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GiACTA

Giant-Cell Arteritis Actemra Trial - Trial of Tocilizumab in Giant-Cell Arteritis

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Year of Publication: 2017

Authors: John H. Stone, Katie Tuckwell, Sophie Dimonaco, ..., Neil Collinson

Journal: New England Journal of Medicine

Citation: N Engl J Med 2017;377:317-28

PDF: https://www.nejm.org/doi/pdf/10.1056/NEJ...ticleTools=true

Clinical Question

Does tocilizumab, an interleukin-6 receptor alpha inhibitor, result in higher rates of sustained glucocorticoid-free remission compared to placebo during glucocorticoid tapering in patients with giant-cell arteritis?

Study Overview

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

  • Tocilizumab weekly (56%) and every other week (53%) achieved significantly higher sustained remission than placebo with 26-week (14%) or 52-week (18%) prednisone taper (P<0.001 for all comparisons)
  • 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

Patients per Arm

100 TCZ weekly, 50 TCZ every other week, 50 placebo+26wk, 51 placebo+52wk

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

Design

Study Type: Randomized, double-blind, placebo-controlled, phase 3 trial

Randomization: 1

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.

Enrollment Period: July 2013 - April 2015

Follow-up Duration: 52 weeks

Countries: United States, United Kingdom, Germany, Belgium, Netherlands, Spain, Italy

Sample Size: 251

Analysis: Intention-to-treat. Cochran-Mantel-Haenszel test adjusted for baseline prednisone dose (≤30 mg vs >30 mg) for primary outcome. Two independent dose hierarchies with fixed sequential testing to control type I error. Noninferiority margin of -22.5 percentage points for key secondary outcome. Two-sided 99.5% CI used. Cox proportional-hazards models for time-to-event analyses. Van Elteren test for prednisone dose comparisons. Alpha level of 0.01.

Inclusion Criteria

  • Age ≥50 years
  • Active giant-cell arteritis within 6 weeks before baseline
  • History of elevated erythrocyte sedimentation rate (ESR) attributable to giant-cell arteritis
  • Disease activity defined as unequivocal cranial symptoms of GCA or polymyalgia rheumatica plus increased serum acute-phase reactants
  • Diagnosis based on temporal-artery biopsy showing features of GCA OR evidence of large-vessel vasculitis on angiography, CT/MR angiography, or PET
  • Newly diagnosed or relapsing disease eligible
  • Baseline oral prednisone dose between 20-60 mg/day

Exclusion Criteria

  • Use of IV methylprednisolone >100 mg daily within 6 weeks before baseline

Baseline Characteristics

Control (Placebo 26-wk):

  • N: 50
  • Age - mean (SD), years: 69.3 (8.1)
  • Sex - Female: 76%
  • Race - White: 100%
  • Weight - mean (SD), kg: 70.1 (15.8)
  • BMI - mean (SD): 25.7 (4.5)
  • Newly diagnosed GCA: 46%
  • Relapsing GCA: 54%
  • Prednisone dose ≤30 mg/day: 54%
  • Prednisone dose >30 mg/day: 46%
  • Disease duration - mean (SD), days: 365 (570)
  • Cranial signs or symptoms: 80%
  • Symptoms of polymyalgia rheumatica: 60%
  • ESR - mean (SD), mm/hr: 28.8 (25.4)
  • Diagnosis by positive temporal-artery biopsy: 72%
  • Diagnosis by positive imaging: 38%

Control (Placebo 52-wk):

  • N: 51
  • Age - mean (SD), years: 67.8 (7.7)
  • Sex - Female: 73%
  • Race - White: 96%
  • Weight - mean (SD), kg: 73.1 (15.3)
  • BMI - mean (SD): 25.8 (4.1)
  • Newly diagnosed GCA: 45%
  • Relapsing GCA: 55%
  • Prednisone dose ≤30 mg/day: 51%
  • Prednisone dose >30 mg/day: 49%
  • Disease duration - mean (SD), days: 255 (436)
  • Cranial signs or symptoms: 78%
  • Symptoms of polymyalgia rheumatica: 69%
  • ESR - mean (SD), mm/hr: 24.2 (18.2)
  • Diagnosis by positive temporal-artery biopsy: 57%
  • Diagnosis by positive imaging: 45%

Active (TCZ Weekly):

  • N: 100
  • Age - mean (SD), years: 69.5 (8.5)
  • Sex - Female: 78%
  • Race - White: 97%
  • Weight - mean (SD), kg: 69.8 (13.8)
  • BMI - mean (SD): 26.0 (4.4)
  • Newly diagnosed GCA: 47%
  • Relapsing GCA: 53%
  • Prednisone dose ≤30 mg/day: 52%
  • Prednisone dose >30 mg/day: 48%
  • Disease duration - mean (SD), days: 307 (564)
  • Cranial signs or symptoms: 78%
  • Symptoms of polymyalgia rheumatica: 59%
  • ESR - mean (SD), mm/hr: 24.6 (18.7)
  • Diagnosis by positive temporal-artery biopsy: 57%
  • Diagnosis by positive imaging: 50%

Active (TCZ Q2W):

  • N: 50 (49 in ITT)
  • Age - mean (SD), years: 69.4 (8.2)
  • Sex - Female: 70%
  • Race - White: 94%
  • Weight - mean (SD), kg: 70.8 (16.1)
  • BMI - mean (SD): 26.0 (6.2)
  • Newly diagnosed GCA: 52%
  • Relapsing GCA: 48%
  • Prednisone dose ≤30 mg/day: 50%
  • Prednisone dose >30 mg/day: 50%
  • Disease duration - mean (SD), days: 258 (501)
  • Cranial signs or symptoms: 82%
  • Symptoms of polymyalgia rheumatica: 64%
  • ESR - mean (SD), mm/hr: 20.8 (18.1)
  • Diagnosis by positive temporal-artery biopsy: 68%
  • Diagnosis by positive imaging: 46%

Arms

FieldControlControlTocilizumab weekly + 26-week prednisone taperTocilizumab every other week + 26-week prednisone taper
InterventionWeekly subcutaneous placebo injections plus protocol-defined 26-week prednisone taper. Starting prednisone dose 20-60 mg/day, tapered weekly per protocol. Doses ≥20 mg open-label; <20 mg blinded. Escape therapy with open-label prednisone permitted for flares.Weekly subcutaneous placebo injections plus protocol-defined 52-week prednisone taper. Starting prednisone dose 20-60 mg/day, tapered weekly per protocol. Doses ≥20 mg open-label; <20 mg blinded. Escape therapy with open-label prednisone permitted for flares.Subcutaneous tocilizumab 162 mg weekly plus protocol-defined 26-week prednisone taper. Starting prednisone dose 20-60 mg/day, tapered weekly per protocol. Escape therapy with open-label prednisone permitted for flares while continuing tocilizumab.Subcutaneous tocilizumab 162 mg every other week (with placebo injections on alternate weeks) plus protocol-defined 26-week prednisone taper. Starting prednisone dose 20-60 mg/day, tapered weekly per protocol. Escape therapy with open-label prednisone permitted for flares while continuing tocilizumab.
Duration52 weeks52 weeks52 weeks52 weeks

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
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.Primary<0.001 for all comparisons of tocilizumab vs placebo
Sustained remission excluding CRP normalization (sensitivity analysis) vs PBO 26-wk | Control (26-wk): 20% (10/50); Control (52-wk): 33% (17/51); Intervention (TCZ weekly): 59% (59/100); Intervention (TCZ Q2W): 55% (27/49)Secondary<0.001 for TCZ weekly; <0.001 for TCZ Q2W vs PBO 26-wk
Sustained remission excluding CRP normalization (sensitivity analysis) vs PBO 52-wk | Control (52-wk): 33%; Intervention (TCZ weekly): 59%; Intervention (TCZ Q2W): 55%Secondary0.003 for TCZ weekly; 0.03 for TCZ Q2W (met noninferiority but not superiority for Q2W)
Patients with flare | Control (26-wk): 68%; Control (52-wk): 49%; Intervention (TCZ weekly): 23%; Intervention (TCZ Q2W): 26%; 99% CI: 0.11-0.46 (weekly); 0.12-0.66 (Q2W)SecondaryHR 0.23 (TCZ weekly vs PBO 26-wk); HR 0.28 (TCZ Q2W vs PBO 26-wk)<0.001 for both
Cumulative prednisone dose - median (95% CI), mg | Control (26-wk): 3296 (2730-4024); Control (52-wk): 3818 (2818-4426); Intervention (TCZ weekly): 1862 (1582-1942); Intervention (TCZ Q2W): 1862 (1568-2240)Secondary<0.001 for all comparisons of tocilizumab vs placebo
Patients receiving open-label escape prednisone (post hoc) | Control (26-wk): 74%; Control (52-wk): 55%; Intervention (TCZ weekly): 23%; Intervention (TCZ Q2W): 33%Secondary26-wk taper: 74%; 52-wk taper: 55%TCZ weekly: 23%; TCZ Q2W: 33%
SF-36 Physical Component Summary score change from baseline to week 52 | Control (26-wk): -0.28; Control (52-wk): -1.49; Intervention (TCZ weekly): +4.10; Intervention (TCZ Q2W): +2.76; Difference (TCZ weekly vs PBO 52-wk): 5.59 (99% CI 0.86-10.32)Secondary0.002 for TCZ weekly vs PBO 52-wk; NS for TCZ Q2W comparisons
SF-36 Mental Component Summary score change from baseline | Control (26-wk): 6.67; Control (52-wk): 2.84; Intervention (TCZ weekly): 7.28; Intervention (TCZ Q2W): 6.12SecondaryNot significant
Patient global assessment VAS score change from baseline (improvement = decrease) | Control (26-wk): -3.4; Control (52-wk): -7.2; Intervention (TCZ weekly): -19.0; Intervention (TCZ Q2W): -25.3Secondary<0.05 for TCZ weekly vs placebo; <0.01 for TCZ Q2W vs placebo
Patients with ≥1 AEAdverseControl (26-wk): 96% (48/50); Control (52-wk): 92% (47/51); Intervention (TCZ weekly): 98% (98/100); Intervention (TCZ Q2W): 96% (47/49)
Patients with ≥1 serious AEAdverseControl (26-wk): 22% (11/50); Control (52-wk): 25% (13/51); Intervention (TCZ weekly): 15% (15/100); Intervention (TCZ Q2W): 14% (7/49)
Patients with ≥1 infectionAdverseControl (26-wk): 76% (38/50); Control (52-wk): 65% (33/51); Intervention (TCZ weekly): 75% (75/100); Intervention (TCZ Q2W): 73% (36/49)
Patients with serious infectionAdverseControl (26-wk): 4% (2/50); Control (52-wk): 12% (6/51); Intervention (TCZ weekly): 7% (7/100); Intervention (TCZ Q2W): 4% (2/49)
Withdrawal due to AEAdverseControl (26-wk): 4% (2/50); Control (52-wk): 0%; Intervention (TCZ weekly): 6% (6/100); Intervention (TCZ Q2W): 6% (3/50)
Injection-site reactionAdverseControl (26-wk): 10% (5/50); Control (52-wk): 2% (1/51); Intervention (TCZ weekly): 7% (7/100); Intervention (TCZ Q2W): 14% (7/49)
DeathAdverseControl (26-wk): 0; Control (52-wk): 0; Intervention (TCZ weekly): 0; Intervention (TCZ Q2W): 0
Grade 3 neutropeniaAdverseControl (26-wk): 0; Control (52-wk): 0; Intervention (TCZ weekly): 4% (4/100); Intervention (TCZ Q2W): 4% (2/49)
Grade 3 ALT elevationAdverseControl (26-wk): 0; Control (52-wk): 2% (1/51); Intervention (TCZ weekly): 2% (2/100); Intervention (TCZ Q2W): 2% (1/49)
Anterior ischemic optic neuropathyAdverseControl (26-wk): 0; Control (52-wk): 0; Intervention (TCZ weekly): 0; Intervention (TCZ Q2W): 1 (2%); Note: Occurred during disease flare; resolved with glucocorticoid treatment
Thrombotic strokeAdverseControl (26-wk): 0; Control (52-wk): 0; Intervention (TCZ weekly): 0; Intervention (TCZ Q2W): 1 (2%); Note: Attributed to warfarin discontinuation for unrelated surgery
Gastrointestinal perforationAdverseAll groups: 0
Myocardial infarctionAdverseAll groups: 0
AnaphylaxisAdverseAll groups: 0

Subgroup Analysis

In patients with relapsing disease at baseline (n=131): TCZ weekly had significantly lower flare risk vs placebo 26-wk (HR 0.23, 99% CI 0.09-0.61, P<0.001) and vs placebo 52-wk (HR 0.36, 99% CI 0.13-1.00, P=0.01). TCZ every other week did not show significant benefit in relapsing disease subgroup (HR 0.42 vs PBO 26-wk, P=0.05; HR 0.67 vs PBO 52-wk, P=0.37). This differential between dosing regimens was not seen in newly diagnosed patients.

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

Funding

F. Hoffmann-La Roche. Medical writing assistance provided by Maxwell Chang and Sara Duggan, paid by sponsor. Roche provided tocilizumab and placebo.

Based on: GiACTA (New England Journal of Medicine, 2017)

Authors: John H. Stone, Katie Tuckwell, Sophie Dimonaco, ..., Neil Collinson

Citation: N Engl J Med 2017;377:317-28

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