Abatacept will be more effective than placebo in inducing complete renal response of active lupus glomerulonephritis after 1 year of treatment in subjects receiving background MMF and corticosteroids (CS).
The study comprises a 104 week double-blind treatment period. The primary endpoint will be assessed at Day 365.
The primary objective of this study is to compare the proportion of subjects with Complete Renal Response (CR) of lupus glomerulonephritis at Day 365 following 1 year treatment with abatacept or placebo administered on a background of MMF and corticosteroids.
1) Assess the proportion of subjects with Complete Renal Response (CR) of lupus glomerulonephritis at Day 729 following 2 years treatment with abatacept or placebo administered on a background of MMF and corticosteroids.
2) Assess the proportion of subjects achieving the ranked outcomes of Complete Renal Response (CR), Partial Renal Response (PR) or No Response (NR) at Day 365 and Day 729 following 2 years treatment with abatacept or placebo administered on a background of MF plus corticosteroids.
3) Assess the time to first achievement of CR, and the time to first achievement of CR and/or PR between the abatacept and placebo arms (a) in all subjects, (b) in subjects who achieved CR and/or PR at Day 365, and (c) in subjects who achieved CR and who achieve CR and/or PR at Day 729.
4) Assess each of the components of response over time including the proportion of subjects who meet each component of the criteria (eg, UPCR < 0.5, UPCR 50% reduced and reaching target for PR; eGFR at or above target for CR and PR; no cellular casts; dose of prednisone or prednisone equivalent no greater than 10 mg/day) and the values of UPCR and eGFR over time.
5) Assess the safety and immunogenicity of abatacept in subjects with lupus nephritis.
6) Assess the change in overall disease activity using the BILAG 2004 disease activity index from Study Day 1 through Day 365 and Day 729, and from Day 365 through Day 729.
7) Assess durability of CR and PR achieved during the treatment period, assessed as time to, and proportion with:
- Change from a sustained higher level of response to a sustained lower level of response (eg, CR to PR or NR; PR to NR), where sustained is defined as present at 2 consecutive visits approximately 4 weeks apart.
- Lupus treatment failure occurring after achievement of CR or PR.
- Overall treatment failure occurring after achievement of CR or PR.
1) Assess the proportion with, and time to, lupus treatment failure and overall treatment
2) Assess proportion with, and time to, renal flare.
3) Assess the number, time to occurrence, and proportion of subjects who develop, new severe (BILAG A) or moderate (BILAG B) increase in non-renal activity of SLE.
4) Evaluate and compare corticosteroid use in abatacept and placebo arms, assessed as cumulative dose over time.
5) Assess biomarkers potentially associated with SLE, LN, or abatacept mechanism of action, including complement components C3 and C4 levels, titer of anti-ds DNA/other auto antibodies, UPCR, and changes from baseline in serum/plasma biomarkers (eg chemokines, cytokines, soluble receptors, RNA, total IgG, total IgM, total IgA), RNA transcripts discovered in whole blood, proteins discovered in urine, lymphocyte phenotype, and pharmacogenomic markers. Selected assessments including lymphocyte phenotype, may be performed in only a subset of subjects.
6) Assess the following health outcomes: improvement in quality of life using the Short Form-36 (SF-36); reduction in fatigue using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and Fatigue Visual Analog Scale (VAS); SLICC/ACR Damage Index during the double-blind period, and use of Emergency Room/Hospitalization.
7) Characterize the pharmacokinetics of abatacept in subjects with lupus nephritis.
Principal Investigator: Jo Abraham