When designing either biomarker-stratified or phenotype-directed protocols for asthma-related clinical trials, including a  contingency plan can help manage scenarios in which phenotypes in the study sample differ in prevalence from expected values, according to a study published in Contemporary Clinical Trials.

Researchers of the National Heart, Lung, and Blood Institute AsthmaNet Consortium conducted the double-blind, placebo-controlled Steroids in Eosinophil Negative Asthma (SIENA; ClinicalTrials.gov Identifier: NCT02066298) trial with participants ≥12 years old who had mild asthma. Sputum inductions were performed in individuals not using inhaled corticosteroids, and participants were categorized 1:1 as either eosinophil high (Eos High) or eosinophil low (Eos Low). A run-in period of 4 to 6 weeks included placebo-long-acting muscarinic antagonist (LAMA), which determined the intensity of asthma control and let sputum inflammatory cells be analyzed. In each group, participants were treated with inhaled tiotropium (LAMA), inhaled medium dose mometasone (ICS), or placebo.

Clinical visits took place every 6 weeks and phone calls every 3 weeks, with the primary objective to investigate whether treatment effects were heterogeneous for treatment failure, asthma control days, and forced expired volume in 1 second. The secondary objective examined whether participants in the Eos Low stratum preferred inhaled corticosteroids or LAMAs.

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Researchers found a roughly 3:1 ratio of Eos Low to Eos High in the sample, which was a concerning imbalance, given the desired 1:1 ratio. Consequently, they chose to use the secondary objective as the new primary objective. However, they were unable to complete this research due to time constraints and complications with recruitment.

“SIENA was designed to challenge the paradigm that ICS are the appropriate first-line treatment for all patients with mild persistent asthma,” the researchers noted. “Recent data demonstrate different patterns of airway inflammation in asthma, and have shown convincingly that eosinophilic T2 inflammation is not ubiquitous.”

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As a result of their study’s outcome, the researchers advised “investigators [to] incorporate pre-specified contingency plans into phenotype-directed or biomarker-stratified protocols in the future, to address the potential for differences in observed versus expected prevalence of different phenotypes in the study population. Such contingencies could include planned interim analyses, and pre-specified approaches to sample size reassessment based on tabulating potential scenarios with varying study design assumptions.”


Sorkness CA, King TS, Dyer A-M, et al. Adapting clinical trial design to maintain meaningful outcomes during a multicenter asthma trial in the precision medicine eraContemp Clin Trials. 2019;77:98-103.