In patients with moderate to severe systemic lupus erythematosus (SLE), the Lupus Low Disease Activity State (LLDAS) was able to discriminate between active treatment with belimumab and placebo, supporting the validity of its use as an outcome measure in clinical trials, according to study findings published in the Annals of the Rheumatic Diseases.
The LLDAS is well known to accurately predict clinical responses to treatment and has shown promise in discriminating responders during early trial stages. Investigators sought to determine whether this discriminatory ability would be observed retrospectively in two phase 3 studies of belimumab in patients with SLE.
A post-hoc analysis of results from the multicenter BLISS-52 and BLISS-76 SLE trials (ClincalTrials.gov identifiers: NCT00424476 and NCT00410384, respectively) examined attainment of LLDAS and its ability to accurately discriminate between treatment and placebo groups. In both trials, seropositive patients with SLE were enrolled and randomly assigned to receive either intravenous belimumab 1 mg/kg (low dose), belimumab 10 mg/kg (high dose), or placebo, with the Systemic Lupus Erythematosus Responder Index-4 (SRI-4) score serving as the primary outcome.
In this analysis, LLDAS, defined as SLE Disease Activity Index 2000 ≤4, physician global assessment of activity ≤1 and no new disease or major organ activity was the primary end point, as this is considered a more stringent measure than SRI-4.
After 52 weeks, in the BLISS-52 and BLISS-76 studies 17.0% and 19.3% of participants in the belimumab 10 mg/kg groups, respectively, who reached SRI-4 also achieved LLDAS. Compared with placebo, a significantly greater number of individuals from the high-dose group attained LLDAS in both BLISS-52 (12.5% vs 5.8%; odds ratio [OR], 2.32; 95% CI, 1.20-4.71; P =.02) and BLISS-76 (14.4% vs 7.8%; OR 1.98; 95% CI 1.04-3.91; P =.04). The low-dose group in the BLISS-52 trial also demonstrated borderline significance in the percentage of participants (10.9%) reaching LLDAS compared with placebo (OR, 2.00; 95% CI, 1.02-4.11; P =.05). The treatment groups of both studies had lower attainment of LLDAS compared with SRI-4.
This analysis was the first to demonstrate LLDAS discrimination of belimumab in phase 3 SLE trials. Subgroup analyses further revealed that the differences between the high-dose and placebo groups in terms of LLDAS attainment were larger in patients with higher baseline disease activity.
Study strengths included prospective data collection and strict application of the LLDAS definition. Study limitations included a post-hoc approach.
“This study lends weight to the potential utility of LLDAS as a novel clinical trial outcome measure for SLE [randomized] controlled trials,” concluded the investigators.
Oon S, Huq M, Golder V, Ong PX, Morand EF, Nikpour M. Lupus Low Disease Activity State (LLDAS) discriminates responders in the BLISS-52 and BLISS-76 phase III trials of belimumab in systemic lupus erythematosus [published online January 24, 2019]. Ann Rheum Dis. doi:10.1136/annrheumdis-2018-214427