The evaluation of disease activity in systemic lupus erythematosus (SLE) clinical trials is challenging due to the multi-organ presentation of SLE, interindividual variability, unpredictability of disease course, medication effects, and interobserver rating differences. While composite endpoints have been widely adopted to study other diseases, single disease activity indices (DAIs) have been the norm in SLE. The purpose of this study was to develop a composite responder index for use in SLE clinical trials.
An expert panel was consulted to review the characteristics of DAIs commonly used in SLE trials. These included the British Isles Lupus Assessment Group index (BILAG-2004), the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), and the Physician's Global Assessment (PGA). Characteristics considered included basis of scoring and the number and types of items assessed. Following this review, the BILAG-based Composite Lupus Assessment (BICLA) was developed as a composite of multiple DAIs based on early epratuzumab clinical trial data. The BICLA requires patients to meet response criteria across three assessment tools.
BICLA responders must achieve BILAG disease activity improvement with no worsening in BILAG or other DAIs and no treatment failure at any time point (Table). The BICLA was used to evaluate response in the EMBLEMTM phase II study (SL0007), a 12-week, randomized, double-blind, placebo-controlled study that recruited 227 patients with moderate to severe SLE. BICLA was sensitive to epratuzumab treatment response (epratuzumab 600 mg QW 45.9% response at 12 weeks; epratuzumab 1200 mg EOW 40.5%; epratuzumab 2400 mg cumulative dose 43.2%) with a limited placebo response rate (21%; p = 0.02 vs 2400 mg at 12 weeks). The use of BILAG as the primary component of the BICLA requires simultaneous improvement across all body systems with severe or moderate disease activity at baseline. BILAG gives balanced weight to all affected body systems and can reflect incremental improvements within a body system. The BICLA is also the 48-week primary efficacy variable in the EMBODYTM phase III studies (SL0009 [NCT01262365] and SL0010 [NCT01261793]) of epratuzumab in patients with moderate to severe SLE.
The BICLA is a sensitive, clinically meaningful composite measure of SLE disease activity that requires disease improvement across all body systems with moderate or severe baseline activity without worsening or change in background medication, and which has discriminated between placebo and treatment responses in a phase II clinical trial. The three DAIs included in the BICLA require clinical assessment, physician assessment, laboratory assessment, and recording of medication use. Further analysis of data from studies using the BICLA composite endpoint may help to guide the design of future trials in SLE.
Disclosure: D. Wallace, UCB, 5 ; V. Strand, UCB, 5 ; R. Furie, UCB, 5 ; M. Petri, UCB, 5 ; K. Kalunian, UCB, 5 ; M. Pike, UCB, 5 ; L. Kelley, UCB, 3 ; C. Gordon, UCB, 5 .