Surrogate endpoint for severe asthma exacerbations could facilitate drug trials
medwireNews: Researchers have devised a composite, surrogate endpoint – CompEx – that strongly mirrors severe asthma exacerbation response to treatment, but can be measured earlier in the trial process and in smaller patient samples.
They found that CompEx increased event frequencies, preserved treatment effect, and reduced the required number of patients and trial duration compared with severe exacerbations.
This could “facilitate accelerated drug development, reduce costs, and bring novel drugs faster to patients with asthma,” say Malin Fageräs (AstraZeneca, Global Product and Portfolio Strategy, Gothenburg, Sweden) and colleagues.
J Mark FitzGerald and Mohsen Sadatsafavi, both from the University of British Columbia in Vancouver, Canada, say in a related comment that the findings are particularly welcome in “an era of funding shortages, in which bringing new therapies to the patient is challenging (especially for severe asthma).”
The CompEx endpoint is defined as a first occurrence of a diary event or a severe exacerbation. To determine the diary events, the researchers assessed a series of combinations of diary variables in a post-hoc analysis of five randomized trials involving around 10,000 patients to find the best composite for an increased number of events not offset by a reduction in the treatment effect. Those variables giving the best balance were morning and evening measurements of peak expiratory flow, reliever use, and symptoms.
Deterioration criteria for these variables were a predefined change – 15% from baseline for peak expiratory flow, 1.5 times increase from baseline for reliever use, and a 1-point score increase from baseline or absolute maximum score for symptoms – in one variable on 2 consecutive days or in all six variables over 5 days.
When censored at 3 months, CompEx resulted in 2.8 times more events than severe exacerbations across the trials, while preserving the treatment effect. The hazard ratio of CompEx over severe exacerbations was closely matched at an average 1.01, confirming that a treatment effect on CompEx is predictive of an effect on severe exacerbations.
This increase in events resulted in a large net gain in power of more than 50% for almost all combinations of CompEx events, with 67% the largest average net gain seen. This would substantially reduce the number of patients to 200 or fewer, equating to a roughly 50% reduction in sample size for six out of the seven comparisons tested, Fageräs and colleagues point out.
The researchers then tested CompEx in an independent cohort of about 7000 patients from seven additional trials with different designs and comparisons and found similar results.
The 12 trials in total compared different treatments, including inhaled corticosteroids, leukotriene receptor antagonists, and biologics, and a broad spectrum of asthma disease severity, they note in The Lancet Respiratory Medicine.
CompEx was validated in independent subpopulations, remaining robustly associated with severe exacerbations when examined across different patient strata based on age, forced expiratory volume exhaled in 1 second, reversibility, reliever use, asthma symptoms, and peak expiratory flow variability. The only exception was for the lowest quartile of patients for reversibility, reliever use, and asthma symptoms.
The team found that trials in which twice-daily recordings were collected were more likely to yield the 50% gain in number of patients than trials using once-daily recordings.
There was also evidence to support the feasibility of smaller phase II trials, with CompEx events occurring at a higher frequency during 3 months than severe exacerbations over 12 months, while still mirroring the treatment effects. This would improve the time- and cost-efficiency of trials, as well as lessening safety risk among patients on a new drug that is shown to be ineffective, say the researchers.
“CompEx has the potential to be [an] unprecedented, surrogate drug development tool for severe exacerbations in asthma clinical trials,” the researchers believe.
They now call for prospective assessment and validation in order for it to meet the acceptance of regulatory agencies.
The commentators add that while the main use of CompEx is to improve trial design it could also be useful in a 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),” say FitzGerald and Sadatsafavi.
By Lucy Piper
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