A Phase III, Multicenter, Randomized, Double-Blind Placebo-Controlled Study to Assess the Efficacy and Safety of Tocilizumab in Subjects With Giant Cell Arteritis
Overview
- Phase
- Phase 3
- Intervention
- Tocilizumab
- Conditions
- Giant Cell Arteritis
- Sponsor
- Hoffmann-La Roche
- Enrollment
- 251
- Locations
- 78
- Primary Endpoint
- Percentage of Participants in Sustained Remission at Week 52 (Tocilizumab + 26 Weeks Prednisone Taper Versus Placebo + 26 Weeks Prednisone Taper)
- Status
- Completed
- Last Updated
- 6 years ago
Overview
Brief Summary
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.
Investigators
Eligibility Criteria
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
Arms & Interventions
Part 1: Tocilizumab qw + 26 weeks prednisone taper
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.
Intervention: Tocilizumab
Part 1: Tocilizumab qw + 26 weeks prednisone taper
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.
Intervention: Prednisone
Part 1: Tocilizumab qw + 26 weeks prednisone taper
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.
Intervention: Prednisone Placebo
Part 1: Tocilizumab q2w + 26 weeks prednisone taper
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.
Intervention: Tocilizumab
Part 1: Tocilizumab q2w + 26 weeks prednisone taper
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.
Intervention: Prednisone
Part 1: Tocilizumab q2w + 26 weeks prednisone taper
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.
Intervention: Tocilizumab Placebo
Part 1: Tocilizumab q2w + 26 weeks prednisone taper
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.
Intervention: Prednisone Placebo
Part 1: Placebo + 26 weeks prednisone taper
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.
Intervention: Prednisone
Part 1: Placebo + 26 weeks prednisone taper
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.
Intervention: Tocilizumab Placebo
Part 1: Placebo + 26 weeks prednisone taper
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.
Intervention: Prednisone Placebo
Part 1: Placebo + 52 weeks prednisone taper
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.
Intervention: Prednisone
Part 1: Placebo + 52 weeks prednisone taper
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.
Intervention: Tocilizumab Placebo
Part 1: Placebo + 52 weeks prednisone taper
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.
Intervention: Prednisone Placebo
Part 2: Open-Label Tocilizumab qw
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.
Intervention: Tocilizumab
Part 2: Open-Label Tocilizumab qw
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.
Intervention: Corticosteroids
Part 2: Open-Label Tocilizumab qw
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.
Intervention: Methotrexate
Outcomes
Primary Outcomes
Percentage of Participants in Sustained Remission at Week 52 (Tocilizumab + 26 Weeks Prednisone Taper Versus Placebo + 26 Weeks Prednisone Taper)
Time Frame: Week 52
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.
Secondary Outcomes
- Time to First GCA Disease Flare(Up to 52 weeks)
- Minimum Serum Concentration at Steady State (Cmin,ss) of Tocilizumab(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]))
- 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)(Baseline and Week 52)
- C-Reactive Protein (CRP) Level(Baseline and Week 52)
- Percentage of Participants With Anti-Tocilizumab Antibodies(Baseline up to Week 52)
- Percentage of Participants in Sustained Remission at Week 52 (Tocilizumab + 26 Weeks Prednisone Taper Versus Placebo + 52 Weeks Prednisone Taper)(Week 52)
- Minimum Observed Serum Concentration (Ctrough) of Tocilizumab(Predose (Hour 0) at Baseline and Week 52)
- Total Cumulative Prednisone Dose(Up to 52 weeks)
- Change From Baseline in Short Form (SF)-36 Questionnaire Score at Week 52(Baseline, Week 52)
- Change From Baseline in Patient Global Assessment (PGA) of Disease Activity Assessed Using Visual Analogue Scale (VAS) at Week 52(Baseline, Week 52)
- Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) at Steady State of Tocilizumab(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(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]))