Giant Cell Arteritis (GCA) MedDRA version: 19.1 Level: HLGT Classification code 10047116 Term: Vascular inflammations System Organ Class: 10047065 - Vascular disorders
Conditions
Interventions
Product Name: Sirukumab
Product Code: GSK2973327
Pharmaceutical Form: Injection
INN or Proposed INN: Sirukumab
Current Sponsor code: GSK2973327
Other descriptive name: CNTO 136
Concentration unit: mg
Sponsors
GlaxoSmithKline Research and Development Limited
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1.Diagnosis of GCA defined by the following Revised GCA Diagnosis Criteria: •Age =50 years. •History of ESR = 50 mm/hour or CRP = 2.45 mg/dL (= 24.5 mg/L) •Presence of at least one of the following: oUnequivocal cranial symptoms of GCA (new onset localized headache, scalp or temporal artery tenderness, ischemia-related vision loss, or otherwise unexplained mouth or jaw pain upon mastication). oUnequivocal symptoms of PMR, defined as shoulder and/or hip girdle pain associated with inflammatory stiffness. •Presence of at least one of the following: oTemporal artery abnormality on biopsy revealing features of GCA. oEvidence of large-vessel vasculitis by angiography or cross-sectional imaging, including but not limited to magnetic resonance angiography (MRA), computed tomography angiography (CTA), ultra sound (US) or positron emission tomography-computed tomography (PET-CT). oEvidence of temporal artery vasculitis on US (for US imaging qualified centers only) 2.Active GCA within 6 weeks of Randomization (Baseline) where active disease is defined by an ESR = 30 mm/hr or CRP = 1 mg/dL (= 10 mg/L) AND the presence of at least one of the following: • Unequivocal cranial signs and symptoms of GCA (new onset localized headache, scalp or temporal artery tenderness, reduced or absent pulsation in temporal artery, stroke, scalp necrosis, pain over face/scalp arteries or otherwise unexplained mouth or jaw pain upon mastication [i.e., jaw claudication]). • Visual signs and symptoms associated with GCA, including ischemia-related vision loss [permanent vision loss due to AION, amaurosis fugax, episodic blurry vision], diplopia, scotoma nerve palsies, relative afferent papillary defects, central retinal artery occlusions. •Unequivocal symptoms of PMR, defined as shoulder and/or hip girdle pain associated with inflammatory stiffness. •Other features judged by the clinician investigator to be consistent with GCA or PMR flares (i.e., new or worsened extremity claudication, unexplained systemic symptoms such as fever of unknown origin). 3.At screening, receiving prednisone treatment with a minimum dose of 20mg/day for the treatment of active GCA. Subjects not currently receiving prednisone treatment must commence dosing (minimum 20mg/day of prednisone) at the screening visit. 4.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. 5.Practicing acceptable methods of birth control as follows: Males: Male subjects with female partners of child bearing potential must comply with the following contraception requirements from the time of first dose of study medication until 4 months after the last dose of study medication: a. Vasectomy with documentation of azoospermia. b. Male condom plus female partner use of one of the GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Childbearing potential. Male subjects should also not donate sperm from the time of first dose of study medication until 4 months after the last dose of study medication. Females: Female subjects of child-bearing potential must use one of the GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Childbearing potential. 6.No evidence of active or latent infection with Mycobacterium tuberculosis (TB), as defined by all of the following: •No history of active or latent TB infection. •A nega
Exclusion criteria
Exclusion criteria: A subject will not be eligible for inclusion in this study if any of the following criteria apply: 1. Are pregnant or breastfeeding. 2. Recent (within the past 12 weeks) or planned major surgery that would impact on study procedures or assessments. 3. Organ transplantation recipients (except corneas within 3 months prior to baseline visit). 4. Had prior treatment with any of the following: •Systemic immunosuppressives, including azathioprine, oral cyclosporine A,tacrolimus, mycophenolate mofetil, leflunomide, oral or parenteral gold, and IL-1ra (anakinra) within 4 weeks of baseline. •Biologic agents targeted at reducing TNF (including but not limited to infliximab, golimumab, certolizumab pegol, etanercept, yisaipu, and adalimumab)within 4-8 weeks of baseline, depending on the agent*. •Anti-IL6 (tocilizumab or any other anti-IL-6 agent) if: ? -Used within 8 weeks of randomization ? -Associated with a history of intolerance that precluded further treatment ? Associated with an inadequate response to 3 months of therapy 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 IV (or equivalent) within 8 weeks of baseline. 5. Regular or continuous systemic corticosteroid use for > 4 years. 6. Requires continued or repeated use of systemic corticosteroids for conditions other than GCA. 7. History of severe allergic reactions to monoclonal antibodies, human proteins, or excipients. 8. Evidence of serious concomitant disease, which in the opinion of the investigator makes them unsuitable for participation in the study. 9. Major ischemic event, unrelated to giant cell arteritis, within 12 weeks of screening. 10. Marked baseline prolongation of QTc interval > 480 msec (QTcB or QTcF) or QTc > 500 msec in subjects with Bundle Branch Block**, history of Torsade de Pointes, family history of long QT syndrome, history of second or third degree heart block. ** The QTc should be based on averaged QTc values of triplicate ECGs obtained over a brief (e.g., 5-10 minute) recording period. 11. Current liver disease that could interfere with the trial as determined by the physician investigator. 12. History of or current active diverticulitis, inflammatory bowel disease, or other symptomatic GI tract condition that might predispose to bowel perforation. 13. History of known demyelinating diseases such as multiple sclerosis or optic neuritis. 14. 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 (such as tuberculosis, pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical mycobacteria, •History or suspicion of chronic infection (e.g joint infection). OR •Hospitalization for treatment of infection within 60 days of the baseline visit. OR •Use of parenteral (IV or IM) antimicrobials (antibacterials, antivirals, antifungals, or antiparasitic agents) within 60 days of baseline or oral antimicrobials within 30 days of baseline. 15.Primary or secondary immunodeficiency. 16.HIV infection (p
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To investigate the efficacy of sirukumab (100 mg q2w for 12 months) as compared to placebo, each administered in addition to a 6-month prednisone treatment regimen ;Secondary Objective: 1. To assess cumulative prednisone doses in subjects treated with sirukumab plus prednisone as compared to placebo plus prednisone 2. To investigate the efficacy of Sirukumab (100 mg q2w for 12 months) with 3-month prednisone treatment versus placebo with a 6-month prednisone treatment 3. To investigate the efficacy of sirukumab (100 mg q2w for 12 months) with a 6-month prednisone treatment as compared to placebo with a 12-month prednisone treatment 4. To investigate the efficacy of sirukumab (100 mg q2w for 12 months) with a 3-month prednisone treatment versus placebo with a 12-month prednisone treatment 5. To investigate the efficacy of sirukumab (50 mg q4w for 12 months) as compared to placebo, each administered in addition to a 6-month prednisone treatment 6. To investigate the efficacy of Sirukumab (50 mg q4w for 12 months) with a 6-month prednisone treatment as compared to placebo with a 12-month prednisone treatment ;Primary end point(s): •Proportion of subjects in sustained remission at Week 52 ;Timepoint(s) of evaluation of this end point: Week 52 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Part A: 52-week double blind treatment phase •Median and cumulative prednisone dose over time •Proportion of subjects in sustained remission at each time point of assessment from week 12 to week 52 •Proportion of subjects in remission over time •Time to first GCA flare after clinical remission •Number of disease flares per patient over time •Proportion of subjects requiring hospitalizations for disease flare and number of hospitalizations for disease flare •Incidence of adverse events and serious adverse events, incidence of corticosteroid-related adverse events, changes in vital signs, hematology and clinical chemistry parameters •Patient and clinician reported outcomes including SF-36v2, EQ-5D (5L), FACITFatigue, Pain NRS, Steroid Impact PRO, HAQ-DI, PGIC, PtGA, PhGA •Change from baseline in ESR over time •Change from baseline in serum CRP over time •Serum concentrations of sirukumab •Serum anti-sirukumab antibodies •Change from baseline in IFN-? and IL-17A •Change from baseline in serum markers of bone formation/resorption: CTX1/P1NP •Correlation of genetic markers with the safety and efficacy response to sirukumab;Timepoint(s) of evaluation of this end point: Week -6, 0, 2, 4, then every 4 weeks to week 52 | — |
Countries
Australia, Belgium, Bulgaria, France, Germany, Hungary, Italy, Netherlands, New Zealand, Poland, Spain, United Kingdom, United States
Contacts
Public ContactGSK Clinical Support Helpdesk
GlaxoSmithKline Research and Development Ltd
Outcome results
None listed