Efficacy and Safety Study of Sirukumab in Patients With Giant Cell Arteritis
Condition: Giant Cell Arteritis
MeSH terms: Polymyalgia Rheumatica; Giant Cell Arteritis; Arteritis
Intervention: Sirukumab; Placebo to match sirukumab; Prednisone; Placebo to match prednisone
Intervention description: Sirukumab will be provided as 1 millilitre (mL) Pre-filled Syringe (PFS), containing 100 mg/mL or 50 mg/mL of sirukuma, fitted with a spring-powered, disposable autoinjector device for single use SC administration of liquid biologic drug.; Placebo to match sirukumab will be provided as 1.0 mL PFS fitted with a spring-powered, disposable autoinjector device for single use SC administration of liquid biologic drug.; Prednisone will be provided as tablets with dosage level up to-60 mg/day. The prednisone dose for all subjects will be determined by the Investigator and starting doses will be within 20-60 mg prednisone at Baseline (Randomization).; Placebo to match prednisone will be provided as tablets.
Intervention MeSH terms: Prednisone; Antibodies, Monoclonal
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 161.0
Sex: All
Minimum age: 50 Years
Healthy volunteers: No
Keywords: Giant Cell Arteritis, Sirukumab, Prednisone

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