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

NCT ID: NCT02531633

Last Updated: 2019-07-31

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 161 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-10-16
• Study Completion Date: 2018-03-21

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evaluations for at least 16 weeks after receiving the last dose of study drug, applicable only for those who are withdrawn prematurely from the study or whose open-label sirukumab treatment in Part B completes after Week 88.

Conditions

Giant Cell Arteritis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

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

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.

Group Type: EXPERIMENTAL

Sirukumab

Intervention Type: DRUG

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.

Prednisone

Intervention Type: 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

Intervention Type: DRUG

Placebo to match prednisone will be provided as tablets.

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

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

Group Type: EXPERIMENTAL

Sirukumab

Intervention Type: DRUG

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.

Prednisone

Intervention Type: 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

Intervention Type: DRUG

Placebo to match prednisone will be provided as tablets.

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

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.

Group Type: EXPERIMENTAL

Sirukumab

Intervention Type: DRUG

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.

Prednisone

Intervention Type: 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

Intervention Type: DRUG

Placebo to match prednisone will be provided as tablets.

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

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

Group Type: PLACEBO_COMPARATOR

Placebo to match sirukumab

Intervention Type: 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

Intervention Type: 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

Intervention Type: DRUG

Placebo to match prednisone will be provided as tablets.

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

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

Group Type: PLACEBO_COMPARATOR

Placebo to match sirukumab

Intervention Type: 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

Intervention Type: 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

Intervention Type: DRUG

Placebo to match prednisone will be provided as tablets.

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

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.

Group Type: EXPERIMENTAL

Sirukumab

Intervention Type: DRUG

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.

Interventions

Sirukumab

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.

Intervention Type: DRUG

Placebo to match sirukumab

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.

Intervention Type: DRUG

Prednisone

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).

Intervention Type: DRUG

Placebo to match prednisone

Placebo to match prednisone will be provided as tablets.

Intervention Type: DRUG

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

• Minimum Eligible Age: 50 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

GlaxoSmithKline

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

GSK Clinical Trials

Role: STUDY_DIRECTOR

GlaxoSmithKline

Locations

GSK Investigational Site

Aurora, Colorado, United States

GSK Investigational Site

Boca Raton, Florida, United States

GSK Investigational Site

Naples, Florida, United States

GSK Investigational Site

Iowa City, Iowa, United States

GSK Investigational Site

Boston, Massachusetts, United States

GSK Investigational Site

Boston, Massachusetts, United States

GSK Investigational Site

Rochester, Minnesota, United States

GSK Investigational Site

New York, New York, United States

GSK Investigational Site

Philadelphia, Pennsylvania, United States

GSK Investigational Site

Jackson, Tennessee, United States

GSK Investigational Site

Dallas, Texas, United States

GSK Investigational Site

Seattle, Washington, United States

GSK Investigational Site

Vancouver, Washington, United States

GSK Investigational Site

Camperdown, New South Wales, Australia

GSK Investigational Site

Kogarah, New South Wales, Australia

GSK Investigational Site

Woodville, South Australia, Australia

GSK Investigational Site

Heidelberg, Victoria, Australia

GSK Investigational Site

Malvern East, Victoria, Australia

GSK Investigational Site

Victoria Park, Western Australia, Australia

GSK Investigational Site

Leuven, , Belgium

GSK Investigational Site

Liège, , Belgium

GSK Investigational Site

Plovdiv, , Bulgaria

GSK Investigational Site

Sofia, , Bulgaria

GSK Investigational Site

Bobigny, , France

GSK Investigational Site

Orléans, , France

GSK Investigational Site

Paris, , France

GSK Investigational Site

Paris, , France

GSK Investigational Site

Tübingen, Baden-Wurttemberg, Germany

GSK Investigational Site

Hanover, Lower Saxony, Germany

GSK Investigational Site

Düsseldorf, North Rhine-Westphalia, Germany

GSK Investigational Site

Dresden, Saxony, Germany

GSK Investigational Site

Jena, Thuringia, Germany

GSK Investigational Site

Bad Abbach, , Germany

GSK Investigational Site

Berlin, , Germany

GSK Investigational Site

Berlin, , Germany

GSK Investigational Site

Hamburg, , Germany

GSK Investigational Site

Kirchheim unter Teck, , Germany

GSK Investigational Site

München, , Germany

GSK Investigational Site

Budapest, , Hungary

GSK Investigational Site

Debrecen, , Hungary

GSK Investigational Site

Reggio Emilia, Emilia-Romagna, Italy

GSK Investigational Site

Milan, Lombardy, Italy

GSK Investigational Site

Rozzano, , Italy

GSK Investigational Site

Almelo, , Netherlands

GSK Investigational Site

Groningen, , Netherlands

GSK Investigational Site

Nijmegen, , Netherlands

GSK Investigational Site

Hamilton, , New Zealand

GSK Investigational Site

Timaru, , New Zealand

GSK Investigational Site

Krakow, , Poland

GSK Investigational Site

A Coruña, , Spain

GSK Investigational Site

Barcelona, , Spain

GSK Investigational Site

Barcelona, , Spain

GSK Investigational Site

Barcelona, , Spain

GSK Investigational Site

Bilbao, , Spain

GSK Investigational Site

San Cristóbal de La Laguna, , Spain

GSK Investigational Site

Westcliff-on-Sea, Essex, United Kingdom

GSK Investigational Site

Metropolitan Borough of Wirral, Merseyside, United Kingdom

GSK Investigational Site

Bury St Edmunds, Suffolk, United Kingdom

GSK Investigational Site

Sheffield, Yorkshire, United Kingdom

GSK Investigational Site

Edinburgh, , United Kingdom

GSK Investigational Site

Leeds, , United Kingdom

GSK Investigational Site

Oxford, , United Kingdom

GSK Investigational Site

Reading, , United Kingdom

Countries

United States; Australia; Belgium; Bulgaria; France; Germany; Hungary; Italy; Netherlands; New Zealand; Poland; Spain; United Kingdom

References

Schmidt WA, Dasgupta B, Luqmani R, Unizony SH, Blockmans D, Lai Z, Kurrasch RH, Lazic I, Brown K, Rao R. A Multicentre, Randomised, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Sirukumab in the Treatment of Giant Cell Arteritis. Rheumatol Ther. 2020 Dec;7(4):793-810. doi: 10.1007/s40744-020-00227-2. Epub 2020 Aug 25.

Reference Type: DERIVED

PMID: 32844378 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

201677

Identifier Type: -

Identifier Source: org_study_id