Rheumatology Common Toxicity Criteria (RCTC): An Update Reflecting Real-World Use.

INTRODUCTION: The Outcome Measures in Rheumatology Clinical Trials (OMERACT) Rheumatology Common Toxicity Criteria (RCTC) version 2.0 was published in 2007 by the OMERACT Drug Safety Working Group, building on limited experience with RCTC version 1.0, to facilitate standardization of assessment (grading) and reporting of adverse events (AEs) commonly seen in rheumatic disease clinical trials (Woodworth et al. in J Rheumatol 34:1401-1414, 2007). OBJECTIVES: The objectives of this study were to (1) report the real-world performance of RCTC 2.0; (2) report immediately correctable errors in RCTC 2.0, and provide a revised RCTC 2.1; and (3) begin to identify the need for a comprehensive revision of RCTC 2.0. METHODS: Safety data outputs for several large rheumatic/autoimmune disease clinical trials in which RCTC 2.0 was used were evaluated for accuracy of reporting and the ability to assess differences among treatments. We examined RCTC 2.0 tables for errors, as well as for omission of terms for AEs that commonly occur in more recent rheumatology clinical trials. We also considered recommendations from recent US Food and Drug Administration (FDA) and international initiatives such CDISC (Clinical Data Interchange Standards Consortium) to improve the consistency of safety data collection and interpretability of safety data analyses. RESULTS: RCTC 2.0 enabled comparisons of safety data across treatment groups, including grading. However, we discovered inaccuracies in laboratory results grading and omission of AE terms now recognized to occur in rheumatic disease clinical trials. CONCLUSION: The RCTC 2.0 performed as intended, although some inaccuracies and omissions were found. We provide a corrected version, RCTC 2.1, and also recommend further revision of the RCTC within OMERACT guidances to include AEs that have been reported in rheumatology clinical trials since RCTC 2.0 was published. Ideally, a revised RCTC 3.0 would not only facilitate standardized assessment and reporting of AEs, but would also expand and encourage accurate comparison of the safety profiles of treatments for rheumatic/autoimmune diseases.

A Fifty-Two-Week, Randomized, Placebo-Controlled Trial of Certolizumab Pegol in Nonradiographic Axial Spondyloarthritis.

OBJECTIVE: The natural history of nonradiographic axial spondyloarthritis (SpA) is incompletely characterized, and there are concerns that nonsteroidal antiinflammatory drugs provide inadequate disease control in patients with active disease. This study was undertaken to investigate the effects of certolizumab pegol (CZP), an anti-tumor necrosis factor treatment, in patients with nonradiographic axial SpA with objective signs of inflammation. METHODS: In this ongoing parallel-group double-blind study, adults with active disease were recruited from 80 centers in Australia, Europe, North America, and Taiwan, and were randomized 1:1 to receive placebo or CZP (400 mg at weeks 0, 2, and 4, followed by 200 mg every 2 weeks) in addition to nonbiologic background medication (NBBM). Switching to open-label CZP (or other biologic) or making background medication changes was permitted at any point during the trial, although changes before week 12 were discouraged. The primary end point was the proportion of patients achieving major improvement (MI) (i.e., a ≥2.0-point decrease in the score from baseline or achievement of the lowest possible score [0.6]) in the Ankylosing Spondylitis Disease Activity Score (ASDAS) at week 52. RESULTS: A total of 317 patients were randomized to receive placebo plus NBBM (n = 158) or CZP plus NBBM (n = 159). ASDAS-MI at week 52 was achieved in 47.2% (75 of 159) of CZP plus NBBM patients, which was significantly greater (P < 0.0001) than the 7.0% (11 of 158) of placebo plus NBBM patients in whom ASDAS-MI was achieved. Of the placebo plus NBBM patients, 60.8% (96 of 158) switched to open-label treatment before week 52 compared to 12.6% (20 of 159) of the CZP plus NBBM patients. CONCLUSION: Adding CZP to background medication is superior to adding placebo in patients with active nonradiographic axial SpA. These results indicate that remission in nonradiographic axial SpA treated without biologics occurs infrequently, demonstrating the need for treatment beyond nonbiologic therapy.

Efficacy and Safety of Epratuzumab in Moderately to Severely Active Systemic Lupus Erythematosus: Results From Two Phase III Randomized, Double-Blind, Placebo-Controlled Trials.

OBJECTIVE: Epratuzumab, a monoclonal antibody that targets CD22, modulates B cell signaling without substantial reductions in the number of B cells. The aim of this study was to report the results of 2 phase III multicenter randomized, double-blind, placebo-controlled trials, the EMBODY 1 and EMBODY 2 trials, assessing the efficacy and safety of epratuzumab in patients with moderately to severely active systemic lupus erythematosus (SLE). METHODS: Patients met ≥4 of the American College of Rheumatology revised classification criteria for SLE, were positive for antinuclear antibodies and/or anti-double-stranded DNA antibodies, had an SLE Disease Activity Index 2000 (SLEDAI-2K) score of ≥6 (increased disease activity), had British Isles Lupus Assessment Group 2004 index (BILAG-2004) scores of grade A (severe disease activity) in ≥1 body system or grade B (moderate disease activity) in ≥2 body systems (in the mucocutaneous, musculoskeletal, or cardiorespiratory domains), and were receiving standard therapy, including mandatory treatment with corticosteroids (5-60 mg/day). BILAG-2004 grade A scores in the renal and central nervous system domains were excluded. Patients were randomized 1:1:1 to receive either placebo, epratuzumab 600 mg every week, or epratuzumab 1,200 mg every other week, with infusions delivered for the first 4 weeks of each 12-week dosing cycle, for 4 cycles. Patients across all 3 treatment groups also continued with their standard therapy. The primary end point was the response rate at week 48 according to the BILAG-based Combined Lupus Assessment (BICLA) definition, requiring improvement in the BILAG-2004 score, no worsening in the BILAG-2004 score, SLEDAI-2K score, or physician's global assessment of disease activity, and no disallowed changes in concomitant medications. Patients who discontinued the study medication were classified as nonresponders. RESULTS: In the EMBODY 1 and EMBODY 2 trials of epratuzumab, 793 patients and 791 patients, respectively, were randomized, 786 (99.1%) and 788 (99.6%), respectively, received study medication, and 528 (66.6%) and 533 (67.4%), respectively, completed the study. There was no statistically significant difference in the primary end point between the groups, with the week 48 BICLA response rates being similar between the epratuzumab groups and the placebo group (response rates ranging from 33.5% to 39.8%). No new safety signals were identified. CONCLUSION: In patients with moderate or severely active SLE, treatment with epratuzumab + standard therapy did not result in improvements in response rates over that observed in the placebo + standard therapy group.

Efficacy and safety of epratuzumab in patients with moderate/severe active systemic lupus erythematosus: results from EMBLEM, a phase IIb, randomised, double-blind, placebo-controlled, multicentre study.

OBJECTIVE: To identify a suitable dosing regimen of the CD22-targeted monoclonal antibody epratuzumab in adults with moderately to severely active systemic lupus erythematosus (SLE). METHODS: A phase IIb, multicentre, randomised controlled study (NCT00624351) was conducted with 227 patients (37-39 per arm) receiving either: placebo, epratuzumab 200 mg cumulative dose (cd) (100 mg every other week (EOW)), 800 mg cd (400 mg EOW), 2400 mg cd (600 mg weekly), 2400 mg cd (1200 mg EOW), or 3600 mg cd (1800 mg EOW). The primary endpoint (not powered for significance) was the week 12 responder rate measured using a novel composite endpoint, the British Isles Lupus Assessment Group (BILAG)-based Combined Lupus Assessment (BICLA). RESULTS: Proportion of responders was higher in all epratuzumab groups than with placebo (overall treatment effect test p=0.148). Exploratory pairwise analysis demonstrated clinical improvement in patients receiving a cd of 2400 mg epratuzumab (OR for 600 mg weekly vs placebo: 3.2 (95% CI 1.1 to 8.8), nominal p=0.03; OR for 1200 mg EOW vs placebo: 2.6 (0.9 to 7.1), nominal p=0.07). Post-hoc comparison of all 2400 mg cd patients versus placebo found an overall treatment effect (OR=2.9 (1.2 to 7.1), nominal p=0.02). Incidence of adverse events (AEs), serious AEs and infusion reactions was similar between epratuzumab and placebo groups, without decreases in immunoglobulin levels and only partial reduction in B-cell levels. CONCLUSIONS: Treatment with epratuzumab 2400 mg cd was well tolerated in patients with moderately to severely active SLE, and associated with improvements in disease activity. Phase III studies are ongoing.

Epratuzumab for patients with moderate to severe flaring SLE: health-related quality of life outcomes and corticosteroid use in the randomized controlled ALLEVIATE trials and extension study SL0006.

OBJECTIVE: To evaluate health-related quality of life (HRQOL) and corticosteroid use in patients with moderate to severely active SLE enrolled in two international, multicentre, randomized controlled trials of epratuzumab (ALLEVIATE-1 and -2) and a long-term extension study (SL0006). METHODS: Ninety ALLEVIATE patients (43% BILAG A, mean BILAG score 13.2) were randomized to receive 360 mg/m(2) (n = 42) or 720 mg/m(2) (n = 11) epratuzumab or placebo (n = 37), plus standard of care, in 12-week cycles. Corticosteroid use, patient and physician global assessments of disease activity (PtGA and PGA) and 36-item Medical Outcomes Survey Short Form (SF-36) results were recorded at baseline and every 4 weeks. Both trials were prematurely discontinued due to a drug supply interruption; patients followed for ≥6 months were analysed. Twenty-nine patients continued in SL0006, with interim analysis at a median exposure of 120 (range 13-184) weeks. RESULTS: At week 12, proportions of patients with a PGA ≥20% above baseline or with a PtGA improvement greater than or equal to the minimum clinically important difference were higher in the epratuzumab arms than the placebo arm. PGA and PtGA improvements were sustained but did not reach statistical significance. At week 24, mean cumulative corticosteroid doses with epratuzumab 360 and 720 mg/m(2) were 1051 and 1973 mg less than placebo (P = 0.034 and 0.081, respectively). At week 48, SF-36 scores approached or exceeded US age- and gender-matched norms in five domains with the 360 mg/m(2) treatment. Improvements were maintained in SL0006 over ∼2 years. CONCLUSION: Epratuzumab treatment produced clinically meaningful and sustained improvements in PGA, PtGA and HRQOL and reductions in corticosteroid doses.

Efficacy and safety of epratuzumab in patients with moderate/severe flaring systemic lupus erythematosus: results from two randomized, double-blind, placebo-controlled, multicentre studies (ALLEVIATE) and follow-up.

OBJECTIVE: To evaluate epratuzumab treatment in patients with moderately-to-severely active SLE in two international, randomized, controlled trials (ALLEVIATE-1 and -2) and an open-label extension study (SL0006). METHODS: Ninety ALLEVIATE patients (43% BILAG A, median BILAG score 12.0) received standard of care plus 10 total doses of placebo (n = 37) or 360 mg/m(2) (n = 42) or 720 mg/m(2) (n = 11) epratuzumab, administered across 12-week cycles for up to 48 weeks, with BILAG assessments every 4 weeks. Patients were followed for ≥ 6 months and their data combined for analysis. The primary endpoint was BILAG response at week 12 (all BILAG A scores reduced to B/C/D and B scores to C/D, no new A and <2 new B scores). Twenty-nine patients continued in SL0006, receiving 12-week cycles of 360 mg/m(2) epratuzumab; this interim analysis was performed at median 120 weeks (range 13-184) of exposure. RESULTS: Both ALLEVIATE trials were discontinued prematurely because of interruption in drug supply. Exploratory pooled analyses found that responses at week 12 were 15/34 (44.1%) and 2/10 (20.0%) for epratuzumab 360 and 720 mg/m(2), respectively, vs 9/30 (30.0%) for placebo. Total BILAG scores were lower in both epratuzumab arms vs placebo at week 48 and at all but two time points. The incidence of adverse events was similar between groups. In SL0006, median total BILAG score was 8.0 (n = 29) at study entry and 7.0 (n = 19) at week 100, with no additional safety signals. CONCLUSION: This initial efficacy and safety profile of epratuzumab supports its continued development for SLE treatment.