Tocilizumab for Patients With Giant Cell Arteritis

Study Overview
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Brief Summary
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Giant-cell arteritis (GCA) is an immune-mediated disease that mostly affects people older than 50 years of age. Glucocorticoid (GC) treatment dramatically alters the symptoms and course of GCA, reducing the likelihood of vascular complications that could lead e.g. to blindness. However, relapses usually occur when GC dosages are tapered, resulting in frequent re-treatment with high cumulative dosages of GC over time with substantial toxicity and morbidity (e.g. diabetes mellitus, infections, enhanced cardiovascular risk, osteoporotic fractures, cataracts). Therefore, novel therapies are needed that effectively reduce the dose and duration of GC treatment and provide more durable remissions of GCA. Tocilizumab (TCZ) is a humanized monoclonal antibody directed against the human interleukin-6 receptor (IL-6R). Elevated tissue and serum levels of IL-6 have been implicated in giant cell arteritis. Inhibition of IL-6 and/or its receptor therefore represents a new and novel approach for the treatment of RA. The primary endpoint is the proportion of patients that have achieved complete remission of disease after treatment with TCZ compared to treatment with placebo at week 12. All patients will receive glucocorticoids in a standardized form.

Detailed Description
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Background Giant-cell arteritis (GCA) is an immune-mediated disease that mostly affects people older than 50 years of age. Glucocorticoid (GC) treatment dramatically alters the symptoms and course of GCA, reducing the likelihood of vascular complications that could lead e.g. to blindness. However, relapses usually occur when GC dosages are tapered, resulting in frequent re-treatment with high cumulative dosages of GC over time with substantial toxicity and morbidity (e.g. diabetes mellitus, infections, enhanced cardiovascular risk, osteoporotic fractures, cataracts). Therefore, novel therapies are needed that effectively reduce the dose and duration of GC treatment and provide more durable remissions of GCA. Tocilizumab (TCZ) is a humanized monoclonal antibody directed against the human interleukin-6 receptor (IL-6R). Elevated tissue and serum levels of IL-6 have been implicated in giant cell arteritis. Inhibition of IL-6 and/or its receptor therefore represents a new and novel approach for the treatment of RA. Objective The primary endpoint is the proportion of patients that have achieved complete remission of disease (normal ESR and CRP + absence of signs and symptoms) at Week 12 at a GC dose of 0.1 mg/kg/d of prednisone. Methods 2-arm (Tocilizumab + Glucocorticoids (GCs) vs. Placebo + GCs), randomized, placebo-controlled, double blind, monocentric trial in patients with newly onset or relapsing giant cell arteritis (GCA), satisfying ACR criteria AND an elevated sedimentation rate above 40 mm/h and a CRP > 20 mg/L AND a biopsy proven GCA OR a large vessel vasculitis assessed by MR Angiography (MRA).

Official Title
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A Phase II, Randomized, Double-blind, Placebo Controlled Study of Tocilizumab in Patients With Giant Cell Arteritis

Conditions
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Giant Cell Arteritis

Intervention / Treatment
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* Drug: Tocilizumab + Glucocorticoids (GCs)
* Drug: Placebo + Glucocorticoids (GCs)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with newly onset or relapsed GCA > 50 years of age satisfying ACR criteria elevated sedimentation rate above 40 mm CRP > 20 mg/L Patients with histologically proven GCA or with large vessel vasculitis assessed by MRI Exclusion Criteria Rheumatic diseases (except for CPPD/chondrocalcinosis) other than GCA/Takayasu disease or polymyalgia rheumatica (i.e., RA, autoimmune connectivitides, other systemic vasculitides, a.o.) Evidence of significant and/or uncontrolled concomitant disease Diagnosis of GCA > 4 weeks before screening visit and beginning of GC treatment > 4 weeks before screening (only valid for new onset GCA), or when a patient received treatment with tocilizumab or with other biological agents (such as TNFα-blockers) within 3 months before screening Any condition or general state of health which, in the Investigator's opinion, would preclude participation in the study Actual or recent myocardial infarction (within the last 3 months before screening visit) Significant cardiac disease (NYHA Class III and IV), known severe chronic obstructive pulmonary disease (COPD) (FEV1 < 50% predicted or Functional dyspnoea > Grade 3 on the MRC Dyspnoea Scale) or other significant pulmonary disease Uncontrolled disease (such as asthma, psoriasis or inflammatory bowel disease) where flares are commonly treated with oral or injectable corticosteroids Known active infection of any kind, or any major episode of infection requiring hospitalization or treatment with i.v. anti-infectives within 4 weeks of baseline or completion of oral anti-infectives within 2 weeks prior to baseline History of deep space/tissue infection (e.g. fasciitis, abscess, osteomyelitis) within 52 weeks prior to baseline Any surgical procedure, including bone/joint surgery within 8 weeks prior to baseline or planned within the duration of the study History of serious recurrent or chronic infection (for screening for a chest infection a chest radiograph will be performed at screening if not performed within 12 weeks prior to screening) Lack of peripheral venous access Body weight > 150 kg or BMI > 35 Previous treatment with tocilizumab or any other biological agent Treatment with any investigational agent within 28 days of screening or 5 half-lives of the investigational drug (whichever is the longer) History of severe allergic or anaphylactic reaction to any biologic agent or known hypersensitivity to any component of tocilizumab (RoActemra) Receipt of any vaccine within 28 days prior to baseline (a patient's vaccination record and need for immunization prior to receiving tocilizumab/placebo must be carefully investigated) Positive tests for hepatitis B surface antigen (HBsAg), Hepatitis B core antibody (HbcAb) or hepatitis C serology Positive Quantiferon-TB® test for latent Tb without subsequent INH prophylaxis Patients with active Tb which had to be treated for Tb within 2 years before the screening visit

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tocilizumab<br>Tocilizumab 8mg/kg every 4 weeks until week 52. | Drug: Tocilizumab + Glucocorticoids (GCs)<br>* Tocilizumab 8mg/kg every 4 weeks until week 52.<br>|
| Placebo Comparator: Placebo<br>Placebo every 4 weeks until week 52. | Drug: Placebo + Glucocorticoids (GCs)<br>* Placebo every 4 weeks until week 52.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients That Have Achieved Complete Remission of Disease |  | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Relapse Free Patients |  | 12 months | 
| Cumulative Dose of GCs in mg/kg | cumulative weight-adapted prednisolone dose | 12 months | 
| Restricted Mean Survival Time to First Relapse After Induction of Remission |  | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tocilizumab, Giant Cell Arteritis, Antibodies, Monoclonal, Glucocorticoids