. nicole.hamblett@seattlechildrens.org
authors.forename: Nicole
authors.initials: N
authors.lastname: Mayer-Hamblett
authors.forename: Lisa
authors.initials: L
authors.lastname: Saiman
authors.forename: Larry C
authors.initials: LC
authors.lastname: Lands
authors.forename: Michael
authors.initials: M
authors.lastname: Anstead
authors.forename: Margaret
authors.initials: M
authors.lastname: Rosenfeld
authors.forename: Margaret
authors.initials: M
authors.lastname: Kloster
authors.forename: Leigh
authors.initials: L
authors.lastname: Fisher
authors.forename: Felix
authors.initials: F
authors.lastname: Ratjen
mesh_terms: D000293:Adolescent; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D017963:Azithromycin / Q000008:administration & dosage* / Q000627:therapeutic use; D002648:Child; D002985:Clinical Protocols; D003550:Cystic Fibrosis / Q000150:complications*; D005260:Female; D006801:Humans; D008171:Lung Diseases / Q000188:drug therapy* / Q000209:etiology*; D008297:Male; D012107:Research Design; D018401:Sample Size
chemical_list: D000900:Anti-Bacterial Agents; D017963:Azithromycin
keywords: AZ; Antibiotic therapy; CF; CI; Cystic fibrosis; HR; IV; PE; PRO; Pulmonary exacerbation definitions; Sample size; Study design; azithromycin; confidence interval; cystic fibrosis; hazard ratio; intravenous; p; p-value; patient reported outcomes; pulmonary exacerbation