EMBRACE: One Small Story in Lupus-One Giant Challenge in Clinical Trials.

Clinical trials of novel therapeutics in the United States have not been adequately representative of diverse populations, particularly racial and ethnic minorities. The challenges and consequences of underrepresentation in clinical trial recruitment are exemplified by the case of belimumab, a biologic treatment for systemic lupus erythematosus (SLE), a disease that is more prevalent in patients of Black African ancestry and of Hispanic/Latino ethnicity than in other patient populations. Although belimumab was found to be effective in phase 2 and 3 clinical trials in the general population, post hoc analyses of efficacy data in patients of Black African ancestry showed inconsistent results. Consequently, a cautionary statement regarding belimumab use in this population was added to the product label. To alleviate concerns that belimumab may not be safe and effective for patients of Black African ancestry, the Efficacy and Safety of Belimumab in Black Race Patients with SLE (EMBRACE) study was conducted in a post-marketing commitment to the Food and Drug Administration. The study recruited only patients who self-identified as being of Black race; its findings led to the removal of the cautionary labeling of belimumab use in patients of Black African ancestry. Our manuscript highlights the critical lessons learned from the successes and failures of the EMBRACE study. It also provides suggestions for overcoming health disparities, highlighting strategies for conducting well-designed clinical trials to overcome systematic barriers to diversity in recruitment, with a focus on enacting long-term support to ensure equity in the process, products, and benefits from drug development and clinical trials.

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.

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.

Clinical response beyond the Systemic Lupus Erythematosus Responder Index: post-hoc analysis of the BLISS-SC study.

OBJECTIVE: The Systemic Lupus Erythematosus (SLE) Responder Index (SRI), developed as a primary outcome measure for use in clinical trials, captures improvement in SLE disease activity without concomitant worsening in disease manifestations. This study investigated the relationships between the SRI and clinical/laboratory correlates of SRI response in patients with SLE. METHODS: This was a post-hoc analysis of the phase III, double-blind, placebo-controlled study of subcutaneous BeLimumab in Subjects with Systemic lupus erythematosus - SubCutaneous (BLISS-SC). Patients were randomised to weekly belimumab 200 mg subcutaneously or placebo, plus standard SLE therapy. Changes from baseline to week 52 in clinical and laboratory parameters were compared among SRI responders and non-responders, irrespective of the treatment received. RESULTS: SRI responders (n=475) had significantly better (p<0.0001) outcomes compared with non-responders (n=358), including (by definition) higher proportions achieving ≥4-point improvement in Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (100.0% vs 2.0%), no worsening in British Isles Lupus Assessment Group (BILAG; 0 new BILAG A or ≤1 new BILAG B score; 100.0 % vs 50.3%) and no worsening (<0.3-point increase) in Physician's Global Assessment score (100.0% vs 49.7%). Among patients receiving >7.5 mg/day corticosteroids at baseline, significantly more SRI responders had reductions in prednisone dose to ≤7.5 mg/day than non-responders. SRI responders reported lower flare rates and improvements in serological markers and Functional Assessment of Chronic Illness Therapy-Fatigue score than non-responders. CONCLUSION: SRI response is associated with improvements in clinical and laboratory measures, strengthening its value as a clinically meaningful primary endpoint in clinical trials.