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

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ClinicalTrials.gov Identifier: NCT02531633
Recruitment Status : Terminated (GSK decision to return rights to sirukumab to Janssen and discontinue sirukumab development in giant cell arteritis.)
First Posted : August 24, 2015
Last Update Posted : November 14, 2017
Sponsor:
Information provided by (Responsible Party):

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evaluations for at least 16 weeks after receiving the last dose of study drug, applicable only for those who are withdrawn prematurely from the study or whose open-label sirukumab treatment in Part B completes after Week 88.


Condition or disease Intervention/treatment Phase
Giant Cell Arteritis Drug: Sirukumab Drug: Placebo to match sirukumab Drug: Prednisone Drug: Placebo to match prednisone Phase 3

Study Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 160 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of Sirukumab in the Treatment of Patients With Giant Cell Arteritis
Actual Study Start Date : October 16, 2015
Primary Completion Date : October 10, 2017
Study Completion Date : October 10, 2017


Arms and Interventions

Arm Intervention/treatment
Experimental: 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.
Drug: 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.
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).
Drug: Placebo to match prednisone
Placebo to match prednisone will be provided as tablets.
Experimental: 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.
Drug: 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.
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).
Drug: Placebo to match prednisone
Placebo to match prednisone will be provided as tablets.
Experimental: 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.
Drug: 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.
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).
Drug: Placebo to match prednisone
Placebo to match prednisone will be provided as tablets.
Placebo Comparator: 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.
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.
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).
Drug: Placebo to match prednisone
Placebo to match prednisone will be provided as tablets.
Placebo Comparator: 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.
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.
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).
Drug: Placebo to match prednisone
Placebo to match prednisone will be provided as tablets.
Experimental: 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.
Drug: 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.


Outcome Measures

Primary Outcome Measures :
  1. Proportion of subjects in sustained remission at Week 52 for sirukumab (100 mg every 2 weeks [q2w] for 12 months) as compared to placebo, each administered in addition to a 6-month prednisone treatment regimen [ Time Frame: Week 52 ]
    Sustained remission at Week 52 is defined as having achieved all of the following: Remission by Week 12; Absence of disease flare following remission at Week 12 through Week 52; Completion of the assigned prednisone taper protocol; No requirement for rescue therapy any time through Week 52.


Secondary Outcome Measures :
  1. Part A & B: Cumulative prednisone doses in subjects treated with sirukumab plus prednisone [ Time Frame: 52 Weeks (Part A) and 104 Weeks (Part B) ]
    Median and cumulative prednisone dose over time

  2. Part A & B: Proportion of subjects in sustained remission [ Time Frame: At Week 52 (Part A) and from Week 52 to Week 78 (Part B) ]
  3. Part A & B: Measure of remission rates over time [ Time Frame: 52 Weeks (Part A) and 104 Weeks (Part B) ]
    Proportion of subjects in remission at all time points of assessment

  4. Part A & B: Time to first GCA flare [ Time Frame: 52 Weeks (Part A) and 104 Weeks (Part B) ]
    Time to first GCA flare after clinical remission

  5. Part A & B: Number of disease flares per subject over time [ Time Frame: 52 Weeks (Part A) and 104 Weeks (Part B) ]
  6. Part A & B: Safety: Incidence of adverse events [ Time Frame: 52 Weeks (Part A) and 120 Weeks (Part B) ]
  7. Part A & B: Safety: Incidence of corticosteroid-related adverse events [ Time Frame: 52 Weeks (Part A) and 120 Weeks (Part B) ]
  8. Part A & B: Composite of vital signs assessment as a measure of safety: blood pressure, pulse rate and temperature [ Time Frame: 52 Weeks (Part A) and 120 Weeks (Part B) ]
    Vital signs assessment will include systolic and diastolic blood pressure, pulse rate and body temperature

  9. Part A & B: Composite of clinical laboratory tests assessment as a measure of safety: clinical chemistry and hematology [ Time Frame: 52 Weeks (Part A) and 104 Weeks (Part B) ]
    Clinical laboratory tests will include clinical chemistry and hematology

  10. Part A: Assessment of Patient Global Impression of Change (PGIC) [ Time Frame: Up to Week 52 ]
    Estimate of the magnitude of patient response to treatment at different time points by patient report

  11. Part A & B: Pain assessment [ Time Frame: 52 Weeks (Part A) and 104 Weeks (Part B) ]
    Average pain assessed by patient report of rating on score of 0 to 100

  12. Part A & B: Health Assessment Questionnaire-Disability Index (HAQ-DI) [ Time Frame: 52 Weeks (Part A) and 104 Weeks (Part B) ]
    Patient reported outcome of difficulties in 8 functional areas

  13. Part A & B: Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) [ Time Frame: 52 Weeks (Part A) and 104 Weeks (Part B) ]
    Patient report of elements of fatigue

  14. Part A & B: Assessment of steroid impact [ Time Frame: 52 Weeks (Part A) and 104 Weeks (Part B) ]
    Patient assessment of the side effects and impact of steroids on GCA symptoms over time

  15. Part A & B: Assessment of quality of life using the 36-item Short Form Version 2 Acute (SF-36v2 Acute) [ Time Frame: 52 Weeks (Part A) and 104 Weeks (Part B) ]
    Patient report of quality of life

  16. Part A & B: Assessment of health status using the EuroQoL-5D (EQ-5D) [ Time Frame: 52 Weeks (Part A) and 104 Weeks (Part B) ]
    Patient report of health status

  17. Part A: Pharmacodynamics: Change from baseline in erythrocyte sedimentation rate (ESR) over time [ Time Frame: Up to Week 52 ]
  18. Part A: Pharmacodynamics: Change from baseline in serum C-reactive protein (CRP) over time [ Time Frame: Up to Week 52 ]
  19. Part A: Pharmacokinetics: Serum concentrations of sirukumab [ Time Frame: Up to Week 44 ]
    Blood samples will be collected at Baseline (Week 0), Week 2, 4, 8, 12, 16, 20, 24, 28,and at Week 44 for determination for serum concentrations of sirukumab

  20. Part A & B: Immunogenicity: Serum anti-sirukumab antibodies [ Time Frame: 52 Weeks (Part A) and 120 Weeks (Part B) ]
    Blood samples will be collected at Baseline (Week 0), Week 24, 44, 52 of Part A and Baseline (Week 52 of Part A), Week 12, 52, 104 of Part B and at Follow up (Week 120) for determination of serum anti-sirukumab antibodies


Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   50 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02531633


  Show 88 Study Locations
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
More Information

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT02531633     History of Changes
Other Study ID Numbers: 201677
First Posted: August 24, 2015    Key Record Dates
Last Update Posted: November 14, 2017
Last Verified: November 2017

Keywords provided by GlaxoSmithKline:
Giant Cell Arteritis, Sirukumab, Prednisone

Additional relevant MeSH terms:
Arteritis
Giant Cell Arteritis
Polymyalgia Rheumatica
Vasculitis
Vascular Diseases
Cardiovascular Diseases
Vasculitis, Central Nervous System
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Skin Diseases, Vascular
Skin Diseases
Autoimmune Diseases
Immune System Diseases
Muscular Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Prednisone
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents