Table 2:
Summary of results of efficacy outcomes showing GRADE criteria for certainty of evidence
| Individuals with eosinophil count ≥300 cells per microliter |
| Exacerbation rate ratio | ⊺DUPILUMAB | BENRALIZUMAB | MEPOLIZUMAB |
|---|---|---|---|
| DUPILUMAB | 1.00 | ||
| BENRALIZUMAB | ***1.52 (1.06, 2.13) | 1.00 | |
| MEPOLIZUMAB | **1.10 (0.74, 1.70) | ***0.75 (0.60, 0.95) | 1.00 |
| Mean difference in FEV1 in milliliters | |||
| DUPILUMAB | 1.00 | ||
| BENRALIZUMAB | **−76 (−160, 9.9) | 1.00 | |
| MEPOLIZUMAB | *−85 (−190, 19) | *−8.5 (−100, 83) | 1.00 |
| Mean difference in ACQ | |||
| DUPILUMAB | 1.00 | ||
| BENRALIZUMAB | **0.16 (−0.2, 0.53) | 1.00 | |
| MEPOLIZUMAB | *−0.14 (−0.53, 0.24) | *−0.31 (−0.52, 0.10) | 1.00 |
| Individuals with eosinophil count 150–299 cells per microliter |
| Exacerbation rate ratio | DUPILUMAB | BENRALIZUMAB | MEPOLIZUMAB |
|---|---|---|---|
| DUPILUMAB | 1.00 | ||
| BENRALIZUMAB | ***1.03 (0.63, 1.69) | 1.00 | |
| MEPOLIZUMAB | **1.20 (0.61, 2.20) | ***1.10 (0.70, 1.80) | 1.00 |
| Mean difference in FEV1 | |||
| DUPILUMAB | 1.00 | ||
| BENRALIZUMAB | **27 (−97, 150) | 1.00 | |
| MEPOLIZUMAB | *28 (−180, 120) | *−1.3 (−130, 130) | 1.00 |
High certainty:
moderate:
low:
very low:
ACQ, Asthma Control Questionnaire; FEV1, Forced Expiratory Volume in 1 second
The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to rating the quality of evidence used. This incorporates the risk of bias, inconsistency and heterogeneity of estimates, indirectness or intransitivity, imprecision of estimates, and publication bias.
The monoclonal antibody in the column is the reference category
Evidence supporting the GRADE criteria for certainty evidence
Starting point: All comparisons were rated as “high” at the start given the inclusion of only randomized placebo-controlled trials.
Downgrading:
Risk of bias: Most of the included studies had an overall assessment of ‘low’ risk of bias. Studies with ‘some’ risk of bias were mostly due to ‘missing outcome data’ which we defined as ≥10% dropout rate or due to the ‘selection of results. (eTable 3)
Studies for which selection of results was a concern were downgraded by 1. Thus,
Mepolizumab comparisons (MUSCA) of exacerbation rates were downgraded
Mepolizumab comparisons (MENSA) of ACQ were downgraded
Missing outcome data was not considered a reason for downgrade due to the relatively balanced dropout rate between study arms
Inconsistency/intransitivity/heterogeneity of estimates: All comparisons were downgraded by 1 due to potential bias introduced by indirect comparison using aggregate data and the varying distributions of effect modifiers.
Comparisons to mepolizumab for FEV1 and ACQ were downgraded by an additional point (i.e., 2 in total for this domain) due to the larger differences in placebo effect compared to the benralizumab and dupilumab trials.
Imprecision of estimates: comparisons were downgraded for small effect estimates and wide confidence intervals. We also incorporated whether differences in the continuous outcomes met a presumed minimal clinical important difference (100 mls for FEV1 and 0.5 for ACQ).
All FEV1 comparisons and ACQ were downgraded by a point given the wide confidence intervals and the relatively small effect sizes
Publication bias: no significant evidence supporting publication bias was found based on publication of clinical trial protocols, spread of results, and funnel plots.