Phase III/IV, Randomized, Fifty-Two-Week Study of the Efficacy and Safety of Belimumab in Patients of Black African Ancestry With Systemic Lupus Erythematosus

Abstract

Objective: Enrollment of patients of Black African ancestry with systemic lupus erythematosus (SLE) in phase II and phase III of the belimumab trials was not reflective of the racial distribution observed in the lupus population. This study was undertaken to assess the efficacy and safety of intravenous (IV) belimumab plus standard therapy in patients of self-identified Black race.

Methods: EMBRACE (GSK Study BEL115471; ClinicalTrials.gov identifier: NCT01632241) was a 52-week multicenter, double-blind, placebo-controlled trial in adults of self-identified Black race with active SLE who received monthly belimumab 10 mg/kg IV, or placebo, plus standard therapy. The optional 26-week open-label extension phase included patients who completed the double-blind phase. The primary end point of the study was SLE Responder Index (SRI) response rate at week 52 with modified proteinuria scoring adapted from the SLE Disease Activity Index 2000 (SLEDAI-2K) (SRI-SLEDAI-2K). Key secondary end points included SRI response rate at week 52, time to first severe SLE flare, and reductions in prednisone dose.

Results: The modified intent-to-treat population comprised 448 patients, of whom 96.9% were women and the mean ± SD age was 38.8 ± 11.42 years. The primary end point (improvement in the SRI-SLEDAI-2K response rate at week 52) was not achieved (belimumab 48.7%, placebo 41.6%; odds ratio 1.40 [95% confidence interval 0.93, 2.11], P = 0.1068); however, numerical improvements favoring belimumab were observed, in which the SRI-SLEDAI-2K response rates were higher in those who received belimumab compared with those who received placebo, especially in patients with SLE who had high disease activity or renal manifestations at baseline. The safety profile of belimumab was generally consistent with that observed in previous SLE trials. Adverse events were the primary reasons for double-blind phase withdrawals (belimumab 5.4%, placebo 6.7%).

Conclusion: The primary end point of this study was not achieved, but improvement with belimumab versus placebo was observed, suggesting that belimumab remains a suitable treatment option for SLE management in patients of Black African ancestry.

Figure 1

Study design. SELENA–SLEDAI = Safety of Estrogens in Lupus Erythematosus National Assessment–Systemic Lupus Erythematosus Disease Activity Index; IV = intravenous.

Figure 2

Flow chart of patient disposition. * The modified intent‐to‐treat (mITT) population consisted of all patients who were randomized and received ≥1 dose of the study agent (48 patients were excluded from efficacy analyses due to noncompliance). IV = intravenous; AE = adverse event.

Figure 3

Response rates based on the 3 individual components of the Systemic Lupus Erythematosus (SLE) Responder Index–SLE Disease Activity Index 2000 (SLEDAI‐2K) response, with modified SLEDAI scoring for proteinuria, at week 52 of the double‐blind phase and at week 24 of the open‐label extension (OLE) phase in the modified intent‐to‐treat population. Odds ratios (ORs) with 95% confidence intervals (95% CIs) and P values were derived using a logistic regression model to compare belimumab with placebo, with covariates of treatment group, baseline Safety of Estrogens in Lupus Erythematosus National Assessment–SLEDAI (SELENA–SLEDAI)–SLEDAI‐2K (SS‐S2K) score (≤9 versus ≥10), baseline complement levels (≥1 test finding showing low C3/C4 [less than the lower limit of normal] versus C3/C4 other [the lower limit of normal or above]), and region (US/Canada versus rest of world). The open‐label extension phase used observed data, and the double‐blind phase used nonresponder imputation for withdrawals or treatment failures. The OR was not calculated for the open‐label extension phase, as no formal hypothesis testing was performed. * Open‐label extension baseline (pre‐belimumab) was used for the SELENA–SLEDAI–SLEDAI‐2K analysis, with modified SLEDAI scoring for proteinuria, of the open‐label extension phase. Patients in the continuous belimumab group received belimumab for 18 months, and those in the placebo‐to‐belimumab group received belimumab for 6 months. IV = intravenous; PGA = physician global assessment; BILAG = British Isles Lupus Assessment Group.

Figure 4

Subgroup analysis of SLE Responder Index–SLEDAI‐2K (SS‐S2K) response rates at week 52. * Low C3/C4 is defined as C3/C4 levels less than the lower limit of normal (<90 mg/dl for C3 and <10 mg/dl for C4), and C3/C4 other is defined as levels at the lower limit of normal or above. Anti‐dsDNA = anti–double‐stranded DNA (see Figure 3 for other definitions).