Mirror, mirror on the wall: is CompEx the fairest endpoint of all?

Extract

Preventing exacerbations is a key goal in asthma management [1]. Over the decades, novel asthma biologics have been approved to reduce the risk of exacerbation in patients with severe or uncontrolled asthma [1, 2]. Clinical trials have traditionally relied on severe exacerbation (SevEx) as the primary endpoint [3]. SevEx is typically defined as events that require systemic corticosteroids, asthma-related hospitalisations, or emergency department visits due to asthma requiring systemic corticosteroids [1, 3]. However, using SevEx as the sole endpoint may overlook subtler but impactful worsening events that patients experience daily [3]. Therefore, extending beyond SevEx as a single endpoint is important to facilitate the development of new therapies.

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CompEx is a validated endpoint in asthma trials, incorporating both severe exacerbation and acute worsening events https://bit.ly/4hHgeue

Preventing exacerbations is a key goal in asthma management [1]. Over the decades, novel asthma biologics have been approved to reduce the risk of exacerbation in patients with severe or uncontrolled asthma [1, 2]. Clinical trials have traditionally relied on severe exacerbation (SevEx) as the primary endpoint [3]. SevEx is typically defined as events that require systemic corticosteroids, asthma-related hospitalisations, or emergency department visits due to asthma requiring systemic corticosteroids [1, 3]. However, using SevEx as the sole endpoint may overlook subtler but impactful worsening events that patients experience daily [3]. Therefore, extending beyond SevEx as a single endpoint is important to facilitate the development of new therapies.

One such alternative is CompEx, a composite endpoint that incorporates both SevEx and acute worsening events (AWEs) [3, 4]. AWEs are diary-based events recorded from changes in peak expiratory flow (PEF), reliever use, and symptoms [3, 4]. By including these diary events, CompEx is expected to capture meaningful asthma worsening and better reflect the complete burden of asthma instability. Existing evidence demonstrates CompEx as a sensitive and clinically relevant tool for asthma trials [3]. Furthermore, CompEx has been validated in a prior post-hoc analysis of the SIROCCO and CALIMA trial data, which found that benralizumab reduced CompEx rates similarly to SevEx and AWE in patients with severe, uncontrolled, eosinophilic asthma [4].

In this issue of ERJ Open Research, Bolton et al. [5] revisit and further investigate the application of CompEx as a measure of exacerbation events. Building on previous achievements [3, 4], their present post-hoc analysis pooled data from the SIROCCO and CALIMA phase 3 trials, including patients aged ≥12 years with severe, uncontrolled eosinophilic asthma (baseline eosinophils ≥300 cells per µL) randomised to receive benralizumab or placebo. CompEx events were classified into three subtypes: SevEx only (40%), AWE only (21%) and mixed SevEx/AWE (39%). The association between CompEx subtypes and disease trajectories was assessed, as well as the treatment effects of benralizumab on these outcomes. Importantly, the authors evaluated not only lung function parameters (PEF and forced expiratory volume in 1 s) but also patient-reported outcomes such as the disease-specific instrument, Asthma Quality of Life Questionnaire, and symptom control using the Asthma Control Questionnaire, thus providing a multidimensional view of asthma control.

Greater declines in PEF, increased symptoms, and higher reliever use were found for AWE-only or SevEx/AWE mixed events compared to SevEx-only events. Recovery profiles further demonstrated that after 14 days, 89% of patients recovered to baseline PEF following SevEx, versus 79% for AWE and 74% for mixed events. Based on these differences, the authors proposed that AWE contributes meaningfully to exacerbation burden and highlighted the underestimated role of AWE in asthma trials [5]. Therefore, examining AWEs in addition to SevEx could better depict the full spectrum of exacerbations.

Another key finding in this study is that benralizumab's effects were subtype-specific. Benralizumab reduced the risk of exacerbations in those experiencing SevEx only and mixed SevEx/AWE, consistent with its eosinophil-depleting mechanism [2]. However, benralizumab showed no significant benefit for patients with AWE only. This suggests, as the authors explained, that AWEs may involve non-eosinophilic triggers such as respiratory infections, allergen exposure, or behavioural factors such as patients delaying seeking healthcare at the start of an acute exacerbation [5].

A notable feature of this study is that it extends the prior work by Bolton et al. [4] on benralizumab and CompEx [4]. The present analysis evaluates treatment effects using lung function and patient-reported outcomes, whereas the previous work focused on comparing event rates among CompEx subtypes. Taken together, the innovation from Bolton and co-workers represents a significant paradigm shift. But do their findings close the chapter on identifying severe exacerbations in asthma trials?

To put their conclusions in perspective, it is important to consider how exacerbation events are classified and compared. Differences in trajectories across CompEx subtypes may be partly expected, since PEF, symptoms, and reliever use are components of the AWE definition. Thus, greater deterioration in these measures in the AWE-only and mixed groups compared to the SevEx-only group are not entirely surprising. Integrating CompEx with biomarkers may further enhance its value. Additionally, this study lacks randomisation by CompEx subtype. Combining data from both placebo and benralizumab arms can introduce confounders such as differences in treatment, blood eosinophil levels, or fractional exhaled nitric oxide [1, 2]. The authors addressed this by conducting additional analyses stratified by treatment arm, which yielded consistent findings [5].

Incorporating CompEx in future trials has the potential to detect more exacerbation events and thereby increase statistical power. However, these gains come with challenges. Patient diary compliance may not always be perfect, and missing or backfilled entries can bias AWE rates. Nevertheless, Bolton et al. [5] reported that diary compliance exceeded 90% in both trials analysed, suggesting that the data were reliable. Ensuring high-quality diary data will be essential if CompEx is adopted as a future endpoint. Looking ahead, CompEx could also be applied in comparative effectiveness studies of asthma biologics using real-world data, providing head-to-head comparisons to guide personalised treatment selection [6].

In summary, asthma exacerbations can be measured by multiple approaches. To fully capture patients' exacerbation experience, it is crucial to adopt sensitive and objective outcome measures. From our perspective, CompEx stands as a clinically meaningful, patient-centred endpoint that is sensitive to a broad spectrum of relevant events in asthma trials. As precision medicine advances in the era of biological agents, embracing CompEx could transform how we evaluate emerging asthma therapies.