Dataset Information

Post Hoc Biomarker Analyses from a Phase 4, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Repository Corticotropin Injection (Acthar® Gel) for Persistently Active Systemic Lupus Erythematosus.

ABSTRACT:

Introduction

We conducted post hoc analyses of biomarker results from a multicenter, randomized, double-blind, placebo-controlled study of repository corticotropin injection (RCI; Acthar® Gel) in patients with persistently active systemic lupus erythematosus (SLE) despite treatment with moderate-dose glucocorticoids.

Methods

Adults with active SLE and moderate to severe rash and/or arthritis were enrolled in the primary study. Patients had active SLE despite treatment with stable glucocorticoids, antimalarials, and nonsteroidal anti-inflammatory drugs and/or immunosuppressants. Patients were randomly assigned to 80 U of RCI or placebo subcutaneously every other day for 4 weeks and then twice weekly through week 24. Blood samples were analyzed for serum cytokines and complement proteins using enzyme-linked immunosorbent or Luminex assays and for circulating leukocytes using flow cytometry. Biomarker levels were reported as percentages of the baseline and were further evaluated in subgroups stratified by baseline SLE Disease Activity Index-2000 (SLEDAI-2K) scores (< 10 vs. ≥ 10), baseline anti-double-stranded DNA levels (< 15 IU/mL vs. ≥ 15 IU/mL), and BILAG-based Combined Lupus Assessment (BICLA) responses at week 20 and 24.

Results

RCI treatment resulted in reduced levels of B cell-activating factor and interleukin-6 cytokines in all subgroups compared with placebo. RCI treatment also resulted in lower levels of CD19⁺ B cells and CD19⁺IgD^-CD27^-CD95⁺ atypical activated memory B cells than did placebo in the higher baseline disease activity subgroups and in BICLA non-responders. Furthermore, RCI treatment led to greater increases in complement component (C)3 and C4 levels than did placebo in the higher baseline disease activity subgroups and in BICLA responders.

Conclusions

RCI may reduce inflammation through B cell immunomodulation in patients with persistently active SLE, particularly in those with higher disease activity.

Trial registration

ClinicalTrials.gov identifier NCT02953821.

SUBMITTER: Askanase AD

PROVIDER: S-EPMC8572274 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionWe assessed patient-reported outcomes from a multicenter, randomized, double-blind, placebo-controlled study of repository corticotropin injection (RCI; Acthar® Gel) in patients with persistently active systemic lupus erythematosus (SLE) despite treatment with moderate-dose glucocorticoids.MethodsThe trial enrolled adults with active SLE and moderate-to-severe rash and/or arthritis despite use of stable glucocorticoids (7.5 mg/day to 30 mg/day prednisone equivalent), antimalarials, and nonsteroidal anti-inflammatory drugs for ≥ 4 weeks and/or immunosuppressants for ≥ 8 weeks before screening. Patients were randomly assigned to 80 U of RCI or placebo subcutaneously every other day through week 4, then twice weekly through week 24. Primary analyses evaluated the change from baseline to week 24 in the Lupus Quality of Life (QoL) and Work Productivity and Activity Impairment (WPAI)-Lupus questionnaires. Post hoc analyses stratified results by baseline disease activity (SLE Disease Activity Index-2000 [SLEDAI-2K] < 10 or ≥ 10; Cutaneous Lupus Erythematosus Disease Area and Severity Index [CLASI]-Activity < 11 or ≥ 11; and British Isles Lupus Assessment Group [BILAG]-2004 < 20 or ≥ 20) and by BILAG-based Combined Lupus Assessment (BICLA) response at weeks 20 and 24.ResultsRCI treatment resulted in greater improvement in the LupusQoL pain domain at week 16 and planning domain at week 24 compared with placebo. Post hoc analyses demonstrated greater improvements with RCI in the pain, planning, and fatigue domains than with placebo at multiple time points in patients with higher disease activity by baseline SLEDAI-2K ≥ 10, CLASI-Activity ≥ 11, and BILAG-2004 ≥ 20 and/or in BICLA responders. Compared with placebo, RCI also resulted in greater improvements in percentage work time missed at week 24 in patients with baseline CLASI-Activity < 11 and in percentage impairment while working at week 16 in BICLA responders.ConclusionsRCI may improve QoL and work productivity in patients who have persistently active SLE despite treatment with standard SLE therapy.Trial registrationClinicalTrials.gov identifier NCT02953821.

Project description:Background and Purpose: Effective relapse treatment is critical for minimizing disability in patients with multiple sclerosis (MS). Repository corticotropin injection (RCI; Acthar® Gel) has demonstrated efficacy for the treatment of MS exacerbations. However, there is limited real-world evidence available regarding the relationship between the use of RCI for MS relapses and patient demographics, disease characteristics, and dosing regimens. In this multicenter, prospective, observational registry, patients receiving RCI for acute MS relapse were characterized, and recovery and safety outcomes were described. Methods: Patients were invited by their treating clinician to participate in the registry during a routine care visit. The decision to initiate RCI occurred before determination of study eligibility. All treatment decisions were made at the discretion of the patient's health care provider and were not mandated by the study design or protocol. Each enrolled patient was followed for up to 24 Months or until the date of study termination. The primary endpoint was the change from baseline in MS Impact Scale Version 1 (MSIS-29v1) physical subscale scores at Month 2. Additional assessments included the MSIS-29v1 psychological subscale, Expanded Disability Status Scale (EDSS), Clinical Global Impression of Improvement (CGI-I), Work Productivity and Activity Impairment Questionnaire: MS (WPAI:MS), and Health Resource Utilization (HRU) questionnaire. Results: Of 145 patients enrolled, 82 (56.6%) completed 24 Months of follow-up. Mean MSIS-29v1 physical subscale scores improved at 2 Months (-8.0; P = 0.0002) and 6 Months (-9.6; P < 0.0001). Mean MSIS-29v1 psychological subscale scores also improved at 2 Months (-7.9; P = 0.0040) and 6 Months (-9.9; P = 0.0012). Mean EDSS scores improved at 2 Months (-0.4; P < 0.0001) and 6 Months (-0.5; P < 0.0001). CGI-I scores indicated improvement in 63.4% of 71 patients at 2 Months and 61.4% of 57 patients at 6 Months (both P < 0.0001). Improvements on the WPAI:MS activity impairment domain (P < 0.001) and reductions in outpatient, specialist, and emergency department visits were observed at 2 and 6 Months. A total of 35 (28.0%) patients reported 83 adverse events; 11 (8.8%) patients reported 16 serious adverse events. Conclusions: This observational study found significant improvements in MS assessment scores after RCI treatment and supports the efficacy and tolerability of RCI for MS relapse. Clinical Trial Registration: This trial is registered on ClinicalTrials.gov with the identifier NCT02633033.

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Project description:IntroductionNoninfectious keratitis is a painful corneal inflammation treated with topical cyclosporine and other immunosuppressants. Additional treatment options are needed for keratitis that does not improve with standard therapies. Repository corticotropin injection (RCI; Acthar® Gel) is approved to treat severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa, including keratitis. This phase 4, multicenter, open-label study assessed the efficacy and safety of RCI for refractory severe noninfectious keratitis.MethodsPatients were ≥ 18 years old with persistent severe keratitis despite treatment with topical immunosuppressants. Patients received 80 U of RCI subcutaneously twice weekly for 12 weeks followed by a 4-week taper. Assessments included all domains of the Impact of Dry Eye on Everyday Life (IDEEL) Questionnaire, Ocular Discomfort and 4-Symptom Questionnaire, and Visual Analog Scale (VAS). Corneal fluorescein and conjunctival lissamine green staining, Conjunctival Redness Scale, tear production (Schirmer's test), visual acuity, slit lamp examination, and intraocular pressure were also assessed. Safety was evaluated via treatment-emergent adverse events. Analyses were performed using the modified intent-to-treat (mITT) population (patients who received ≥ 1 dose of RCI and contributed any post-baseline efficacy data).ResultsIn the mITT population (N = 35), 50.0% (95% confidence interval, 33.2% to 66.8%) of patients experienced clinically important improvements in the symptom bother domain of the IDEEL Questionnaire at week 12 of RCI therapy. All domains of the IDEEL and the Ocular Discomfort and 4-Symptom Questionnaire showed improvements at week 12 of RCI treatment. The most pronounced improvements in the VAS at week 12 were for eye dryness and eye discomfort. Corneal staining, conjunctival staining, conjunctival redness, and tear production showed early improvements that were sustained through week 12. No new safety signals for RCI were identified.ConclusionsRCI is safe and effective for refractory severe noninfectious keratitis that has not improved with other approved therapies.Trial registration numberClinicalTrials.gov NCT04169061.

Project description:IntroductionWe 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.MethodsThis 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.ResultsIn 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.ConclusionsDespite failure to achieve the primary endpoint, these results support the utility of RCI for treating persistently active SLE.Trial registrationClinicalTrials.gov identifier NCT02953821.

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