Repository Corticotropin Injection for Persistently Active Systemic Lupus Erythematosus: Results from a Phase 4, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial

Abstract

Introduction: We assessed the efficacy and safety of repository corticotropin injection (RCI; Acthar® Gel) for persistently active systemic lupus erythematosus (SLE) despite use of moderate-dose glucocorticoids.

Methods: This multicenter, double-blind, randomized, placebo-controlled study enrolled patients ≥ 18 years with active SLE and moderate to severe rash and/or arthritis despite stable glucocorticoid doses (7.5-30 mg/day prednisone equivalent) and antimalarials for ≥ 4 weeks and/or immunosuppressants for ≥ 8 weeks before screening. Stable glucocorticoid doses were required through week 16 with optional taper from weeks 16 to 24. Patients were randomized (1:1) to 80 U RCI subcutaneously or placebo every other day to week 4, then twice weekly to week 24. Endpoints included the proportion of SLE Responder Index (SRI)-4 responders at week 16; changes from baseline to week 16 in 28 Swollen Joint Count/Tender Joint Count (28 SJC/TJC) and Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI)-Activity score; and changes from baseline to week 24 in inflammatory cytokines. Safety was assessed by adverse events.

Results: In the modified intention-to-treat population (RCI, n = 84; placebo, n = 85), the proportion of SRI-4 responders at week 16 was not significantly different between groups (RCI, 47.6%; placebo, 43.5%; OR [95% CI] 1.2 [0.6 to 2.2]; p = 0.5762). RCI treatment resulted in a reduction from baseline to week 16 in 28 SJC/TJC and CLASI-Activity score and from baseline to week 8 in a proliferation-inducing ligand cytokine. Post hoc analyses demonstrated a greater proportion of BILAG-based Combined Lupus Assessment responders for RCI than placebo at weeks 4, 12, and 20 and greater SRI-4 response in RCI-treated patients with baseline SLE Disease Activity Index-2000 ≥ 10 and CLASI-Activity ≥ 11. No new safety signals were identified.

Conclusions: Despite failure to achieve the primary endpoint, these results support the utility of RCI for treating persistently active SLE.

Trial registration: ClinicalTrials.gov identifier NCT02953821.

Keywords: Acthar Gel; Autoimmune disease; Clinical trial; Corticosteroid; Glucocorticoid; Inflammation; Repository corticotropin injection; Systemic lupus erythematosus.

Figures

Fig. 1

Trial profile

Fig. 2

SRI-4 responders in the mITT population. aThe 95% CI is asymptotic Wald confidence limits. bThe p values were assessed using a CMH test stratified for location (US and outside the US) and baseline glucocorticoid dose (≤ 20 and > 20 mg per day). CMH Cochran–Mantel–Haenszel, mITT modified intention-to-treat, OR odds ratio, PBO placebo, RCI repository corticotropin injection. SRI-4 Systemic Lupus Erythematosus Responder Index-4

Fig. 3

Percentage of baseline over time for BAFF in the mITT population. **p < 0.01 for the LS mean difference using ANCOVA models with the change from baseline as the dependent variable, treatment as the factor, and baseline value of the corresponding endpoint as the covariate, with stratification for location (US and outside the US) and baseline glucocorticoid dose (≤ 20 and > 20 mg per day). ANCOVA analysis of covariance, BAFF B-cell activating factor, LS  least square, mITT modified intention-to-treat, PBO placebo, RCI repository corticotropin injection, SE standard error

Fig. 4

BICLA responders in the mITT population. *p < 0.05 from CMH test stratified for location (US and outside the US) and baseline glucocorticoid dose (≤ 20 and > 20 mg per day). BICLA BILAG-Based Combined Lupus Assessment, BILAG British Isles Lupus Assessment Group, CMH Cochran–Mantel–Haenszel, mITT modified intention-to-treat, OR odds ratio, PBO placebo, RCI repository corticotropin injection

Fig. 5

SRI-4 responders by baseline disease severity on the basis of SLEDAI-2K (a), CLASI-Activity (b), and BILAG-2004 (c) scores in the mITT population *p < 0.05; **p < 0.01 from CMH test stratified for location (US and outside the US) and baseline glucocorticoid dose (≤ 20 and > 20 mg per day). BILAG-2004 British Isles Lupus Assessment Group-2004, CLASI-Activity Cutaneous Lupus Erythematosus Disease Area and Severity Index-Activity, CMH Cochran–Mantel–Haenszel, mITT modified intention-to-treat, OR odds ratio, PBO placebo, RCI repository corticotropin injection, SLEDAI-2K Systemic Lupus Erythematosus Disease Activity Index-2000, SRI-4 Systemic Lupus Erythematosus Responder Index-4

Fig. 6

SRI-4 responders by ANA/anti-dsDNA/ENA positivity at baseline in the mITT population. *p < 0.05 from CMH test stratified for location (US and outside the US) and baseline glucocorticoid dose (≤ 20 and > 20 mg per day). ANA antinuclear antibody, CMH Cochran–Mantel–Haenszel, dsDNA double-stranded deoxyribonucleic acid, ENA extractable nuclear antigen, mITT modified intention-to-treat, OR odds ratio, PBO placebo, RCI repository corticotropin injection, SRI-4 Systemic Lupus Erythematosus Responder Index-4

Fig. 7

SRI-4 responders by complement C4 results at screening in the mITT population. *p < 0.05 from CMH test stratified for location (US and outside the US) and baseline glucocorticoid dose (≤ 20 and > 20 mg per day). C component, CMH Cochran–Mantel–Haenszel, mITT modified intention-to-treat, OR odds ratio, PBO placebo, RCI repository corticotropin injection, SRI-4 Systemic Lupus Erythematosus Responder Index-4