Background The choice of composite clinical assessment tools in lupus clinical trials is expanding, but it is important to understand the differences between what these endpoints measure. The SLE Responder Index (SRI) was developed for the successful Phase III belimumab (BLISS) program which defines response as ≥ 4 (SRI-4) or 5 (SRI-5) point decrease in SLEDAI, no new BILAG A (severe disease) or 2 new B (moderate disease) organ scores plus increase in PGA of < 0.3 points (10% of scale). The best treatment corrected difference achieved with SRI-4 were 9.8% (1), and 14.4% (2) in the two phase III BLISS trials. The BICLA was tested in a Phase II study of epratuzumab (EMBLEM) with response defined by at least one grade improvement in all BILAG moderate or severe scores, no new BILAG A or 2 new B scores, no increase in SLEDAI, <10% worsening in PGA and no off-protocol treatment. Optimal treatment corrected differences in this trial was 24.8% (3). A comparison of BICLA and SRI has been reported using EMBLEM data (4), but was complicated by scoring of many 8 point features on SLEDAI which are not common in lupus. BICLA data from the BLISS studies have not been reported.
Objectives To compare the SRI and BICLA to a physician-weighted definition of improvement in the BOLD study
Methods The BOLD study was designed to test the impact of clinical, biologic and background treatment variables on lupus trials and scoring of 8 point SLEDAI features were rare. 41 patients entered with active disease (minimum SLEDAI of 6 or two BILAG B scores) in a single study center, then background immune suppressives were withdrawn, brief intramuscular steroids given until improvement, and patients followed until they flared. BOLD improvement was defined as either a 4 point drop in SLEDAI or one grade improvement in BILAG and required physician determination of clinically significant improvement. This allowed for simpler quantitative criteria, anchored by clinician judgment.
Results At the improving visit, the mean decrease from baseline in PGA was 1.06 ± 0.38 (scale 0-3). Count of responders by SRI and BICLA are shown in the table below with McNemar’s test p-value for comparisons to the BOLD (physician-weighted) definition of improvement.
Conclusions The BICLA was more likely to agree with a physician weighted definition of improvement than SRI, and less likely to score a physician designated flare visit as improvement. Differences in treatment efficacy, clinical trial design, and adjudication of trial endpoints may have accounted for the improved discrimination seen between treatment groups in the EMBLEM study (using BICLA) compared to the BLISS studies (using SRI). However, if further validated, these observations from BOLD may be helpful in optimizing the choice of clinical endpoints for future lupus trials.
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Disclosure of Interest: None Declared
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