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

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

Efficacy and safety of mavrilimumab in giant cell arteritis:a phase 2, randomised, double-blind, placebo-controlled trial

OBJECTIVES: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is implicated in pathogenesis of giant cell arteritis. We evaluated the efficacy of the GM-CSF receptor antagonist mavrilimumab in maintaining disease remission. METHODS: This phase 2, double-blind, placebo-controlled trial enrolled patients with biopsy-confirmed or imaging-confirmed giant cell arteritis in 50 centres (North America, Europe, Australia). Active disease within 6 weeks of baseline was required for inclusion. Patients in glucocorticoid-induced remission were randomly assigned (3:2 ratio) to mavrilimumab 150 mg or placebo injected subcutaneously every 2 weeks. Both groups received a 26-week prednisone taper. The primary outcome was time to adjudicated flare by week 26. A prespecified secondary efficacy outcome was sustained remission at week 26 by Kaplan-Meier estimation. Safety was also assessed. RESULTS: Of 42 mavrilimumab recipients, flare occurred in 19% (n=8). Of 28 placebo recipients, flare occurred in 46% (n=13). Median time to flare (primary outcome) was 25.1 weeks in the placebo group, but the median was not reached in the mavrilimumab group (HR 0.38; 95% CI 0.15 to 0.92; p=0.026). Sustained remission at week 26 was 83% for mavrilimumab and 50% for placebo recipients (p=0.0038). Adverse events occurred in 78.6% (n=33) of mavrilimumab and 89.3% (n=25) of placebo recipients. No deaths or vision loss occurred in either group. CONCLUSIONS: Mavrilimumab plus 26 weeks of prednisone was superior to placebo plus 26 weeks of prednisone for time to flare by week 26 and sustained remission in patients with giant cell arteritis. Longer treatment is needed to determine response durability and quantify the glucocorticoid-sparing potential of mavrilimumab. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number: NCT03827018, Europe (EUdraCT number: 2018-001003-36), and Australia (CT-2018-CTN-01 865-1)

Improved Visual Outcomes in Giant Cell Arteritis From Prior Use of Corticosteroids May Be Dose-Dependent (.pdf)

The literature suggests high-dose steroids have a protective effect in preserving vision in giant cell arteritis (GCA), however, the optimal dose has not been well elucidated. Clinical observation has noted that prior use of corticosteroids may result in less GCArelated visual dysfunction. Our hypothesis was that patients with corticosteroid use prior to visual dysfunction had a dose dependent benefit with improved visual outcomes in comparison to patients not on prior corticosteroids

Newly diagnosed vs. relapsing giant cell arteritis:Baseline data from the GiACTA trial

OBJECTIVE: To report entry criteria and clinical features of patients with newly diagnosed and relapsing giant cell arteritis (GCA) enrolled in a randomized trial of tocilizumab, an interleukin-6 receptor-alpha inhibitor.METHODS: Newly diagnosed GCA was defined as diagnosis ≤6 weeks before baseline. Relapsing GCA was defined as diagnosis &gt;6 weeks before baseline with ≥2 consecutive weeks of prednisone ≥40mg/day. All patients had active GCA within 6 weeks of baseline. All statistical results are exploratory.RESULTS: Of 251 patients, 119 (47%) had newly diagnosed and 132 (53%) had relapsing GCA. Mean age was 69 years in both subsets; 75% were women. Relapsing patients were heavier [difference in means (95% CI): women, 4.18kg (0.49-7.87, P = 0.027); men, 8.25kg (1.42-15.09, P = 0.019)] and had higher mean body mass index [difference in means (95% CI): women, 1.72kg/m(2) (0.44-2.99, P = 0.009); men, 2.85kg/m(2) (0.3(2)-5.37, P = 0.028)]. Relapsers had higher baseline prevalence of depression (16% vs. 4%) and osteopenia/osteoporosis (33% vs. 23%, P = 0.002 and P = 0.062, respectively). At diagnosis, 67% had new-onset headaches; 34% had mouth pain/jaw claudication. One-fifth had polymyalgia rheumatica symptoms but no cranial manifestations; 62% had positive temporal artery biopsy findings; 37% were enrolled on the basis of cross-sectional imaging study findings.CONCLUSIONS: Demographics of the GiACTA population reflect the epidemiologic profile of GCA. Baseline comorbidities associated with glucocorticoids were more prevalent among relapsing patients than among those with newly diagnosed disease, highlighting the need for new GCA treatment options. More than one-third of patients were enrolled based on large-vessel imaging.</p

Newly diagnosed vs. relapsing giant cell arteritis: Baseline data from the GiACTA trial

OBJECTIVE: To report entry criteria and clinical features of patients with newly diagnosed and relapsing giant cell arteritis (GCA) enrolled in a randomized trial of tocilizumab, an interleukin-6 receptor-alpha inhibitor. METHODS: Newly diagnosed GCA was defined as diagnosis ≤6 weeks before baseline. Relapsing GCA was defined as diagnosis >6 weeks before baseline with ≥2 consecutive weeks of prednisone ≥40mg/day. All patients had active GCA within 6 weeks of baseline. All statistical results are exploratory. RESULTS: Of 251 patients, 119 (47%) had newly diagnosed and 132 (53%) had relapsing GCA. Mean age was 69 years in both subsets; 75% were women. Relapsing patients were heavier [difference in means (95% CI): women, 4.18kg (0.49-7.87, P = 0.027); men, 8.25kg (1.42-15.09, P = 0.019)] and had higher mean body mass index [difference in means (95% CI): women, 1.72kg/m2 (0.44-2.99, P = 0.009); men, 2.85kg/m2 (0.32-5.37, P = 0.028)]. Relapsers had higher baseline prevalence of depression (16% vs. 4%) and osteopenia/osteoporosis (33% vs. 23%, P = 0.002 and P = 0.062, respectively). At diagnosis, 67% had new-onset headaches; 34% had mouth pain/jaw claudication. One-fifth had polymyalgia rheumatica symptoms but no cranial manifestations; 62% had positive temporal artery biopsy findings; 37% were enrolled on the basis of cross-sectional imaging study findings. CONCLUSIONS: Demographics of the GiACTA population reflect the epidemiologic profile of GCA. Baseline comorbidities associated with glucocorticoids were more prevalent among relapsing patients than among those with newly diagnosed disease, highlighting the need for new GCA treatment options. More than one-third of patients were enrolled based on large-vessel imaging.status: publishe