Surrogate for Asthma Exacerbation Helps Treatment Development

The marker could serve in treatment trials in lieu of participants prone to exacerbation and the accompanying morbidity and risk of death.

A new surrogate marker for asthma exacerbation reduces the number of clinical trial participants required to test treatment efficacy for exacerbation and could have a role in predicting and preventing exacerbation of severe asthma in clinical practice.

Malin Fagerås (pictured), PhD, a senior medical affairs leader at AstraZeneca and colleagues indicated that CompEx, a composite measure derived from diary events associated with deterioration preceding exacerbation, should facilitate the design of clinical trials of shorter duration and with fewer patients than traditional trials assessing treatments for severe exacerbation.

In an accompanying commentary, J Mark FitzGerald, MD, and Mohsen Sadatsafavi, MD, PhD, of the Respiratory Evaluation Service Program at the Institute for Heart and Lung Health at the University of British Columbia, in Vancouver, Canada welcomed the development of the CompEx as not only a robust, surrogate measure for severe exacerbation that can “improve the efficiency of trial design and reduce costs in phase 2 and 3 trials,” but which also has promise in the clinical setting.

"If temporal clustering between diary symptoms and exacerbations can be shown, CompEx could also be used as a predictor of an imminent severe exacerbation, giving the patient and care provider time to react to reduce the intensity of an imminent exacerbation (or potentially averting it altogether)," they wrote.

The CompEx measure was based on data from 12 trials with different asthma products from 2 pharmaceutical manufacturers, conducted over periods of 6 or 12 months. The final CompEx measure was based on 7 diary card variables including peak expiratory flow, reliever use, symptoms assessed in the morning and evening, and night-time awakenings.

FitzGerald and Sadatsafavi praised the use of multiple data sets from the trials with inhaled corticosteroids, leukotriene receptor antagonists, and biologics, in approximately 10000 subjects in developing CompEx, and for the application of data from an additional 7000 subjects in its validation. They remarked that "Derivation and validation of such a scoring system in datasets from different vendors and different treatments adds to the credibility and generalizability of the results", they remarked.

Fagerås and colleagues tested CompEx against the occurrences of exacerbation across trials, finding it revealed approximately 3 times the number of events, and that these were closely matched to the severe exacerbations in the responses to the study treatment, with similar treatment effect hazard ratios (HR). The increased statistical power afforded by CompEx identifying a higher number of events with similar treatment effect was estimated to allow a 50% to 67% mean reduction in the number of patients in trials for severe exacerbation.

"CompEx allows [the] design of shorter trials with fewer patients than studies of severe exacerbations while preserving the ability to show a treatment effect compared with severe exacerbation," Fagerås and colleagues concluded.

FitzGerald and Sadatsafavi concurred but also pointed out that additional external validation will be necessary. “We strongly propose that CompEx be used in parallel with a dedicated analysis of exacerbation risk. Appropriate statistical tests can test whether the treatment effect on CompEx is different to the effect on exacerbations.”

The report on the development of CompEx as a surrogate for asthma exacerbations in treatment trials was published in the July issue of The Lancet Respiratory Medicine.

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