Giant Cell Arteritis
Conditions
Keywords
Giant Cell Arteritis, Tocilizumab, Antibodies, Monoclonal, Glucocorticoids
Brief summary
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
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).
Interventions
DRUGTocilizumab + Glucocorticoids (GCs)
Tocilizumab 8mg/kg every 4 weeks until week 52.
DRUGPlacebo + Glucocorticoids (GCs)
Placebo every 4 weeks until week 52.
Sponsors
University of Bern
Roche Pharma AG
Insel Gruppe AG, University Hospital Bern
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Number of Patients That Have Achieved Complete Remission of Disease | 12 weeks |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Relapse Free Patients | 12 months | — |
| Cumulative Dose of GCs in mg/kg | 12 months | cumulative weight-adapted prednisolone dose |
| Restricted Mean Survival Time to First Relapse After Induction of Remission | 12 months | — |
Countries
Switzerland
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tocilizumab Tocilizumab 8mg/kg every 4 weeks until week 52.
Tocilizumab + Glucocorticoids (GCs): Tocilizumab 8mg/kg every 4 weeks until week 52. | 20 |
| Placebo Placebo every 4 weeks until week 52.
Placebo + Glucocorticoids (GCs): Placebo every 4 weeks until week 52. | 10 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Up to Week 12 | Adverse Event | 2 | 1 |
| Up to Week 12 | Withdrawal by Subject | 0 | 2 |
| Week 12 to Study End | Death | 0 | 1 |
| Week 12 to Study End | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Total | Tocilizumab |
|---|---|---|---|
| Age, Continuous | 68.8 years STANDARD_DEVIATION 16.9 | 70.5 years STANDARD_DEVIATION 11.9 | 71.3 years STANDARD_DEVIATION 8.9 |
| Biopsy of the temporal artery Abnormal | 8 Participants | 21 Participants | 13 Participants |
| Biopsy of the temporal artery Normal | 0 Participants | 5 Participants | 5 Participants |
| Biopsy of the temporal artery Not done | 2 Participants | 4 Participants | 2 Participants |
| Blood pressure Diastolic left arm | 82.8 mmHg STANDARD_DEVIATION 8.5 | 77.3 mmHg STANDARD_DEVIATION 11.1 | 75.1 mmHg STANDARD_DEVIATION 11.5 |
| Blood pressure Diastolic right arm | 77.7 mmHg STANDARD_DEVIATION 15.2 | 75.3 mmHg STANDARD_DEVIATION 12.8 | 74.3 mmHg STANDARD_DEVIATION 11.8 |
| Blood pressure Systolic left arm | 136.9 mmHg STANDARD_DEVIATION 13 | 132.9 mmHg STANDARD_DEVIATION 15.3 | 131.3 mmHg STANDARD_DEVIATION 16.3 |
| Blood pressure Systolic right arm | 137.7 mmHg STANDARD_DEVIATION 16.4 | 132.8 mmHg STANDARD_DEVIATION 17.5 | 130.6 mmHg STANDARD_DEVIATION 18 |
| Body Mass Index (BMI) | 27.9 kg/m^2 STANDARD_DEVIATION 3.7 | 25.0 kg/m^2 STANDARD_DEVIATION 3.8 | 23.6 kg/m^2 STANDARD_DEVIATION 3 |
| C-reactive protein | 39.0 mg/L | 31.5 mg/L | 25.5 mg/L |
| Erythrocyte sedimentation rate | 40.0 mm/h | 54.5 mm/h | 69.0 mm/h |
| New onset giant cell arteritis | 7 Participants | 23 Participants | 16 Participants |
| Sex: Female, Male Female | 8 Participants | 21 Participants | 13 Participants |
| Sex: Female, Male Male | 2 Participants | 9 Participants | 7 Participants |
| Symptoms and signs of giant cell arteritis Claudication of lower limbs | 2 Participants | 2 Participants | 0 Participants |
| Symptoms and signs of giant cell arteritis Claudication of tongue | 0 Participants | 2 Participants | 2 Participants |
| Symptoms and signs of giant cell arteritis Claudication of upper limbs | 2 Participants | 6 Participants | 4 Participants |
| Symptoms and signs of giant cell arteritis Fever >= 38°C | 1 Participants | 2 Participants | 1 Participants |
| Symptoms and signs of giant cell arteritis Headache | 5 Participants | 18 Participants | 13 Participants |
| Symptoms and signs of giant cell arteritis Masseter muscle claudication | 4 Participants | 15 Participants | 11 Participants |
| Symptoms and signs of giant cell arteritis Night sweats | 2 Participants | 5 Participants | 3 Participants |
| Symptoms and signs of giant cell arteritis Scalp tenderness | 1 Participants | 10 Participants | 9 Participants |
| Symptoms and signs of giant cell arteritis Visual impairment | 2 Participants | 7 Participants | 5 Participants |
| Symptoms and signs of giant cell arteritis Weight loss > 2kg within 4 weeks | 3 Participants | 9 Participants | 6 Participants |
| Thoracoabdominal MR angiography Abnormal | 6 Participants | 17 Participants | 11 Participants |
| Thoracoabdominal MR angiography Normal | 2 Participants | 11 Participants | 9 Participants |
| Thoracoabdominal MR angiography Not done | 2 Participants | 2 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 1 / 10 |
| other Total, other adverse events | 11 / 20 | 6 / 10 |
| serious Total, serious adverse events | 7 / 20 | 5 / 10 |
Outcome results
Primary
Number of Patients That Have Achieved Complete Remission of Disease
Time frame: 12 weeks
Population: All randomized patients, intention-to-treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tocilizumab | Number of Patients That Have Achieved Complete Remission of Disease | 17 Participants |
| Placebo | Number of Patients That Have Achieved Complete Remission of Disease | 4 Participants |
p-value: 0.030195% CI: [0.11, 0.79]Fisher Exact
Secondary
Cumulative Dose of GCs in mg/kg
cumulative weight-adapted prednisolone dose
Time frame: 12 months
Population: All randomized patients, intention-to-treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tocilizumab | Cumulative Dose of GCs in mg/kg | 43 mg/kg |
| Placebo | Cumulative Dose of GCs in mg/kg | 110 mg/kg |
p-value: 0.0005Wilcoxon (Mann-Whitney)
Secondary
Number of Relapse Free Patients
Time frame: 12 months
Population: All randomized patients, intention-to-treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tocilizumab | Number of Relapse Free Patients | 17 Participants |
| Placebo | Number of Relapse Free Patients | 2 Participants |
p-value: 0.00195% CI: [0.36, 0.94]Fisher Exact
Secondary
Restricted Mean Survival Time to First Relapse After Induction of Remission
Time frame: 12 months
Population: All randomized patients, intention-to-treat
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Tocilizumab | Restricted Mean Survival Time to First Relapse After Induction of Remission | 50 Weeks |
| Placebo | Restricted Mean Survival Time to First Relapse After Induction of Remission | 25 Weeks |
p-value: 0.000595% CI: [11, 39]z-test