title: Respiratory adverse event profiles in cystic fibrosis placebo subjects in short- and long-term inhaled therapy trials.
abstract: The frequency and nature of adverse events (AEs) are important safety endpoints in clinical trials of therapies for cystic fibrosis (CF) subjects, yet published tables of background AE rates in the CF population are not readily available. Our objective in this study was to produce tables of respiratory AE rates for placebo subjects (pediatric and adult) for inhaled therapy trials in CF subjects. Respiratory AE rates in inhaled therapy trials were computed by combining data on placebo subjects from early-phase dosing studies and middle/late-phase studies, where placebo consisted of 4 or 5 mL of inhaled saline solution. AE rates were computed as number of events divided by number of placebo-subject days of observation, and 95% confidence intervals were computed based on a Poisson model. AEs were categorized as both broad (e.g., respiratory, reactive airway disease) and specific (e.g., cough, chest tightness, hemoptysis). In short-term studies, respiratory AE rates (95% confidence interval) were 1.1(0.7, 1.6)/person-week and 1.0(0.7, 1.4)/person-week in pediatric and adult subjects, respectively. In long-term studies, respiratory AE rates were 1.7(1.6, 1.8)/person-month and 2.2(2.1, 2.3)/person-month in pediatric and adult subjects, respectively. Stepwise Poisson models were fit to determine if baseline covariates were important in predicting AE rates. Forced expiratory volume in one second (FEV(1)) percent of predicted and age in short-term studies, and FEV(1) percent predicted and gender in long-term studies were statistically important in predicting respiratory AE rates. Although these variables were statistically significant, the models' predictive abilities were low, with adjusted R(2)'s of 0.06 and 0.12 in the short- and long-term studies, respectively. Combining placebo-subject AE data recorded from multiple CF clinical trials yields better estimates of true rates of occurrence in the CF population. The tables published from this study can be used to assist those charged with safety monitoring in CF clinical trials.
authors.affiliation: CF Therapeutics Development Network Coordinating Center, Seattle, WA, United States.
authors.forename: Heidi
authors.initials: H
authors.lastname: Sucharew
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Goss
authors.forename: Steven P
authors.initials: SP
authors.lastname: Millard
authors.forename: Bonnie W
authors.initials: BW
authors.lastname: Ramsey
mesh_terms: D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D026661:Clinical Trials Data Monitoring Committees; D003550:Cystic Fibrosis / Q000188:drug therapy*; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D008134:Long-Term Care; D008297:Male; D010919:Placebos / Q000009:adverse effects*; D016032:Randomized Controlled Trials as Topic / Q000009:adverse effects*; D012140:Respiratory Tract Diseases / Q000175:diagnosis / Q000209:etiology*; D012306:Risk; D018401:Sample Size; D014481:United States
chemical_list: D010919:Placebos