GiACTA
(2017)Objective
To investigate whether tocilizumab results in higher rates of sustained glucocorticoid-free remission of giant-cell arteritis compared to placebo through 52 weeks
Study Summary
• Cumulative prednisone dose reduced by ~50% with tocilizumab (1862 mg vs 3296-3818 mg)
• Similar adverse event rates; serious adverse events numerically lower with tocilizumab (14-15% vs 22-25%)
Intervention
Subcutaneous tocilizumab 162 mg weekly or every other week plus 26-week prednisone taper vs placebo plus 26-week or 52-week prednisone taper
Inclusion Criteria
Adults ≥50 years with active giant-cell arteritis within 6 weeks before baseline, history of elevated ESR, diagnosis by temporal artery biopsy or imaging evidence of large-vessel vasculitis
Study Design
Arms: Tocilizumab weekly + 26-wk taper vs Tocilizumab every other week + 26-wk taper vs Placebo + 26-wk taper vs Placebo + 52-wk taper
Patients per Arm: 100 TCZ weekly, 50 TCZ every other week, 50 placebo+26wk, 51 placebo+52wk
Outcome
• Flare rates: 23% (TCZ weekly), 26% (TCZ Q2W) vs 68% (PBO 26-wk), 49% (PBO 52-wk)
• Cumulative prednisone: 1862 mg (both TCZ) vs 3296-3818 mg (PBO); P<0.001
Bottom Line
Tocilizumab weekly or every other week combined with a 26-week prednisone taper was superior to either 26-week or 52-week prednisone tapering plus placebo for achieving sustained glucocorticoid-free remission in patients with giant-cell arteritis, while reducing cumulative glucocorticoid exposure by approximately 50%.
Major Points
- Sustained remission at 52 weeks: 56% (tocilizumab weekly), 53% (tocilizumab Q2W) vs 14% (placebo 26-wk taper) and 18% (placebo 52-wk taper); P<0.001 for all comparisons
- Cumulative prednisone dose reduced by ~50%: 1862 mg (both tocilizumab groups) vs 3296-3818 mg (placebo groups)
- Flare rates significantly lower with tocilizumab: 23-26% vs 49-68% in placebo groups
- Hazard ratio for flare: 0.23 (TCZ weekly) and 0.28 (TCZ Q2W) vs placebo 26-week taper
- Serious adverse events numerically lower with tocilizumab (14-15%) than placebo (22-25%)
- One case of anterior ischemic optic neuropathy in tocilizumab every-other-week group that resolved with glucocorticoid treatment
- No deaths during the 1-year trial period
- Weekly tocilizumab appeared superior to every-other-week dosing in patients with relapsing disease
Study Design
- Study Type
- Randomized, double-blind, placebo-controlled, phase 3 trial
- Randomization
- Yes
- Blinding
- Double-blind. Patients and all trial personnel were unaware of CRP levels to prevent unblinding from tocilizumab's effect on CRP. Prednisone doses <20 mg/day were blinded; ≥20 mg/day were open-label. Dual-assessor approach: laboratory assessor monitored lab variables independently of efficacy assessor. Placebo tablets used after prednisone tapered to 0 mg.
- Sample Size
- 251
- Follow-up
- 52 weeks
- Countries
- United States, United Kingdom, Germany, Belgium, Netherlands, Spain, Italy
Primary Outcome
Definition: Sustained glucocorticoid-free remission at week 52, defined as remission from week 12 through week 52 with adherence to protocol-defined prednisone taper. Remission = absence of flare and CRP <1 mg/dL. Flare = recurrence of GCA signs/symptoms or ESR ≥30 mm/hr attributable to GCA requiring increased prednisone dose.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| - | - | - | <0.001 for all comparisons of tocilizumab vs placebo |
Limitations & Criticisms
- No validated outcome measures for GCA clinical trials; trial used stringent but not standardized definitions
- 52-week duration limits understanding of long-term efficacy and safety
- Tocilizumab's effect on CRP required complex blinding procedures that may affect generalizability
- One patient had anterior ischemic optic neuropathy while on tocilizumab, highlighting ongoing vision risk
- Weekly tocilizumab appeared more effective than every-other-week in relapsing disease subgroup analysis
- Escape therapy was permitted which complicates interpretation
- Trial not powered for safety outcomes
- Durability of remission after tocilizumab discontinuation unknown
- Predominantly white, female population limits generalizability
Citation
N Engl J Med 2017;377:317-28