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

NCT02531633 | Terminated Phase 3 Results DMC

• 1 other identifier: 201677
• Study Type: interventional
• Target: 161
• Locations: 13 countries
• Sites: 63

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evaluations for at least 16 weeks after receiving the last dose of study drug, applicable only for those who are withdrawn prematurely from the study or whose open-label sirukumab treatment in Part B completes after Week 88.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

Keywords

Giant Cell Arteritis, Sirukumab, Prednisone

Outcome Measures

Primary Outcomes (1)

• Part A: Number of Participants in Sustained Remission at Week 52

  Sustained remission was defined as having achieved all of the following: 1) remission at Week 12, 2) absence of disease flare Week 12 through Week 52, 3) completion of the assigned prednisone taper, and 4) no requirement for rescue therapy through Week 52. Remission was defined as absence of clinical signs and symptoms of GCA and normalization of erythrocyte sedimentation rate (ESR) \[\<30 millimeters per hour\] and C-reactive Protein (CRP) \[\<1 milligram/deciliter\]) and flare was defined as recurrence of symptoms attributable to active GCA, with or without elevations in ESR and/or CRP. Data for number of participants in sustained remission at Week 52 is presented. Only those participants who completed Week 52 visit or withdrew before 10 Oct 2017 were included in the analysis.

  Week 52

Secondary Outcomes (91)

• Part B: Number of Participants Who Remained in Sustained Remission Without Requirement for Rescue Therapy or Treatment Change at Week 24

  Week 24

• Part A: Cumulative Prednisone Dose Over Time

  Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52

• Part B: Number of Participants in Sustained Remission Over Time

  Weeks 4, 8 and 12

• Part A: Time to First Disease Flare After Clinical Remission

  Week 52

• Part B: Time to First Disease Flare for Participants in Sustained Remission

  Week 52

Study Arms (6)

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

EXPERIMENTAL

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.

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

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

EXPERIMENTAL

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

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

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

EXPERIMENTAL

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.

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

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

PLACEBO COMPARATOR

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

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

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

PLACEBO COMPARATOR

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

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

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

EXPERIMENTAL

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.

Drug: Sirukumab

Interventions

Sirukumab 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.

Part A: Sirukumab, Dose 1+prednisone (3-month taper); Part A: Sirukumab, Dose 1+prednisone (6-month taper); Part A: Sirukumab, Dose 2+prednisone (6-month taper); Part B:Open-label sirukumab 100 mg SC (if applicable)

Placebo to match sirukumab 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.

Part A:Placebo to match sirukumab+prednisone (12-month taper); Part A:Placebo to match sirutkumab+prednisone (6-month taper)

Prednisone 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).

Part A: Sirukumab, Dose 1+prednisone (3-month taper); Part A: Sirukumab, Dose 1+prednisone (6-month taper); Part A: Sirukumab, Dose 2+prednisone (6-month taper); Part A:Placebo to match sirukumab+prednisone (12-month taper); Part A:Placebo to match sirutkumab+prednisone (6-month taper)

Placebo to match prednisone DRUG

Placebo to match prednisone will be provided as tablets.

Part A: Sirukumab, Dose 1+prednisone (3-month taper); Part A: Sirukumab, Dose 1+prednisone (6-month taper); Part A: Sirukumab, Dose 2+prednisone (6-month taper); Part A:Placebo to match sirukumab+prednisone (12-month taper); Part A:Placebo to match sirutkumab+prednisone (6-month taper)

Eligibility Criteria

• Age: 50 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (63)

GSK Investigational Site

Aurora, Colorado, 80210, United States

Location

GSK Investigational Site

Boca Raton, Florida, 33486, United States

Location

GSK Investigational Site

Naples, Florida, 34102, United States

Location

GSK Investigational Site

Iowa City, Iowa, 52242, United States

Location

GSK Investigational Site

Boston, Massachusetts, 02111, United States

Location

GSK Investigational Site

Boston, Massachusetts, 02114, United States

Location

GSK Investigational Site

Rochester, Minnesota, 55905, United States

Location

GSK Investigational Site

New York, New York, 10021, United States

Location

GSK Investigational Site

Philadelphia, Pennsylvania, 19104, United States

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GSK Investigational Site

Jackson, Tennessee, 38305, United States

Location

GSK Investigational Site

Dallas, Texas, 75231, United States

Location

GSK Investigational Site

Seattle, Washington, 98101, United States

Location

GSK Investigational Site

Vancouver, Washington, 98664, United States

Location

GSK Investigational Site

Camperdown, New South Wales, 2050, Australia

Location

GSK Investigational Site

Kogarah, New South Wales, 2217, Australia

Location

GSK Investigational Site

Woodville, South Australia, 5011, Australia

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GSK Investigational Site

Heidelberg, Victoria, 3084, Australia

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GSK Investigational Site

Malvern East, Victoria, 3145, Australia

Location

GSK Investigational Site

Victoria Park, Western Australia, 6100, Australia

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GSK Investigational Site

Leuven, 3000, Belgium

Location

GSK Investigational Site

Liège, 4000, Belgium

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GSK Investigational Site

Plovdiv, 4001, Bulgaria

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GSK Investigational Site

Sofia, 1612, Bulgaria

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GSK Investigational Site

Bobigny, 93009, France

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GSK Investigational Site

Orléans, 45067, France

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GSK Investigational Site

Paris, 75018, France

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GSK Investigational Site

Paris, 75679, France

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GSK Investigational Site

Tübingen, Baden-Wurttemberg, 72076, Germany

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GSK Investigational Site

Hanover, Lower Saxony, 30625, Germany

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GSK Investigational Site

Düsseldorf, North Rhine-Westphalia, 40225, Germany

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GSK Investigational Site

Dresden, Saxony, 01307, Germany

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GSK Investigational Site

Jena, Thuringia, 07747, Germany

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GSK Investigational Site

Bad Abbach, 93077, Germany

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GSK Investigational Site

Berlin, 13125, Germany

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GSK Investigational Site

Berlin, 14059, Germany

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GSK Investigational Site

Hamburg, 22763, Germany

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GSK Investigational Site

Kirchheim unter Teck, 73230, Germany

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GSK Investigational Site

München, 80336, Germany

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GSK Investigational Site

Budapest, 1097, Hungary

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GSK Investigational Site

Debrecen, 4032, Hungary

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GSK Investigational Site

Reggio Emilia, Emilia-Romagna, 42100, Italy

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GSK Investigational Site

Milan, Lombardy, 20132, Italy

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GSK Investigational Site

Rozzano, 20089, Italy

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GSK Investigational Site

Almelo, 7609 PP, Netherlands

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GSK Investigational Site

Groningen, 9713 GZ, Netherlands

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GSK Investigational Site

Nijmegen, 6525 GA, Netherlands

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GSK Investigational Site

Hamilton, 3240, New Zealand

Location

GSK Investigational Site

Timaru, 7910, New Zealand

Location

GSK Investigational Site

Krakow, 31-121, Poland

Location

GSK Investigational Site

A Coruña, 15006, Spain

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GSK Investigational Site

Barcelona, 08036, Spain

Location

GSK Investigational Site

Barcelona, 08208, Spain

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GSK Investigational Site

Barcelona, 08907, Spain

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GSK Investigational Site

Bilbao, 48013, Spain

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GSK Investigational Site

San Cristóbal de La Laguna, 38320, Spain

Location

GSK Investigational Site

Westcliff-on-Sea, Essex, SS0 0RY, United Kingdom

Location

GSK Investigational Site

Metropolitan Borough of Wirral, Merseyside, CH49 9PE, United Kingdom

Location

GSK Investigational Site

Bury St Edmunds, Suffolk, IP33 2QZ, United Kingdom

Location

GSK Investigational Site

Sheffield, Yorkshire, S10 2JF, United Kingdom

Location

GSK Investigational Site

Edinburgh, EH4 2XR, United Kingdom

Location

GSK Investigational Site

Leeds, LS9 7TF, United Kingdom

Location

GSK Investigational Site

Oxford, OX3 7LD, United Kingdom

Location

GSK Investigational Site

Reading, RG1 5AN, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 32844378 DERIVED

MeSH Terms

Conditions

Giant Cell Arteritis

Interventions

sirukumab; Prednisone

Condition Hierarchy (Ancestors)

Vasculitis, Central Nervous System; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Arteritis; Vasculitis; Skin Diseases, Vascular; Skin Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 6, 2015
• First Posted: August 24, 2015
• Study Start: October 16, 2015
• Primary Completion: March 21, 2018
• Study Completion: March 21, 2018
• Last Updated: July 31, 2019
• Results First Posted: May 31, 2019

Record last verified: 2019-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints of the study.
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

FR (4); ES (6); GB (8); NZ (2); NL (3); DE (11); PL (1); US (13); IT (3); BE (2); HU (2); BU (2); AU (6)