An Efficacy and Safety Study of Tocilizumab (RoActemra/Actemra) in Participants With Giant Cell Arteritis (GCA)

Study Overview
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Brief Summary
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This multicenter, randomized, double-blind, placebo-controlled, parallel-group study will evaluate the efficacy and safety of tocilizumab in participants with GCA. The study will consist of 2 parts: a 52-week double-blind treatment period (Part 1) followed by a 104-week open label long-term follow-up period (Part 2). In Part 1 of the study eligible participants will be randomized to receive either tocilizumab every week (qw) or every 2 weeks (q2w) or placebo for 52 weeks, with tapering oral daily doses of prednisone. After Week 52, participants in remission will stop study treatment and enter long-term follow-up, whereas participants with disease activity or flares will receive open-label tocilizumab or other treatment at the discretion of the investigator for a maximum period of 104 weeks.

Official Title
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A Phase III, Multicenter, Randomized, Double-Blind Placebo-Controlled Study to Assess the Efficacy and Safety of Tocilizumab in Subjects With Giant Cell Arteritis

Conditions
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Giant Cell Arteritis

Intervention / Treatment
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* Drug: Tocilizumab
* Drug: Prednisone
* Drug: Tocilizumab Placebo
* Drug: Prednisone Placebo
* Drug: Corticosteroids
* Drug: Methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of GCA classified according to age >/=50 years; history of ESR >/=50 mm/hr or history of CRP >/=2.45 mg/dL; and at least one of the following: unequivocal cranial symptoms of GCA or symptoms of polymyalgia rheumatica [PMR]; and at least one of the following: temporal artery biopsy revealing features of GCA or evidence of large-vessel vasculitis by angiography or cross-sectional imaging New onset (diagnosis within 6 weeks of baseline) or refractory (diagnosis greater than [>] 6 weeks before baseline and previous treatment with >/= 40 milligrams per day prednisone [or equivalent] for at least 2 consecutive weeks at any time) GCA Active disease (presence of clinical signs and symptoms [cranial or PMR] and ESR >/=30 mm/hour or CRP >/=1 mg/dL) within 6 weeks of baseline visit Exclusion Criteria: Major surgery within 8 weeks prior to screening or planned within 12 months after randomization Transplanted organs (except corneas with transplant performed >3 months prior to screening) Major ischemic event, unrelated to GCA, within 12 weeks of screening Prior treatment with any of the following: investigational agent within 12 weeks (or 5 half-lives of the investigational drug, whichever is longer) of screening; cell-depleting therapies including investigational agent; intravenous (IV) gamma globulin or plasmapheresis within 6 months of baseline; alkylating agents or with total lymphoid irradiation; tocilizumab; hydroxychloroquine, cyclosporine A, azathioprine, or mycophenolate mofetil within 4 weeks of baseline; etanercept within 2 weeks of baseline; infliximab, certolizumab, golimumab, abatacept, or adalimumab within 8 weeks of baseline; anakinra within 1 week of baseline; tofacitinib; cyclophosphamide within 6 months of baseline; >100 milligrams of daily IV methylprednisolone within 6 weeks of baseline Participants requiring systemic glucocorticoids for conditions other than GCA, which, in the opinion of the investigator, would interfere with adherence to the fixed glucocorticoid taper regimen and/or to assessment of efficacy in response to the test article History of severe allergic reactions to monoclonal antibodies or to prednisone Evidence of serious uncontrolled concomitant disease (for example, cardiovascular, respiratory, renal, endocrine, psychiatric, corneal ulcers/injuries, or gastrointestinal [GI] disease) Current liver disease, as determined by the investigator History of diverticulitis, inflammatory bowel disease, or other symptomatic GI tract condition that might predispose to bowel perforation Known active or history of recurrent bacterial, viral fungal, mycobacterial, or other infection Primary or secondary immunodeficiency Evidence of malignancies diagnosed within previous 5 years (except basal and squamous cell carcinoma of the skin or carcinoma in situ of the cervix uteri that have been excised and cured) Inadequate hematologic, renal or liver function Positive for hepatitis B or hepatitis C infection

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Tocilizumab qw + 26 weeks prednisone taper<br>Participants will receive tocilizumab at a dose of 162 milligrams (mg) as subcutaneous (SC) injection qw up to 52 weeks along with prednisone and/or prednisone placebo according to the protocol-defined schedule. Participants will receive prednisone tapering oral daily doses during the first 26 weeks and prednisone placebo from Week 26 up to Week 52. | Drug: Tocilizumab<br>* Tocilizumab will be administered at a dose of 162 mg as SC injection qw or q2w for 52 weeks in Part 1 of the study and at a dose 162 mg as SC injection qw for 104 week at the discretion of the investigator in Part 2 of the study.<br>* Other names: RoActemra, Actemra, RO4877533;Drug: Prednisone<br>* Prednisone will be administered at tapering oral doses as tablets daily for 26 or 52 weeks according to the protocol-defined schedule in Part 1 of the study. Prednisone will also be administered as escape therapy to treat disease flares in an open-label manner during Part 1 at a dose and duration selected by the investigator.<br>Drug: Prednisone Placebo<br>* Prednisone placebo will be administered as tablets orally daily according to the protocol-defined schedule (from Week 26 to Week 52) in Part 1 of the study.<br>|
| Experimental: Part 1: Tocilizumab q2w + 26 weeks prednisone taper<br>Participants will receive tocilizumab at a dose of 162 mg as SC injection q2w (and tocilizumab placebo q2w starting from Week 2) up to 52 weeks along with prednisone and/or prednisone placebo according to the protocol-defined schedule. Participants will receive prednisone tapering oral daily doses during the first 26 weeks and prednisone placebo from Week 26 up to Week 52. | Drug: Tocilizumab<br>* Tocilizumab will be administered at a dose of 162 mg as SC injection qw or q2w for 52 weeks in Part 1 of the study and at a dose 162 mg as SC injection qw for 104 week at the discretion of the investigator in Part 2 of the study.<br>* Other names: RoActemra, Actemra, RO4877533;Drug: Prednisone<br>* Prednisone will be administered at tapering oral doses as tablets daily for 26 or 52 weeks according to the protocol-defined schedule in Part 1 of the study. Prednisone will also be administered as escape therapy to treat disease flares in an open-label manner during Part 1 at a dose and duration selected by the investigator.<br>Drug: Tocilizumab Placebo<br>* Tocilizumab placebo will be administered as SC injection qw or q2w for 52 weeks in Part 1 of the study.<br>Drug: Prednisone Placebo<br>* Prednisone placebo will be administered as tablets orally daily according to the protocol-defined schedule (from Week 26 to Week 52) in Part 1 of the study.<br>|
| Placebo Comparator: Part 1: Placebo + 26 weeks prednisone taper<br>Participants will receive tocilizumab placebo as SC injection qw up to 52 weeks along with prednisone and/or prednisone placebo according to the protocol-defined schedule. Participants will receive prednisone tapering oral daily doses during the first 26 weeks and prednisone placebo from Week 26 up to Week 52. | Drug: Prednisone<br>* Prednisone will be administered at tapering oral doses as tablets daily for 26 or 52 weeks according to the protocol-defined schedule in Part 1 of the study. Prednisone will also be administered as escape therapy to treat disease flares in an open-label manner during Part 1 at a dose and duration selected by the investigator.<br>Drug: Tocilizumab Placebo<br>* Tocilizumab placebo will be administered as SC injection qw or q2w for 52 weeks in Part 1 of the study.<br>Drug: Prednisone Placebo<br>* Prednisone placebo will be administered as tablets orally daily according to the protocol-defined schedule (from Week 26 to Week 52) in Part 1 of the study.<br>|
| Placebo Comparator: Part 1: Placebo + 52 weeks prednisone taper<br>Participants will receive tocilizumab placebo as SC injection qw up to 52 weeks along with prednisone and/or prednisone placebo according to a protocol-defined schedule. Participants will receive prednisone tapering oral daily doses for 52 weeks. | Drug: Prednisone<br>* Prednisone will be administered at tapering oral doses as tablets daily for 26 or 52 weeks according to the protocol-defined schedule in Part 1 of the study. Prednisone will also be administered as escape therapy to treat disease flares in an open-label manner during Part 1 at a dose and duration selected by the investigator.<br>Drug: Tocilizumab Placebo<br>* Tocilizumab placebo will be administered as SC injection qw or q2w for 52 weeks in Part 1 of the study.<br>Drug: Prednisone Placebo<br>* Prednisone placebo will be administered as tablets orally daily according to the protocol-defined schedule (from Week 26 to Week 52) in Part 1 of the study.<br>|
| Experimental: Part 2: Open-Label Tocilizumab qw<br>Participants without sustained remission at Week 52 will receive open-label tocilizumab at a dose of 162 mg as SC injection qw and/or corticosteroids and/or methotrexate at the discretion of the investigator for a maximum of 104 weeks. | Drug: Tocilizumab<br>* Tocilizumab will be administered at a dose of 162 mg as SC injection qw or q2w for 52 weeks in Part 1 of the study and at a dose 162 mg as SC injection qw for 104 week at the discretion of the investigator in Part 2 of the study.<br>* Other names: RoActemra, Actemra, RO4877533;Drug: Corticosteroids<br>* Participants without sustained remission at Week 52 will receive corticosteroids at a dose and schedule at the discretion of the investigator for a maximum of 104 weeks.<br>Drug: Methotrexate<br>* Participants without sustained remission at Week 52 will receive methotrexate at a dose and schedule at the discretion of the investigator for a maximum of 104 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants in Sustained Remission at Week 52 (Tocilizumab + 26 Weeks Prednisone Taper Versus Placebo + 26 Weeks Prednisone Taper) | Remission was defined as the absence of flare and normalization of the C-reactive protein (CRP) (less than [<] 1 milligram per deciliter [mg/dL]). Sustained remission was defined as the absence of flare following induction of remission within 12 weeks of randomization and maintained up to Week 52. Flare was determined by the investigator and was defined as the recurrence of signs or symptoms of GCA and/or erythrocyte sedimentation rate (ESR) greater than or equal to (>/=) 30 millimeters per hour (mm/hr) attributable to GCA. A single CRP elevation (>/=1 mg/dL) was not considered as a sign of flare, unless the CRP remained elevated (>/=1 mg/dL) at the next study visit. | Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants in Sustained Remission at Week 52 (Tocilizumab + 26 Weeks Prednisone Taper Versus Placebo + 52 Weeks Prednisone Taper) | Remission was defined as the absence of flare and normalization of the CRP (<1 mg/dL). Sustained remission was defined as the absence of flare following induction of remission within 12 weeks of randomization and maintained up to Week 52. Flare was determined by the investigator and was defined as the recurrence of signs or symptoms of GCA and/or ESR >/=30 mm/hr attributable to GCA. A single CRP elevation (>/=1 mg/dL) was not considered as a sign of flare, unless the CRP remained elevated (>/=1 mg/dL) at the next study visit. | Week 52 | 
| Time to First GCA Disease Flare | Flare was determined by the investigator and was defined as the recurrence of signs or symptoms of GCA and/or ESR >/=30 mm/hr attributable to GCA. Participants who withdrew from the study prior to Week 52 were censored from the time of withdrawal. | Up to 52 weeks | 
| Total Cumulative Prednisone Dose | The median total cumulative prednisone dose over the 52 weeks for each treatment group and the corresponding 95% confidence intervals are presented. | Up to 52 weeks | 
| Change From Baseline in Short Form (SF)-36 Questionnaire Score at Week 52 | The SF-36 is a standardized questionnaire used to assess physical functioning and is made up of eight domains: Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional and Mental Health. Transforming and standardizing these domains leads to the calculation of the Physical Component Score (PCS) and Mental Component Score (MCS). The score for a section is an average of the individual question scores, which are scaled 0-100 (100=highest level of functioning). A positive change from baseline indicates improvement. No imputation was used for missing data. Data was set to missing for participants who received escape therapy. | Baseline, Week 52 | 
| Change From Baseline in Patient Global Assessment (PGA) of Disease Activity Assessed Using Visual Analogue Scale (VAS) at Week 52 | Participants assessed their current disease activity on a 0-100 millimeter (mm) VAS, where 0 mm = no disease activity and 100 mm = maximum disease activity. A negative change from baseline indicates improvement. | Baseline, Week 52 | 
| Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) at Steady State of Tocilizumab | AUCtau is the model-predicted area under the tocilizumab serum concentration versus time curve from time zero to the end of dosing interval. AUCtau is measured in microgram*day per milliliter (mcg*day/mL). | Baseline and Week 16 (Predose [Hour 0], 24, 48, 72, 96, and 120 or 144 hours postdose); Weeks 1, 2, 17, and 18 (Predose [Hour 0]) | 
| Maximum Serum Concentration at Steady State (Cmax,ss) of Tocilizumab | Cmax,ss is maximum model-predicted serum steady state concentration of tocilizumab measured in micrograms per milliliter (mcg/mL). | Baseline and Week 16 (Predose [Hour 0], 24, 48, 72, 96, and 120 or 144 hours postdose); Weeks 1, 2, 17, and 18 (Predose [Hour 0]) | 
| Minimum Serum Concentration at Steady State (Cmin,ss) of Tocilizumab | Cmin,ss is minimum model-predicted serum steady state concentration of tocilizumab measured in mcg/mL. | Baseline and Week 16 (Predose [Hour 0], 24, 48, 72, 96, and 120 or 144 hours postdose); Weeks 1, 2, 17, and 18 (Predose [Hour 0]) | 
| Minimum Observed Serum Concentration (Ctrough) of Tocilizumab | Ctrough is minimum observed serum concentration of tocilizumab measured in mcg/mL. | Predose (Hour 0) at Baseline and Week 52 | 
| Serum Interleukin-6 (IL-6) Level |  | Baseline and Week 52 | 
| Serum Soluble IL-6 Receptor (sIL-6R) Level |  | Baseline and Week 52 | 
| Erythrocyte Sedimentation Rate (ESR) | ESR is a laboratory test that provides a non-specific measure of inflammation. The test assesses the rate at which red blood cells fall in a test tube. Normal range is 0-30 mm/hr. A higher rate is consistent with inflammation. | Baseline and Week 52 | 
| C-Reactive Protein (CRP) Level | The test for CRP is a laboratory measurement for evaluation of an acute phase reactant of inflammation through the use of an ultrasensitive assay. A decrease in the level of CRP indicates reduction in inflammation and therefore improvement. | Baseline and Week 52 | 
| Percentage of Participants With Anti-Tocilizumab Antibodies | All samples were tested by screening assay, and those samples that were positive were further analyzed by a confirmation assay to confirm specificity. Percentage of participants who has a positive confirmation assay result any time after the initial drug administration with a negative confirmation assay result at baseline was reported. | Baseline up to Week 52 |