http://orcid.org/0000-0002-0718-213X
Abstract
Objective: To evaluate the efficacy and safety of sirukumab, a human anti-interleukin six monoclonal antibody, in Japanese patients with rheumatoid arthritis who were refractory to anti-tumor necrosis factor therapy.
Methods: This subgroup analysis, based on a double-blind, placebo-controlled, 52-week phase 3, global study (SIRROUND-T) assessed the American College of Rheumatology (ACR) 20 response at week 16 (primary endpoint). Secondary endpoints: ACR 50, Disease Activity Score in 28 joints-C reactive protein, Health Assessment Questionnaire-Disability Index and safety were assessed.
Results 116/878 patients received sirukumab 50 mg/4 weeks (q4w, n = 35), 100 mg/2 weeks (q2w, n = 44) or placebo (n = 37) subcutaneously. Significantly more patients achieved ACR 20 response at week 16 with sirukumab (50 mg q4w:20 [57.1%]; p < .001, 100 mg q2w:24 [54.5%]; p = .001) versus placebo (7 [18.9%]); consistent significant improvement in secondary endpoints at week 24 and 52 was observed. At week 24, incidence of treatment-emergent adverse events (TEAEs) was numerically higher with sirukumab groups (50 mg q4w:29 [82.9%]; 100 mg q2w:38 [86.4%] versus placebo (28 [75.7%]); however, at week 52, sirukumab combined groups had comparable incidence of TEAEs.
Conclusion: Efficacy findings through 52 weeks were comparable between sirukumab doses in Japanese patients and consistent with primary SIRROUND-T study results. No new safety signals were observed.
Introduction
Current therapeutic options for rheumatoid arthritis (RA) include analgesics, conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs), and biological (b) DMARDs [Citation1]. Studies exploring the underlying pathogenesis of RA have highlighted the role of proinflammatory cytokines, such as tumor necrosis factor (TNF), interleukin (IL)-6, IL-1, IL-8 and granulocyte macrophage-colony stimulating factor in pannus formation and joint destruction [Citation1–3]. TNF inhibitors are increasingly used as the first-line of bDMARD therapy in treating RA patients non-responsive to csDMARDs such as methotrexate (MTX) [Citation4]. Despite the effectiveness of anti-TNF therapy, up to two-thirds of RA patients are found to be partially responsive or non-responsive to it [Citation1].
Among the several inflammatory pathways contributing to the underlying pathogenesis of RA, the IL-6 pathway is known to play a critical role. IL-6 induces B-cell autoantibody production and suppresses regulatory T-cell differentiation [Citation5–7]. Also, an increase in IL-6 concentration results in suppression of chondrocytes, activation of synovial fibroblasts and osteoclast maturation, mediating cartilage and bone destruction with perpetuation of inflammation [Citation3].
Tocilizumab, a humanized monoclonal antibody [Citation8,Citation9] that binds to the IL-6 receptor and inhibits downstream IL-6 signaling [Citation10,Citation11], has demonstrated efficacy in RA patients refractory to anti-TNF therapy [Citation12]. Sirukumab is a human anti-IL-6 monoclonal antibody that binds directly to the IL-6 cytokine with high affinity and specificity, thereby inhibiting IL-6-mediated signaling and its related biological effects [Citation13]. Furthermore, it was observed, clazakizumab, an antibody against the IL-6 cytokine, was more potent than tocilizumab in inhibiting IL-6 signaling [Citation14].
The efficacy and safety of sirukumab has recently been evaluated in a randomized, double-blind, placebo-controlled, global, phase 3 study (SIRROUND-T) of sirukumab in patients with active RA refractory or intolerant to anti-TNF agents [Citation15]. In this global study, sirukumab treatment showed significant improvements of signs and symptoms and tolerability. The present subgroup analysis, based on the SIRROUND-T study, was designed to evaluate the efficacy and safety of sirukumab in Japanese patients with RA who were refractory or intolerant to anti-TNF therapy.
Methods
Patients and study design
The detailed study design for the global study, SIRROUND-T (NCT01606761), has been previously reported [Citation15] and is summarized here briefly. SIRROUND-T was conducted between July 2012 and February 2016 at 183 sites located in 20 countries including 38 sites from Japan. It comprised three phases: a screening phase (6 weeks), a blinded treatment phase (52 weeks, including a placebo-controlled period of 24 weeks), and a safety follow-up phase (16 weeks).
Japanese patients (aged ≥20 years) with moderate to severe active RA, who were refractory and had inadequate response to ≥1 or intolerant to ≥2 anti-TNF agents as assessed by the treating physician were included in this subgroup. Patients were also included if they had ≥4 of 68 tender joints, ≥4 of 66 swollen joints, a serum CRP level ≥8.0 mg/L or ESR ≥28 mm/h, and a positive anti-cyclic citrullinated peptide (CCP) antibody or rheumatoid factor (RF) status or history of radiographic evidence of erosive RA in hands or feet. Patients who had received infliximab or intravenous golimumab within 8 weeks, subcutaneous golimumab, adalimumab, or certolizumab pegol within 6 weeks, or etanercept or yisaipu within 4 weeks of study treatment or inadequate response to tocilizumab within 3 months of study treatment were excluded.
This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and in accordance with the International Conference on Harmonization’s Good Clinical Practice guidelines and applicable regulatory requirements. All patients provided written informed consent prior to study enrollment.
Treatment
Patients were randomized (1:1:1) to placebo or sirukumab subcutaneously (50 mg every 4 week [q4w] or 100 mg every 2 week [q2w]) with stratification by MTX use at baseline (0, >0–<12.5 mg/week, ≥12.5 mg/week). Patients on placebo with insufficient (<20%) improvement from baseline in both swollen and tender joint counts at week 18 (early escape [EE]) were re-randomized to receive blinded treatment with 1 of the 2 sirukumab doses. At week 24, all patients who remained on placebo were re-randomized in a blinded manner to receive either of the 2 sirukumab doses through week 52. At or any time after week 24, patients were allowed to adjust or initiate permitted DMARDs including MTX and/or oral corticosteroids at the investigator’s discretion.
Assessments
Treatment failure criteria
In the placebo-controlled period (week 0 to week 24), the treatment was considered to have failed if the patient initiated treatment with csDMARDs, systemic immunosuppressives, oral, intravenous or intramuscular corticosteroids and/or a bDMARD for RA, or increased the dose of MTX or oral corticosteroids for RA above the baseline dose, or discontinued study agent injection due to any reason. In the active-controlled period (week 24 to week 52), discontinuation of the study agent was considered as treatment failure. The treatment failure status in the placebo-controlled period could be reset for the active-controlled period and re-assessed based on the treatment failure criteria from week 24 to week 52.
Efficacy assessments
The primary endpoint of the subgroup analysis was the American College of Rheumatology (ACR) 20 response at week 16. Major secondary efficacy endpoints included change from baseline in HAQ-DI score at week 24, proportion of patients who achieved ACR 50 response at week 24, proportion of patients with disease activity index score 28 joint (DAS28)-CRP remission (defined as a DAS28 [CRP] value of <2.6 at a visit) at week 24. Other secondary endpoints were ACR responses (20/70), DAS28 (CRP) change from baseline and response, change from baseline in Clinical Disease Activity Index (CDAI) and Simple Disease Activity Index (SDAI), Boolean and SDAI-based ACR/European League Against Rheumatism (EULAR) remission, proportions of patients achieving HAQ-DI response (decrease from baseline in HAQ-DI by ≥0.22) and HAQ-DI ≤0.5 at week 24, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), 36-item Short Form Health Survey, and the EuroQol five dimensions health status measure (EQ-5D).
Immunogenicity assessment
Immunogenicity was assessed based on the incidence and titers of antibodies to sirukumab.
Safety assessments
Safety evaluations included assessment of treatment-emergent adverse events (TEAEs), vital signs, and clinical laboratory examinations. Number of patients with abnormal post-baseline values for clinical laboratory test was graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 4.03).
Statistical analysis
In the global study, the sample size was calculated in order to achieve a power of ∼93–99% to detect the treatment difference of 13–22% in the ACR 20 responders at week 16 between each sirukumab treatment group and the placebo group, which corresponded to the odds ratio of 2–2.5. In this analysis, the treatment difference in the proportion of patients who achieved an ACR response and DAS28 (CRP) < 2.6 for each of the subgroups were analyzed using a Cochran–Mantel–Haenszel test stratified by the use of MTX at baseline. The p value for the interaction of the treatment group and the subgroup were provided for subgroups with at least 2 categories and were tested at a two-sided α level of .05. To compare the differences between treatment groups, an analysis of covariance model was used. The 95% confidence intervals (CIs) for differences in least square means between the sirukumab and the placebo groups, and p values were calculated based on contrast test statistics. Since this analysis was exploratory, the statistics was not adjusted for multiple testing.
Efficacy full analysis set (placebo-controlled period) included all randomized patients and efficacy analysis set (active-controlled period) included all randomized patients who were on study agent at week 24. The safety analysis set included patients who received ≥1 dose of study agent. All safety analyses were based on observed data.
Results
Patient disposition and characteristics
Of the 878 total global patients, 116 (13.2%) Japanese patients were randomized to sirukumab 50 mg q4w (n = 35), 100 mg q2w group (n = 44) or placebo (n = 37) (). The mean body weight (56.8 kg) of Japanese patients was comparable across all treatment groups. Of note, 36/116 patients (31.0%) had received two or more anti-TNF agents previously. The proportion of patients taking csDMARDs at baseline was 88.8%, and MTX was the most commonly used concomitant csDMARD (72.4%). Baseline demographics and disease activity were similar among treatment groups (). Furthermore, of the 79 patients in the sirukumab group, 61 patients (50 mg q4w: n = 26, 100 mg q2w: n = 35) completed the study drug treatment at week 52 and 18 patients discontinued the treatment prior to week 52. Of the 37 placebo patients, 14 completed the week 24 visit and were crossed over (CO) to sirukumab (50 mg q4w: 8 patients, 100 mg q2w: 6 patients). Prior to week 24, 7 patients withdrew from the study and 16 patients escaped to sirukumab (50 mg q4w: 7 patients, 100 mg q2w: 9 patients); a total of 26/37 patients completed sirukumab treatment at week 52. The most common reason for study drug discontinuation was TEAEs (placebo to 50 mg q4w CO: 1/15 patients [6.7%], placebo to 100 mg q2w CO: 3/15 patients [20%], and 50 mg q4w: 4/35 patients, 100 mg q2w: 5/44 patients; both [11.4%]).
Figure 1. Study design and patient disposition for Japanese subgroup. EE: easy escape; CO: crossover.
Table 1. Demographic and baseline characteristics.
Efficacy
The proportion of patients with ACR 20 response at week 16 (primary endpoint) was significantly higher in both sirukumab 50 mg q4w (20/35 patients [57.1%]; p < .001) and 100 mg q2w (24/44 patients [54.5%]; p = .001) groups as compared with placebo (7/37 patients [18.9%]). Proportion of patients with ACR 50 response (50 mg q4w: 25.7%, p = .047; 100 mg q2w: 29.5%, p = .014 vs. placebo: 8.1%) () and DAS28 (CRP) < 2.6 (50 mg q4w: 37.1%; 100 mg q2w: 38.6%; both p < .001 vs. placebo: 5.4%) in both sirukumab groups were significantly higher than the placebo group at week 24. In addition, a greater reduction from baseline in HAQ-DI score (50 mg q4w: −0.40, p = .001; 100 mg q2w: −0.34, p = .002) was observed in the sirukumab group versus placebo (−0.01) at week 24. Of the other secondary efficacy endpoints (except SDAI- and Boolean-based ACR/EULAR remission, HAQ-DI response, HAQ-DI ≤0.5 response, and proportions of patients with clinically meaningful improvement in SF-36 summary scores), sirukumab treatment groups showed significant improvement compared with the placebo group in the Japanese patients in this study (, Supplementary Table S1).
Figure 2. Proportion of patients who achieved an ACR 20 and ACR 50 response over time (Efficacy full analysis set). aThe confidence intervals are based on the Wald statistic; bThe p values are based on the CMH test. ACR: American college of rheumatology; CI: confidence interval.
Table 2. Summary of secondary efficacy endpoints through week 24 (full analysis set).
A significantly greater improvement from baseline at week 24 was observed with both sirukumab doses compared with placebo for the SF-36 questionnaire in both the physical and mental component scores, FACIT Fatigue score (mean change from baseline and proportion of responders), and EQ-5D for Visual Analogue Scale (VAS) scores (both sirukumab groups: p = .006) and index scores (50 mg q4w: p = .003 and 100 mg q2w: p < .001) (Supplementary Table S1).
Safety
The average duration of follow up in both the sirukumab groups through week 52 was 42 weeks (). In the placebo-controlled period (through week 24), the incidence of TEAEs in both sirukumab groups (50 mg q4w: 29/35 patients [82.9%], 100 mg q2w: 38/44 patients [86.4%]) was numerically higher compared with those in placebo (28/37 patients [75.7%]), however, those of serious TEAEs and TEAEs leading to discontinuation were comparable in the sirukumab groups and placebo group (). Through 52 weeks, the incidence of TEAEs, serious TEAEs, and TEAEs leading to discontinuation was generally comparable between the sirukumab treatment groups. No deaths were observed in the Japanese patients during the 52 weeks of study treatment. Adverse events of special interest (serious infection, malignancy, gastrointestinal [GI] perforation, major adverse cardiovascular events [MACE]) were minimal in the sirukumab group (serious infection: 2 patients from 50 mg q4w, 3 patients from 100 mg q2w; malignancy and GI perforations: 1 patient each in 100 mg q2w, and MACE: 1 patient in 50 mg q2w group) through week 52. Tuberculosis infection, pneumocystis pneumonia, and interstitial pneumonia were not reported in this Japanese subgroup.
Table 3. Summary of treatment-emergent adverse events (safety analysis set).
The incidence of injection-site reaction in the sirukumab 100 mg q2w combined group (19/59 patients [32.2%]) was higher compared with that in the sirukumab 50 mg q4w combined group (7/49 patients [14.3%]). No severe injection-site reaction was reported.
Through week 52, the most frequently occurring TEAEs (in ≥10% of patients) were nasopharyngitis (50 mg q4w combined: 26.5%; 100 mg q2w combined: 27.1%), and injection-site erythema (50 mg q4w combined: 14.3%; 100 mg q2w combined: 27.1%). The majority of the TEAEs in the sirukumab groups were mild to moderate in severity ().
Grade 3 decrease in neutrophils was observed in a few Japanese patients (sirukumab 50 mg q4w [combined], 3/49 patients [6.1%]; sirukumab 100 mg q4w [combined], 1/59 patients [1.7%]), however, these neutrophil decreases were not associated with the occurrence of severe infection. One patient each was observed to have Grade 3 increase in alanine aminotransferase (ALT) (both sirukumab dose groups) and increase in triglycerides (sirukumab 100 mg q2w [combined]) (Supplementary Table S2). The proportion of patients with laboratory abnormalities of decreased leukocyte or increased aminotransferase showed similar shift from baseline at week 52 to those at week 24 (Supplementary Table S3). There was no incidence of antibodies to sirukumab through week 52 in Japanese patients in this study.
Discussion
In this subgroup analysis of Japanese patients with refractory RA with an inadequate response to TNF inhibitors and csDMARDs, sirukumab therapy (50 mg q4w and 100 mg q2w) resulted in a significantly greater proportion of patients achieving ACR 20 response at week 16 versus placebo; consistent with those in the global study (SIRROUND-T) [Citation15]. Similar improvement in ACR 20 response at week 16 was also observed in patients who had received treatment for RA in the phase 3 studies of sarilumab and tocilizumab [Citation16,Citation17]. Sirukumab treatment in Japanese patients showed early improvement in terms of ACR 20 response (week 4 in the 100 mg q2w and week 8 in the 50 mg q4w group), and responses were maintained through week 52.
As observed, the percentage of Japanese responders was slightly higher in the present study as compared with the global study [Citation15]; this might be due to ethnic differences. Similar differences in relation to ethnic aspects affecting the response have been reported earlier [Citation18,Citation19]. Similar results were observed in a subgroup analysis of Japanese patients in an other phase 3 study (SIRROUND-D) conducted in patients with RA who were refractory to DMARDs [Citation20]. However, the reasons for the difference in response rates between Japan and the global population are unknown.
Improvement for all major secondary endpoints (mean change in baseline of HAQ-DI score, DAS28 remission, and ACR 50 response) and improvement for the physical and mental components of SF-36 and FACIT fatigue scores were observed for both the doses of sirukumab versus placebo at week 24 and maintained through week 52. These sirukumab efficacy findings in Japanese patients were generally similar to the results in overall population [Citation15]. Secondary efficacy parameters, observed in the present study are also consistent with that in the phase 3 studies of sarilumab and tocilizumab [Citation16,Citation17]. There was no clear dose-dependent effect observed in clinical efficacy measures between the 2 sirukumab doses.
The safety profile of sirukumab in the present subgroup analysis through week 52 was consistent with other sirukumab treatment studies [Citation15,Citation20,Citation21], as well as with those reported for agents targeting the IL-6 receptor like tocilizumab, olokizumab, and sarilumab [Citation17,Citation22,Citation23]. The number of TEAEs and study drug discontinuations due to adverse events in the sirukumab-treated patients was similar to the placebo group. Infections were among the most frequently observed serious TEAEs in the sirukumab groups. No apparent dose relationship was observed in the types or frequencies of TEAEs, except for a greater incidence of injection-site reactions in sirukumab 100 mg q2w than sirukumab 50 mg q4w group in the present study, consistent with the global study (SIRROUND-T) [Citation15]. The majority of the TEAEs were of mild to moderate severity. Majority of patients showed no shift from baseline; however, few patients showed post baseline shifts below normal range for neutrophil, platelet, hemoglobin and white blood cell counts and above normal range for ALT and aspartate aminotransferase levels. In the present analysis, 1 case each of GI perforation, malignancy and MACE was observed in the sirukumab group, which are known risks associated with anti-IL-6 therapy. No deaths were reported in the Japanese population. On the other hand, higher incidences of death in sirukumab groups (including deaths due to MACE) compared to placebo were a potential safety signal noted by health authorities in the global SIRROUND phase 3 studies [Citation15,Citation20]. This dissimilarity would be possibly due to the limited sample size of this subpopulation or the lower incidence of MACE in the Japanese RA population [Citation24,Citation25]. None of the patients were positive for antibodies against sirukumab through week 52.
The relatively smaller number of Japanese patients and lack of radiographic data were limitations for this subgroup analysis. The placebo group also included patients who escaped at week 18 and were treated with sirukumab, which could influence the results of the placebo group. Additionally, patients were allowed to adjust or initiate DMARDs after week 24, which could be a confounding factor. Furthermore, as this subgroup analysis included Japanese patients refractory to most of the treatment regimens of RA, generalizability of these results to treatment naïve patients with RA is quite limited.
In conclusion, sirukumab at 50 mg q4w and 100 mg q2w for 52 weeks improved signs and symptoms of RA, function and physical and mental health status of Japanese patients who were refractory to anti-TNF agents. Efficacy outcomes were comparable among the two sirukumab doses. The safety profile of sirukumab in Japanese patients was consistent with previous sirukumab and other studies of IL-6 receptor inhibitors except the potential signal of cardiovascular events, which was not observed in Japanese patients.
Conflict of interest
None.
CNTO136ARA3003_Subgroup_Analysis_MSS_Supplementary_tables.docm
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The authors thank the study participants without whom this study would never have been accomplished and also thank the investigators and their institutions for their participation in the study. Writing assistance was provided by Rukhsar Wasta and additional editorial support was provided by Sangita Patil (both SIRO Clinpharm Pvt. Ltd., Thane, India) funded by Janssen Pharmaceutical K.K., Japan.
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References
- Kim GW, Lee NR, Pi RH, Lim YS, Lee YM, Lee JM, et al. IL-6 inhibitors for treatment of rheumatoid arthritis: past, present, and future. Arch Pharm Res. 2015;38(5):575–84.
- Vasanthi P, Nalini G, Rajasekhar G. Role of tumor necrosis factor-alpha in rheumatoid arthritis: a review. Int J Rheum Dis. 2007;10(4):270–4.
- Feldmann M, Brennan FM, Maini RN. Role of cytokines in rheumatoid arthritis. Annu Rev Immunol. 1996;14(1):397–440.
- Detert J, Klaus P. Biologic monotherapy in the treatment of rheumatoid arthritis. Biol Targets Ther. 2015;9:35–43.
- Hashizume M, Mihara M. The roles of interleukin-6 in the pathogenesis of rheumatoid arthritis. Arthritis. 2011;2011:765624.
- Srirangan S, Choy EH. The role of interleukin-6 in the pathophysiology of rheumatoid arthritis. Ther Adv Musculoskelet Dis. 2010;2(5):247–56.
- Kimura A, Kishimoto T. IL-6: regulator of Treg/Th17 balance. Eur J Immunol. 2010;40(7):1830–5.
- Strand V, Burmester GR, Ogale S, Devenport J, John A, Emery P. Improvements in health-related quality of life after treatment with tocilizumab in patients with rheumatoid arthritis refractory to tumour necrosis factor inhibitors: results from the 24-week randomized controlled RADIATE study. Rheumatology. 2012;51(10):1860–9.
- Smolen JS, Weinblatt ME, Sheng S, Zhuang Y, Hsu B. Sirukumab, a human anti-interleukin-6 monoclonal antibody: a randomised, 2-part (proof-of-concept and dose-finding), phase II study in patients with active rheumatoid arthritis despite methotrexate therapy. Ann Rheum Dis. 2014;73(9):1616–25.
- Hennigan S, Kavanaugh A. Interleukin-6 inhibitors in the treatment of rheumatoid arthritis. Ther Clin Risk Manag. 2008;4(4):767–75.
- Jordan N, Lutalo PM, D’Cruz DP. Novel therapeutic agents in clinical development for systemic lupus erythematosus. BMC Med. 2013;11(1):120.
- Ogata A, Hirano T, Hishitani Y, Tanaka T. Safety and efficacy of tocilizumab for the treatment of rheumatoid arthritis. Clin Med Insights Arthritis Musculoskelet Disord. 2012;5:27–42.
- Xu Z, Bouman-Thio E, Comisar C, Frederick B, Van Hartingsveldt B, Marini JC, et al. Pharmacokinetics, pharmacodynamics and safety of a human anti-IL-6 monoclonal antibody (sirukumab) in healthy subjects in a first-in-human study. Br J Clin Pharmacol. 2011;72(2):270–81.
- Zhao Q, Pang J, Shuster D, Hung C, Baglino S, Dodge R, et al. Anti-IL-6 antibody clazakizumabiIs more potent than tocilizumab in blocking in vitro and ex vivo IL-6-induced functions. Arthritis Rheum. 2013;65(Suppl):S1020.
- Aletaha D, Bingham CO, Tanaka Y, Agarwal P, Kurrasch R, Tak PP, et al. Efficacy and safety of sirukumab in patients with active rheumatoid arthritis refractory to anti-TNF therapy (SIRROUND-T): a randomised, double-blind, placebo-controlled, parallel-group, multinational, phase 3 study. Lancet. 2017;389(10075):1206–17.
- Fleischman R, van Adelsberg J, Lin Y, Castelar-Pinheiro G, Brzezicki J, Hrycaj P, et al. Sarilumab and nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis and inadequate response or intolerance to tumor necrosis factor inhibitors. Arthritis Rheum. 2017;69(2):277–290.
- Emery P, Keystone E, Tony H, Cantagrel A, Van Vollenhoven R, Sanchez A, et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24–week multicentre randomised placebo-controlled trial. Ann Rheum Dis. 2008;67(11):1516–23.
- Weinblatt ME, Kavanaugh A, Genovese MC, Musser TK, Grossbard EB, Magilavy DB. An oral spleen tyrosine kinase (Syk) inhibitor for rheumatoid arthritis. N Engl J Med. 2010;363(14):1303–12.
- Cohen SB, Emery P, Greenwald MW, Dougados M, Furie RA, Genovese MC, et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum. 2006;54(9):2793–806.
- Takeuchi T, Thorne C, Karpouzas G, Sheng S, Xu W, Rao R, et al. Sirukumab for rheumatoid arthritis: the phase III SIRROUND-D study. Ann Rheum Dis. 2017;76(12):2001–8.
- Takeuchi T, Yamanaka H, Harigai M, Tamamura R, Kato Y, Ukyo Y, et al. One-year safety of sirukumab monotherapy: results from a randomized, double-blind, parallel-group, multicenter study in Japanese subjects with moderate to severe rheumatoid arthritis. Arthritis Rheumatol. 2015;67(Suppl 10):2063–5. Abstract 1672.
- Huizinga TW, Fleischmann RM, Jasson M, Radin AR, van Adelsberg J, Fiore S, et al. Sarilumab, a fully human monoclonal antibody against IL-6Rα in patients with rheumatoid arthritis and an inadequate response to methotrexate: efficacy and safety results from the randomised SARIL-RA-MOBILITY Part A trial. Ann Rheum Dis. 2014;73(9):1626–34.
- Genovese MC, Fleischmann R, Furst D, Janssen N, Carter J, Dasgupta B, et al. Efficacy and safety of olokizumab in patients with rheumatoid arthritis with an inadequate response to TNF inhibitor therapy: outcomes of a randomised Phase IIb study. Ann Rheum Dis. 2014;73(9):1607–15.
- Michaud K, Berglind N, Franzén S, Frisell T, Garwood C, Greenberg JD, et al. Can rheumatoid arthritis (RA) registries provide contextual safety data for modern RA clinical trials? The case for mortality and cardiovascular disease. Ann Rheum Dis. 2016;75:1797–805.
- Yamamoto K, Goto H, Hirao K, Nakajima A, Origasa H, Tanaka K, et al. Long term safety of tocilizumab: results from 3 years of follow up postmarketing surveillance of 5573 patients with rheumatoid arthritis in Japan. J Rheumatol. 2015;42:1368–75.