Efficacy and Safety Study of Sirukumab in Patients With Giant Cell Arteritis

GlaxoSmithKline (GSK)

Status and phase: Terminated; Phase 3

Conditions: Giant Cell Arteritis

Treatments: Drug: Placebo to match prednisone; Drug: Sirukumab; Drug: Placebo to match sirukumab; Drug: Prednisone

Study type: Interventional

Funder types: Industry

Identifiers

NCT02531633

201677

Details and patient eligibility

About

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safety evaluations for at least 16 weeks after receiving the last dose of study drug, applicable only for those who are withdrawn prematurely from the study or whose open-label sirukumab treatment in Part B completes after Week 88.

Enrollment: 161 patients

Sex: All

Ages: 50+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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161 participants in 6 patient groups, including a placebo group

Part A: Sirukumab, Dose 1+prednisone (6-month taper)

Experimental group

Description:

Subjects will receive blinded sirukumab 100 mg subcutaneously (SC) every 2 weeks (q2w) for 52 weeks plus a pre-specified maximum of 6-month oral prednisone taper regimen.

Treatment:

Drug: Placebo to match prednisone

Drug: Prednisone

Drug: Sirukumab

Part A: Sirukumab, Dose 1+prednisone (3-month taper)

Experimental group

Description:

Subjects will receive blinded sirukumab 100 mg SC q2w for 52 weeks plus a pre-specified maximum of 3-month oral prednisone taper regimen.

Treatment:

Drug: Placebo to match prednisone

Drug: Prednisone

Drug: Sirukumab

Part A: Sirukumab, Dose 2+prednisone (6-month taper)

Experimental group

Description:

Subjects will receive blinded sirukumab 50 mg SC every 4 weeks (q4w) for 52 weeks plus a pre-specified maximum of 6-month oral prednisone taper regimen.

Treatment:

Drug: Placebo to match prednisone

Drug: Prednisone

Drug: Sirukumab

Part A:Placebo to match sirutkumab+prednisone (6-month taper)

Placebo Comparator group

Description:

Subjects will receive blinded placebo to match sirutkumab q2w for 52 weeks plus a pre-specified maximum of 6-month oral prednisone taper regimen.

Treatment:

Drug: Placebo to match prednisone

Drug: Prednisone

Drug: Placebo to match sirukumab

Part A:Placebo to match sirukumab+prednisone (12-month taper)

Placebo Comparator group

Description:

Subjects will receive blinded placebo to match sirutkumab q2w for 52 weeks plus a pre-specified maximum of 12-month oral prednisone taper regimen.

Treatment:

Drug: Placebo to match prednisone

Drug: Prednisone

Drug: Placebo to match sirukumab

Part B:Open-label sirukumab 100 mg SC (if applicable)

Experimental group

Description:

Subjects completing Part A will receive open label 100 mg SC q2w for a maximum of 52 weeks based on remission status and disease activity at the primary 52-week endpoint or prednisone tapering status of subject during Part A. Methotrexate will be provided to subjects, alone or in addition to sirukumab treatment during Part B, based on the discretion of the investigator.

Treatment:

Drug: Sirukumab