efficacy and safety study of sirukumab in patients with giant cell arteritis

Conditions: Giant Cell Arteritis

Summary: sirukumab is a fully human anti-interleukin-6 (il-6) immunoglobulin g1-kappa with a high affinity and specificity for binding to the human il-6 molecule that may have therapeutic benefit in the treatment of giant cell arteritis (gca) by interruption of multiple pathogenic pathways. sirukumab inhibits il-6-mediated signal transducer and activator of transcription 3 (stat3) phosphorylation, resulting in the inhibition of the biological effect of il-6. this study will evaluate the efficacy and safety of sirukumab to characterize the benefit-to-risk profile of sirukumab in the treatment of active gca. the study will be conducted in 2 distinct parts (part a and part b) and consists of the following phases: screening phase, part a: 52-week double-blind treatment phase, part b: 104-week extension phase with the option to receive open-label sirukumab based on disease status and a 16-week follow-up phase if applicable. approximately 204 subjects with a diagnosis of gca and active disease within 6 weeks of baseline will be randomized into part a, the 52-week double-blind treatment phase, to receive one of two doses of sirukumab or placebo, each in addition to a pre-specified prednisone taper. the efficacy and safety of sirukumab in sustaining remission will be assessed at week 52. subjects completing part a of the study will be eligible to enter part b, the 104-week extension phase, designed to investigate the long-term maintenance of remission and safety following cessation of sirukumab treatment and to assess long-term corticosteroid use. subjects with active gca at the end of part a or those with new onset of gca flare during the first 52 weeks of part b will be eligible to receive open-label sirukumab. subjects will need to have follow-up safety evaluations for at least 16 weeks after receiving the last dose of study drug, applicable only for those who are withdrawn prematurely from the study or whose open-label sirukumab treatment in part b completes after week 88.


Eligibility criteria:
inclusion criteria: * diagnosis of gca defined by the following revised gca diagnosis criteria: age \>=50 years. history of esr \>=50 millimeter/hour (mm/hour) or crp \>=2.45 milligram/deciliter(mg/dl). presence of at least one of the following: unequivocal cranial symptoms of gca; unequivocal symptoms of polymyalgia rheumatic (pmr). presence of at least one of the following: temporal artery biopsy revealing features of gca; evidence of large-vessel vasculitis by angiography or cross-sectional imaging. * active gca within 6 weeks of randomization (baseline) where active disease is defined by an esr \>=30 mm/hr or crp \>=1 mg/dl and the presence of at least one of the following: unequivocal cranial symptoms of gca; unequivocal symptoms of pmr; other features judged by the clinician investigator to be consistent with gca or pmr flares. * at screening, receiving or able to receive prednisone 20-60 mg/day for the treatment of active gca. * clinically stable gca disease at baseline such that the subject is able to safely participate in the blinded prednisone taper regimen in the opinion of the investigator. * practicing acceptable methods of birth control if a female of child-bearing potential. * no evidence of active or latent infection with mycobacterium tuberculosis (tb). exclusion criteria: * are pregnant or breastfeeding. * recent (within the past 12 weeks) or planned major surgery that would impact on study procedures or assessments. * organ transplantation recipients (except corneas within 3 months prior to baseline visit). * had prior treatment with any of the following: systemic immunosuppressives) within 4 weeks of baseline; biologic agents targeted at reducing tumor necrosis factor-alpha (tnf-alpha) within 2-8 weeks of baseline, depending on the agent; any prior use of tocilizumab or other anti-il-6 agents; b-cell depleting agents (eg, rituximab) within 12 months prior to baseline or longer if b cell counts have not returned to normal range or baseline levels; cytotoxic drugs such as cyclophosphamide, chlorambucil, nitrogen mustard, or other alkylating agents within 4 weeks of baseline; abatacept within 8 weeks of baseline; tofacitinib within 4 weeks of baseline; methotrexate use within 2 weeks of baseline. methylprednisolone \> 100 mg/day intravenous (iv) (or equivalent) within 8 weeks of baseline. * history of severe allergic reactions to monoclonal antibodies, human proteins, or excipients. * evidence of serious concomitant disease, which in the opinion of the investigator makes them unsuitable for participation in the study. * major ischemic event, unrelated to gca, within 12 weeks of screening. * marked baseline prolongation of corrected qt (qtc) interval \>= 450 milliseconds (msec) (qtc by bazett's formula \[qtcb \]or qtc by fridericia's formula \[qtcf\] ), history of torsade de pointes, family history of long qt syndrome, history of second or third degree heart block. * current liver disease that could interfere with the trial * history of or current active diverticulitis, inflammatory bowel disease, or other symptomatic gastrointestinal tract condition that might predispose to bowel perforation. * history of known demyelinating diseases such as multiple sclerosis or optic neuritis. * active infections, or history of recurrent infections or have required management of acute or chronic infections, as follows: currently on any suppressive therapy for a chronic infection, history or suspicion of chronic infection, hospitalization for treatment of infection within 60 days of the baseline visit, or use of parenteral (iv) or intra-muscular \[im\]) antimicrobials within 60 days of baseline or oral antimicrobials within 30 days of baseline * primary or secondary immunodeficiency or any other autoimmune disease. * human immunodeficiency virus (hiv) infection, hepatitis c or hepatitis b infection * live virus or bacterial vaccination within 3 months before the first administration of study drug

Keywords: giant cell arteritis, sirukumab, prednisone