Adapting clinical trial design to maintain meaningful outcomes during a multicenter asthma trial in the precision medicine era

On behalf of the National Heart Lung and Blood Institute's “AsthmaNet”

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Precision medicine is expected to impact the care of people with asthma, given its high disease prevalence, heterogeneity of pathophysiologic mechanisms, and consequent clinical phenotypes. A novel phenotype-stratified clinical trial conducted by the NHLBI AsthmaNet Consortium, titled Steroids in Eosinophil Negative Asthma (SIENA), was a randomized, multicenter, clinical trial that prospectively stratified individuals according to their baseline level of sputum inflammation during a screening period. Two phenotypic strata were assigned based on an a priori defined extent of sputum eosinophilia (Eos Low versus Eos High). This article describes: the scientific premise for the trial design, including assumptions used for power calculations; modifications to the analysis plan implemented after the trial started due to a higher than expected prevalence of one phenotypic stratum which impacted the ability to accrue sufficient subjects within the planned budget and study period; investigator alternatives to address the strata imbalance weighing scientific impact and study feasibility; and the final modified SIENA study design and analysis plan. SIENA was successfully completed in a manner that maintained meaningful outcomes. We conclude with recommendations for incorporation of pre-specified contingency plans into phenotype-directed protocols, to address the potential for differences in observed compared to estimated prevalence of different phenotypes in a study population. These approaches can be applied to precision medicine trials for the future.

Original languageEnglish (US)
Pages (from-to)98-103
Number of pages6
JournalContemporary Clinical Trials
StatePublished - Feb 2019


  • Biomarker-stratified
  • Induced sputum eosinophilia
  • Multicenter clinical trial
  • Participant recruitment
  • Phenotype-stratified
  • Precision medicine
  • Study design

ASJC Scopus subject areas

  • Pharmacology (medical)


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