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Repository corticotropin injection in patients with persistently active SLE requiring corticosteroids: post hoc analysis of results from a two-part, 52-week pilot study.

ABSTRACT: Post hoc analyses evaluated the effectiveness and safety of repository corticotropin injection (RCI) in patients with persistently active SLE over 52 weeks.Patients were initially randomised to 40 U daily or 80 U every other day RCI (n=26) or placebo (n=12) for the 8-week double-blind period. Completers entered the open-label extension (OLE; n=33) receiving 16, 40 or 80 U RCI 1-3 times/week and were followed through week 52. Outcomes included proportion of responders based on a novel index (resolution of joint or skin activity using hybrid Systemic Lupus Erythematosus Disease Activity Index (hSLEDAI) without any worsening British Isles Lupus Assessment Group (BILAG) scores in other organ systems) or revised novel index (using SLE Responder Index (SRI) definition of BILAG worsening (1A or 2B)), proportion of responders by SRI and changes in total hSLEDAI and BILAG scores. Adverse events and laboratory values were assessed.At week 52, 12.0% (3/25) RCI/RCI patients and 36.4% (4/11) placebo/RCI patients were responders using the novel index. The revised novel responder index demonstrated response rates of 48.0% (12/25) and 54.5% (6/11) in the RCI/RCI and placebo/RCI groups, respectively. Proportions of SRI responders were 40.0% (10/25) and 54.5% (6/11). In the RCI/RCI group, total hSLEDAI and BILAG scores declined from 10.0 and 15.7 at week 0 to 3.5 and 4.6 at week 52, respectively. Reductions in the placebo/RCI group on switching were observed (mean hSLEDAI: 9.1-3.3; BILAG: 13.5-2.6). Other disease activity endpoints also improved in both groups. No new safety signals were observed during the OLE.RCI demonstrated durable effectiveness in patients with persistently active SLE despite moderate-dose corticosteroid therapy. Switching from placebo resulted in reduced disease activity during the OLE. These data provide the foundation for evaluation of RCI in a robustly powered study.

SUBMITTER: Furie RA

PROVIDER: S-EPMC5761300 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Repository corticotropin injection in patients with persistently active SLE requiring corticosteroids: post hoc analysis of results from a two-part, 52-week pilot study.

Furie Richard A RA Mitrane Margaret M Zhao Enxu E Becker Patrice M PM

Lupus science & medicine 20171227 1

<h4>Objective</h4>Post hoc analyses evaluated the effectiveness and safety of repository corticotropin injection (RCI) in patients with persistently active SLE over 52 weeks.<h4>Methods</h4>Patients were initially randomised to 40 U daily or 80 U every other day RCI (n=26) or placebo (n=12) for the 8-week double-blind period. Completers entered the open-label extension (OLE; n=33) receiving 16, 40 or 80 U RCI 1-3 times/week and were followed through week 52. Outcomes included proportion of respo ...[more]

PMID: 29344387

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Project description:ObjectiveTo evaluate the efficacy of a prolonged-release formulation of a porcine adrenocorticotropic hormone analogue (repository corticotropin injection (RCI)) added to standard of care in patients requiring moderate-dose corticosteroids for symptomatic SLE.MethodsThis prospective, randomised, double-blind, phase 4, pilot study (NCT01753401) enrolled 38 patients with persistently active SLE involving skin and/or joints. Enrolled patients received RCI, 40 U daily or 80 U every other day, or volume-matched placebo gel, for 8 weeks, with dose tapering to twice weekly during weeks 5-8. Efficacy endpoints included proportion of responders at week 4 based on a novel composite measure that included resolution of rash or arthritis measured using the hybrid SLE Disease Activity Index (hSLEDAI) without worsening British Isles Lupus Assessment Group (BILAG) scores in other organ systems at week 4 (primary), as well as improvements in total hSLEDAI and BILAG scores and other measures of skin and joint disease activity over the 8-week treatment period.ResultsResponse, as defined for the primary endpoint, did not differ significantly between the combined placebo and RCI-treated groups at week 4. At week 8, the proportion of responders was higher in RCI-treated patients but did not statistically differ between groups (RCI 40 U (53.8%), RCI 80 U (33.3%), combined placebo (27.3%)). However, RCI treatment was associated with statistically significant improvements in several secondary endpoints, including total hSLEDAI, total BILAG and Cutaneous Lupus Erythematosus Disease Area and Severity Index Activity scores within 8 weeks. Treatment was well tolerated.ConclusionsAlthough the primary endpoint was not met in this pilot study, secondary and post hoc analyses suggested that RCI was associated with improvements in SLE disease activity in a select patient population with steroid-dependent persistent disease.Trial registration numberNCT01753401; results.

Project description:Objective:SLE is a chronic inflammatory autoimmune disease characterised by the excessive production of autoantibodies, immune complexes and proinflammatory cytokines. Repository corticotropin injection (RCI) is a naturally sourced complex mixture of adrenocorticotropic hormone analogues and other pituitary peptides. RCI is approved by the US Food and Drug Administration for use during an exacerbation or as maintenance therapy in select cases of SLE. This paper discusses the design and baseline characteristics of a multicentre, double-blind, randomised, placebo-controlled, 24-week clinical trial evaluating the effect of RCI in reducing disease activity for patients with persistently active SLE despite moderate-dose corticosteroid use. Methods:Efficacy will be evaluated using the SLE Responder Index-4 (SRI-4), SLE Disease Activity Index-2000 (SLEDAI-2K), British Isles Lupus Assessment Group-2004 (BILAG-2004) and Physician's Global Assessment (PGA). The primary efficacy endpoint will be the proportion of SRI-4 responders at week 16. Secondary and exploratory endpoints will include changes in disease activity scores over time, prednisone dose and biomarkers of inflammation and bone turnover. The safety and tolerability profile of RCI will also be evaluated through adverse event profiles, physical examination, clinical laboratory tests and serum cortisol levels. Results:Target enrolment for this global study is 270 patients, and as of 15 November 2019, the modified intent-to-treat population included 169 patients. The study cohort had 91.7% women, had a mean age of 39.7 years, mean SLEDAI-2K total score of 9.9, mean BILAG-2004 total score of 18.1, mean PGA of 59.7 and mean prednisone or equivalent daily dose of 11.1?mg. A total of 79.3% and 64.5% of patients were receiving concomitant antimalarial or immunosuppressive therapy, respectively. Conclusions:Data from this study will provide valuable insights into the therapeutic role of RCI in refractory SLE, as well as important information regarding its safety profile.

Project description:IntroductionWe 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.MethodsAdults 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.ResultsRCI 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.ConclusionsRCI may reduce inflammation through B cell immunomodulation in patients with persistently active SLE, particularly in those with higher disease activity.Trial registrationClinicalTrials.gov identifier NCT02953821.

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.

Project description:BackgroundTreatment goals for patients with systemic lupus erythematosus (SLE) include minimising disease activity and reducing the risk of flares. Although belimumab is effective at reducing disease activity and risk of severe flares, it was previously unknown what the clinical effects were upon treatment discontinuation. The objective of this study was to assess the impact of temporary withdrawal of intravenous (IV) belimumab in patients with SLE.MethodsThis multicentre, open-label, non-randomised, 52-week study (GSK Study BEL116027; NCT02119156) recruited patients with SLE and stable low disease activity, of whom those on belimumab 10 mg/kg IV plus standard therapy either discontinued belimumab for 24 weeks and then restarted belimumab 10 mg/kg IV every 4 weeks (q4w) for 28 weeks (treatment holiday [TH] group), or continued on belimumab 10 mg/kg IV plus standard therapy q4w for 52 weeks (treatment continuation [TC] group). The primary endpoint was median time to first Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) Flare Index flare. Secondary and other endpoints included rate of any flare, time to severe flare, time to renal flare and rebound (SELENA-SLEDAI score exceeding parent study baseline). Data on rebound phenomenon in patients with any disease level of SLE who had permanently withdrawn from further belimumab treatment (long-term discontinuation group [LTD]) were also assessed. Safety was assessed.ResultsThe primary endpoint was not evaluable in the TH (n = 12) and TC (n = 29) groups as fewer than half of patients flared. Unadjusted flare rates per patient-year were 1.0 during treatment discontinuation and 0.3 during treatment restart (0.6 overall) in the TH group and 0.6 in the TC group; there were no severe or renal flares. No TH patients rebounded; 2 (6.9%) TC patients rebounded; 2 (5.1%) patients in the LTD group rebounded. There were no new safety signals.ConclusionsTwenty-four-week belimumab discontinuation did not appear to increase the risk of flares or rebound in patients with low SLE disease activity; flare rates were low in both groups. Further studies may help to fully determine the effect of belimumab discontinuation.Trial registrationClinicalTrials.gov, NCT02119156 . Registered on April 21, 2014.

Project description:ImportanceDespite great expense and little evidence supporting use over corticosteroids, prescriptions for repository corticotropin (H. P. Acthar Gel; Mallinckrodt Pharmaceuticals) have increased markedly. Aggressive sales tactics and payments from the manufacturer may influence prescribing behavior for this expensive medication.ObjectiveTo characterize industry payments to physician specialists who prescribe corticotropin in the Medicare program.Design, setting, and participantsThis study was a cross-sectional analysis of Centers for Medicare & Medicaid Services 2015 Part D prescribing data linked to 2015 Open Payments data. Nephrologists, neurologists, and rheumatologists with more than 10 corticotropin prescriptions (frequent prescribers) in 2015 were included.ExposuresFrequency, category, and magnitude of corticotropin-related payments from Mallinckrodt recorded in the Open Payments database.Main outcomes and measuresFrequency, category, and magnitude of corticotropin-related payments from Mallinckrodt, as well as corticotropin prescriptions and expenditures for Medicare beneficiaries.ResultsOf the 235 included physicians, 65 were nephrologists; 59, neurologists; and 111, rheumatologists. A majority of frequent corticotropin prescribers (207 [88%]) received corticotropin-related payments from Mallinckrodt. The median (range) total payment for 2015 was $189 ($11-$138 321), with the highest payments ranging from $56 549 to $138 321 across the specialties. More than 20% of frequent prescribers received more than $10 000 and the top quartile of recipients received a median (range) of $33 190 ($9934-$138 321) in total payments per prescriber. Payments for compensation for services other than consulting contributed the most to the total amount. Mallinckrodt payments were positively associated with greater Medicare spending on corticotropin (β = 1.079; 95% CI, 1.044-1.115; P < .001), with every $10 000 in payments associated with a 7.9% increase (approximately $53 000) in Medicare spending on corticotropin. There was no association between corticotropin-related payments and spending on prescriptions for synthetic corticosteroids.Conclusions and relevanceIn this study, most nephrologists, neurologists, and rheumatologists who frequently prescribe corticotropin received corticotropin-related payments from Mallinckrodt. These findings suggest that financial conflicts of interest may be driving use of corticotropin in the Medicare program.

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Repository corticotropin injection in patients with persistently active SLE requiring corticosteroids: post hoc analysis of results from a two-part, 52-week pilot study.

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Repository corticotropin injection in patients with persistently active SLE requiring corticosteroids: post hoc analysis of results from a two-part, 52-week pilot study.

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