Population repeated time-to-event analysis of exacerbations in asthma patients: A novel approach for predicting asthma exacerbations based on biomarkers, spirometry, and diaries/questionnaires

CPT Pharmacometrics Syst Pharmacol. 2021 Oct;10(10):1221-1235. doi: 10.1002/psp4.12690. Epub 2021 Aug 5.


Identification of covariates, including biomarkers, spirometry, and diaries/questionnaires, that predict asthma exacerbations would allow better clinical predictions, shorter phase II trials and inform decisions on phase III design, and/or initiation (go/no-go). The objective of this work was to characterize asthma-exacerbation hazard as a function of baseline and time-varying covariates. A repeated time-to-event (RTTE) model for exacerbations was developed using data from a 52-week phase IIb trial, including 502 patients with asthma randomized to placebo or 70 mg, 210 mg, or 490 mg astegolimab every 4 weeks. Covariate analysis was performed for 20 baseline covariates using the full random effects modeling approach, followed by time-varying covariate analysis of nine covariates using the stepwise covariate model (SCM) building procedure. Following the SCM, an astegolimab treatment effect was explored. Diary-based symptom score (difference in objective function value [dOFV] of -83.7) and rescue medication use (dOFV = -33.5), and forced expiratory volume in 1 s (dOFV = -14.9) were identified as significant time-varying covariates. Of note, time-varying covariates become more useful with more frequent measurements, which should favor the daily diary scores over others. The most influential baseline covariates were exacerbation history and diary-based symptom score (i.e., symptom score was important as both time-varying and baseline covariate). A (nonsignificant) astegolimab treatment effect was included in the final model because the limited data set did not allow concluding the remaining effect size as irrelevant. Without time-varying covariates, the treatment effect was statistically significant (p < 0.01). This work demonstrated the utility of a population RTTE approach to characterize exacerbation hazard in patients with severe asthma.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anti-Inflammatory Agents / therapeutic use*
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Asthma / drug therapy*
  • Asthma / physiopathology
  • Biomarkers
  • Disease Progression
  • Double-Blind Method
  • Female
  • Humans
  • Male
  • Middle Aged
  • Progression-Free Survival
  • Proportional Hazards Models
  • Severity of Illness Index
  • Spirometry
  • Surveys and Questionnaires
  • Time Factors


  • Anti-Inflammatory Agents
  • Antibodies, Monoclonal, Humanized
  • Biomarkers
  • astegolimab