Design of the Tocilizumab in Giant Cell Arteritis Trial

Overview. The GiACTA trial is a multicenter, randomized, double-blind, and placebo-controlled study designed to test the ability of tocilizumab (TCZ), an interleukin (IL)-6 receptor antagonist, to maintain disease remission in patients with giant cell arteritis (GCA). Design:. Approximately 100 centers will enroll 250 patients with active disease. The trial consists of a 52-week blinded treatment phase followed by 104 weeks of open-label extension. Patients will be randomized into one of four groups. Group A (TCZ 162 mg weekly plus a 6-month prednisone-taper); group B (TCZ 162 mg every other week plus a 6-month prednisone-taper); group C (placebo plus a 6-month prednisone-taper); and group D (placebo plus a 12-month prednisone taper). We hypothesize that patients assigned to TCZ in addition to a 6-month prednisone course are more likely to achieve the primary efficacy endpoint of sustained remission (SR) at 52 weeks compared with those assigned to a 6-month prednisone course alone, thus potentially minimizing the long-term adverse effects of corticosteroids. Conclusion:. GiACTA will test the hypothesis that interference with IL-6 signaling exerts a beneficial effect on patients with GCA. The objective of this paper is to describe the design of the trial and address major issues related to its development

Long-term effect of tocilizumab in patients with giant cell arteritis:open-label extension phase of the Giant Cell Arteritis Actemra (GiACTA) trial

Background: The combination of tocilizumab plus a glucocorticoid taper is effective in maintaining clinical remission without requiring additional glucocorticoid therapy in patients with giant cell arteritis, as shown in part one of the Giant Cell Arteritis Actemra (GiACTA) trial. However, the duration of the tocilizumab effect after discontinuation is unknown. Here, we explored the maintenance of efficacy 1 year after discontinuation of tocilizumab treatment, the effectiveness of retreatment with tocilizumab after relapse, and the long-term glucocorticoid-sparing effect of tocilizumab. Methods: In part one of the GiACTA trial, 251 patients were randomly assigned (2:1:1:1) to receive subcutaneous tocilizumab (162 mg) once a week or every other week, combined with a 26-week prednisone taper, or placebo combined with a prednisone taper over a period of either 26 weeks or 52 weeks. Patients in clinical remission stopped masked injections at 1 year (the conclusion of part one). In part two, treatment was at the investigators' discretion and could consist of no treatment, tocilizumab, glucocorticoids, methotrexate, or combinations of these, for two years. Maintenance of efficacy as assessed by clinical remission (defined as absence of relapse determined by the investigator), cumulative glucocorticoid dose, and long-term safety were exploratory objectives in part two of the trial. This trial is registered at ClinicalTrials.gov, NCT01791153. Findings: 215 patients participated in part two of the trial; 81 patients who were randomly assigned to tocilizumab once a week in part one were in clinical remission after 1 year, of whom 59 started part two on no treatment. 25 of these 59 patients (42%) maintained tocilizumab-free and glucocorticoid-free clinical remission throughout part two. Median (95% CI) cumulative glucocorticoid doses over 3 years were 2647 mg (1987\u20133507) for tocilizumab once a week, 3948 mg (2352\u20135186) for tocilizumab-every-other-week, 5277 mg (3944\u20136685) for placebo with a 26-week prednisone taper, and 5323 mg (3900\u20136951) for placebo with a 52-week prednisone taper (van Elteren p 640\ub7001, tocilizumab once a week vs placebo groups; p<0\ub705, tocilizumab-every-other-week vs placebo groups). Tocilizumab-based regimens restored clinical remission among patients who experienced relapse in part two and were treated (median time to remission: 15 days for tocilizumab alone [n=17]; 16 days for tocilizumab plus glucocorticoids [n=36]; and 54 days for glucocorticoids alone [n=27]). No new or unexpected safety findings were reported over the full 3 years of the study. Interpretation: Giant cell arteritis remains a chronic disease that entails ongoing management and careful vigilance for disease relapse, but continuous indefinite treatment with immunosuppressive drugs is not required for all patients. A substantial proportion of patients treated with tocilizumab for one year maintain drug-free remission during the two years after tocilizumab cessation. For patients who experience relapse, tocilizumab can be used to manage relapses, but it remains prudent to include prednisone for patients who experience relapse because of the risk for vision loss. Funding: F Hoffmann-La Roche

New-onset versus relapsing giant cell arteritis treated with tocilizumab:3-year results from a randomized controlled trial and extension

OBJECTIVE: Tocilizumab plus prednisone induces sustained glucocorticoid-free remission in patients with giant cell arteritis (GCA). However, its long-term benefits in new-onset vs relapsing disease are uncertain and the value of weekly vs every-other-week dosing has not been evaluated. METHODS: In GiACTA part 1, patients with new-onset or relapsing GCA received blinded tocilizumab weekly (TCZ QW), tocilizumab every-other-week (TCZ Q2W), or placebo for 52 weeks with a prednisone taper. In part 2 (open-label), patients were treated at investigator discretion for 104 weeks. In this analysis, patients were evaluated according to their original treatment assignments and outcomes beyond 52 weeks were assessed. Outcomes of interest included time to first flare and cumulative glucocorticoid exposure over 3 years according to baseline disease status. RESULTS: Part 1 enrolled 250 patients; 215 entered part 2. At baseline, 48% had new-onset disease and 52% had relapsing disease. In patients with new-onset and relapsing disease, median time to first flare in the TCZ QW group was 577 and 575 days, respectively, vs 479 and 428 days with TCZ Q2W and 179 and 224 days with placebo; median cumulative glucocorticoid dose was 3068 mg and 2191 mg with TCZ QW, 4080 mg and 2353 mg with TCZ Q2W, and 4639 mg and 6178 mg with placebo. CONCLUSIONS: TCZ QW delays the time to flare and reduces cumulative glucocorticoid dose in patients with relapsing GCA and new-onset GCA. These data support initiating TCZ QW as part of first-line therapy in all patients with active GCA. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT01791153

Brief Report: The Value of a Patient Global Assessment of Disease Activity in Granulomatosis With Polyangiitis (Wegener's)

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102695/1/art38248.pd

OP0027 TIME TO FLARE AND GLUCOCORTICOID EXPOSURE IN PATIENTS WITH NEW-ONSET VERSUS RELAPSING GIANT CELL ARTERITIS TREATED WITH TOCILIZUMAB OR PLACEBO PLUS PREDNISONE TAPERING: 3-YEAR RESULTS FROM A RANDOMIZED CONTROLLED PHASE 3 TRIAL

Background:In part 1 of the 52-week, double-blind GiACTA trial, tocilizumab (TCZ) every week (QW) or every other week (Q2W) + prednisone tapering reduced the risk for flare versus placebo (PBO) + 26-week prednisone tapering among patients with new-onset giant cell arteritis (GCA) at baseline. Among patients with relapsing GCA, TCZ QW but not Q2W + prednisone reduced the risk for flare versus both PBO groups, and there was separation in the time to flare between the TCZ QW and Q2W groups.1Objectives:To report time to first flare and potential cumulative glucocorticoid (GC) sparing over 3 years of the GiACTA trial (part 1 + 2-year open-label part 2) among patients with new-onset or relapsing GCA.Methods:At the end of part 1, patients entered open-label part 2, in which GCA therapy (including initiation/termination of open-label TCZ and/or GCs) was given at the investigator's discretion according to disease status. Time to first GCA flare during the 3-year study period was assessed using Kaplan-Meier analysis for patients in the intention-to-treat population according to disease onset status at baseline (new-onset/relapsing) based on their originally assigned treatment groups: TCZ QW, TCZ Q2W, or pooled PBO (PBO+26-week and PBO+52-week prednisone taper).Results:Among patients randomly assigned in part 1, 47 of 100 (47%) in the TCZ QW group, 26 of 49 (53%) in the TCZ Q2W group, and 46 of 101 (46%) in the pooled PBO group had new-onset GCA at baseline; the rest had relapsing GCA. Median time to first flare over 3 years was longer for patients assigned to TCZ treatment in part 1 than for patients assigned to PBO; Kaplan-Meier analysis showed a clear separation between the TCZ QW and the pooled PBO groups over 3 years for patients with new-onset and relapsing GCA (Figure 1A). Separation between the TCZ QW and TCZ Q2W groups was also observed over 3 years in patients with new-onset and relapsing GCA, although this was more evident in patients with relapsing GCA (Figure 1B). Higher proportions of patients in the TCZ QW group (new-onset, 49%; relapsing, 47%) than the pooled PBO group (new-onset, 28%; relapsing, 31%) and the TCZ Q2W group (new-onset, 27%; relapsing, 35%) remained flare-free during their entire treatment period. Cumulative prednisone dose over 3 years was lower for patients originally assigned to TCZ QW versus those originally assigned to PBO for patients with new-onset GCA and those with relapsing GCA at baseline (Figure 2).Conclusion:In this 3-year analysis of GiACTA parts 1 and 2, time to first flare favored TCZ QW over TCZ Q2W in patients with new-onset and relapsing GCA. TCZ QW delayed time to first flare and resulted in lower cumulative GC exposure compared with PBO in patients with new-onset and relapsing GCA, supporting TCZ QW dosing in patients with GCA regardless of disease onset.References:[1]Stone JH et al. N Engl J Med 2017;377:317-28.Disclosure of Interests:John H. Stone Grant/research support from: Roche, Consultant of: Roche, Helen Spotswood Shareholder of: Roche Products Ltd, Employee of: Roche Products Ltd, Sebastian Unizony Grant/research support from: Genentech, Inc., Martin Aringer Consultant of: Boehringer Ingelheim, Roche, Speakers bureau: Boehringer Ingelheim, Roche, Daniel Blockmans Consultant of: yes, Speakers bureau: yes, Elisabeth Brouwer Consultant of: Roche (consultancy fee 2017 and 2018 paid to the UMCG), Speakers bureau: Roche (2017 and 2018 paid to the UMCG), Maria C. Cid Speakers bureau: Roche, Bhaskar Dasgupta Grant/research support from: Roche, Consultant of: Roche, Sanofi, GSK, BMS, AbbVie, Speakers bureau: Roche, Jürgen Rech Consultant of: BMS, Celgene, Novartis, Roche, Chugai, Speakers bureau: AbbVie, Biogen, BMS, Celgene, MSD, Novartis, Roche, Chugai, Pfizer, Lilly, Carlo Salvarani: None declared, Robert Spiera Grant/research support from: Roche-Genetech, GSK, Boehringer Ingelheim, Chemocentryx, Corbus, Forbius, Sanofi, Inflarx, Consultant of: Roche-Genetech, GSK, CSL Behring, Sanofi, Janssen, Chemocentryx, Forbius, Mistubishi Tanabe, Min Bao Shareholder of: Roche, Employee of: Genentec

Glucocorticoid Dosages and Acute-Phase Reactant Levels at Giant Cell Arteritis Flare in a Randomized Trial of Tocilizumab

OBJECTIVE: To evaluate glucocorticoid doses and serological findings in patients with giant cell arteritis (GCA) flares. METHODS: Patients with GCA were randomly assigned to receive double-blind dosing with subcutaneous tocilizumab (TCZ) 162 mg weekly plus 26-week prednisone (TCZ-QW+Pred-26), every-other-week TCZ plus 26-week prednisone (TCZ-Q2W+Pred-26), placebo plus 26-week prednisone (PBO+Pred-26), or placebo plus 52-week prednisone (PBO+Pred-52). Outcomes were prednisone dose, C-reactive protein (CRP) level, and erythrocyte sedimentation rate (ESR) at the time of flare and remission during 52 weeks. RESULTS: One hundred patients received TCZ-QW+Pred-26, 49 received TCZ-Q2W+Pred-26, 50 received PBO+Pred-26, and 51 received PBO+Pred-52. Among 149 TCZ-treated patients, 36 (24%) experienced flare, 23 (64%) of whom were still receiving prednisone (median dose, 2.0 mg/day). Among 101 PBO+Pred-treated patients, 59 (58%) experienced flare, 45 (76%) of whom were receiving prednisone (median dose, 5.0 mg/day). Many flares occurred while patients were taking more than 10 mg/day prednisone: 9 (25%) in the TCZ groups and 13 (22.0%) in the placebo groups. Thirty-three flares (92%) in TCZ-treated groups and 20 (34%) in PBO+Pred-treated groups occurred with normal CRP. More than half the PBO+Pred-treated patients had elevated CRP without flare. Benefits of the combination of TCZ plus prednisone over prednisone alone for remission induction were apparent by 8 weeks. CONCLUSION: Most GCA flares occurred while patients were still receiving prednisone. Acute-phase reactants were not reliable indicators of flare in patients treated with TCZ plus prednisone or with prednisone alone. The addition of TCZ to prednisone facilitates earlier GCA control. This article is protected by copyright. All rights reserved

Assessment of the item selection and weighting in the Birmingham Vasculitis Activity Score for Wegener's Granulomatosis

Objective To assess the Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG) with respect to its selection and weighting of items. Methods This study used the BVAS/WG data from the Wegener's Granulomatosis Etanercept Trial. The scoring frequencies of the 34 predefined items and any “other” items added by clinicians were calculated. Using linear regression with generalized estimating equations in which the physician global assessment (PGA) of disease activity was the dependent variable, we computed weights for all predefined items. We also created variables for clinical manifestations frequently added as other items, and computed weights for these as well. We searched for the model that included the items and their generated weights yielding an activity score with the highest R 2 to predict the PGA. Results We analyzed 2,044 BVAS/WG assessments from 180 patients; 734 assessments were scored during active disease. The highest R 2 with the PGA was obtained by scoring WG activity based on the following items: the 25 predefined items rated on ≥5 visits, the 2 newly created fatigue and weight loss variables, the remaining minor other and major other items, and a variable that signified whether new or worse items were present at a specific visit. The weights assigned to the items ranged from 1 to 21. Compared with the original BVAS/WG, this modified score correlated significantly more strongly with the PGA. Conclusion This study suggests possibilities to enhance the item selection and weighting of the BVAS/WG. These changes may increase this instrument's ability to capture the continuum of disease activity in WG.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/60211/1/23707_ftp.pd

Solid malignancies among etanercept‐treated patients with granulomatosis with polyangiitis (Wegener's): Long‐term followup of a multicenter longitudinal cohort

Objective An association between therapeutic inhibition of tumor necrosis factor (TNF) and solid malignancies was observed during the Wegener's Granulomatosis Etanercept Trial (WGET), which included 180 patients with granulomatosis with polyangiitis (Wegener's) (GPA). The present study was conducted to determine the malignancy risk beyond the time of exposure to study therapy. Methods The occurrence and type of solid malignancies were ascertained using a standardized data form. Data collected included vital status, histologic findings, and therapeutic interventions. The Surveillance, Epidemiology, and End‐Results database was used to estimate a standardized incidence rate (SIR) for solid malignancies. Results Post‐trial followup data were available for 153 patients (85% of the original cohort), with a median followup time of 43 months. Fifty percent of these patients had received etanercept. There were no differences in demographic characteristics between the etanercept and placebo groups. Thirteen new solid malignancies were detected, 8 in the etanercept group and 5 in the placebo group. Compared to the general population, the risk of solid malignancies in the etanercept group was increased (SIR 3.92 [95% confidence interval 1.69–7.72]), but was not different from the risk in the placebo group compared to the general population (SIR 2.89 [95% confidence interval 0.94–6.73]). All solid malignancies occurred in patients who had been exposed to cyclophosphamide. The overall duration of disease and a history of malignancy before trial enrollment were associated with the development of malignancy during post‐trial followup. Conclusion The incidence of solid malignancy remained increased during long‐term followup of the WGET cohort. However, this could not be attributed solely to etanercept exposure during the trial. Anti‐TNF therapy with etanercept appears to further increase the risk of malignancy observed in patients with GPA treated with cytotoxic agents and should be avoided in these patients.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/87143/1/30394_ftp.pd

Ovarian reserve diminished by oral cyclophosphamide therapy for granulomatosis with polyangiitis (Wegener's)

Objective Standard treatment for severe granulomatosis with polyangiitis (Wegener's) (GPA) is daily oral cyclophosphamide (CYC), a cytotoxic agent associated with ovarian failure. In this study, we assessed the rate of diminished ovarian reserve in women with GPA who received CYC versus methotrexate (MTX). Methods Patients in the Wegener's Granulomatosis Etanercept Trial received either daily CYC or weekly MTX and were randomized to etanercept or placebo. For all women ages <50 years, plasma samples taken at baseline or early in the study were evaluated against samples taken later in the study to compare levels of anti‐Müllerian hormone (AMH) and follicle‐stimulating hormone (FSH), endocrine markers of remaining egg supply. Diminished ovarian reserve was defined as an AMH level of <1.0 ng/ml. Results Of 42 women in this analysis (mean age 35 years), 24 had CYC exposure prior to enrollment and 28 received the drug during the study. At study entry, women with prior CYC exposure had significantly lower AMH, higher FSH, and a higher rate of early menstruation cessation. For women with normal baseline ovarian function, 6 of 8 who received CYC during the trial developed diminished ovarian reserve, compared to 0 of 4 who did not receive CYC ( P < 0.05). Changes in AMH correlated inversely with cumulative CYC dose ( P < 0.01), with a 0.74 ng/ml decline in AMH level for each 10 gm of CYC. Conclusion Daily oral CYC, even when administered for less than 6 months, causes diminished ovarian reserve, as indicated by low AMH levels. These data highlight the need for alternative treatments for GPA in women of childbearing age.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/88079/1/20605_ftp.pd

Serum Biomarkers of Disease Activity in Longitudinal Assessment of Patients with ANCA-Associated Vasculitis

OBJECTIVE: Improved biomarkers of current disease activity and prediction of relapse are needed in antineutrophil cytoplasmic antibody–associated vasculitis (AAV). For clinical relevance, biomarkers must perform well longitudinally in patients on treatment and in patients with nonsevere flares. METHODS: Twenty‐two proteins were measured in 347 serum samples from 74 patients with AAV enrolled in a clinical trial. Samples were collected at Month 6 after remission induction, then every 3 months until Month 18, or at the time of flare. Associations of protein concentrations with concurrent disease activity and with future flare were analyzed using mixed‐effects models, Cox proportional hazards models, and conditional logistic regression. RESULTS: Forty‐two patients had flares during the 12‐month follow‐up period, and 32 remained in remission. Twenty‐two patients had severe flares. Six experimental markers (CXCL13, IL‐6, IL‐8, IL‐15, IL‐18BP, and matrix metalloproteinase‐3 [MMP‐3]) and ESR were associated with disease activity using all three methods (P < 0.05, with P < 0.01 in at least one method). A rise in IL‐8, IL‐15, or IL‐18BP was associated temporally with flare. Combining C‐reactive protein (CRP), IL‐18BP, neutrophil gelatinase‐associated lipocalin (NGAL), and sIL‐2Rα improved association with active AAV. CXCL13 and MMP‐3 were increased during treatment with prednisone, independent of disease activity. Marker concentrations during remission were not predictive of future flare. CONCLUSION: Serum biomarkers of inflammation and tissue damage and repair have been previously shown to be strongly associated with severe active AAV were less strongly associated with active AAV in a longitudinal study that included mild flares and varying treatment. Markers rising contemporaneously with flare or with an improved association in combination merit further study