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GiACTA

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

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

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?

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

Arms

Field	Control	Control	Tocilizumab weekly + 26-week prednisone taper	Tocilizumab every other week + 26-week prednisone taper
Intervention	Weekly 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.
Duration	52 weeks	52 weeks	52 weeks	52 weeks

Outcomes

Outcome	Type	HR / OR / RR	P-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	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	Secondary		0.003 for TCZ weekly; 0.03 for TCZ Q2W (met noninferiority but not superiority for Q2W)
Patients with flare	Secondary	HR 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	Secondary		<0.001 for all comparisons of tocilizumab vs placebo
Patients receiving open-label escape prednisone (post hoc)	Secondary
SF-36 Physical Component Summary score change from baseline to week 52	Secondary		0.002 for TCZ weekly vs PBO 52-wk; NS for TCZ Q2W comparisons
SF-36 Mental Component Summary score change from baseline	Secondary		Not significant
Patient global assessment VAS score change from baseline (improvement = decrease)	Secondary		<0.05 for TCZ weekly vs placebo; <0.01 for TCZ Q2W vs placebo
Patients with ≥1 AE	Adverse
Patients with ≥1 serious AE	Adverse
Patients with ≥1 infection	Adverse
Patients with serious infection	Adverse
Withdrawal due to AE	Adverse
Injection-site reaction	Adverse
Death	Adverse
Grade 3 neutropenia	Adverse
Grade 3 ALT elevation	Adverse
Anterior ischemic optic neuropathy	Adverse
Thrombotic stroke	Adverse
Gastrointestinal perforation	Adverse
Myocardial infarction	Adverse
Anaphylaxis	Adverse

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

Content summarized and formatted by NeuroTrials.ai.

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

• 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

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

• Primary: Sustained remission at 52 weeks: 56% (TCZ weekly), 53% (TCZ Q2W) vs 14% (PBO 26-wk), 18% (PBO 52-wk); P<0.001
• 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

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

View Original Publication →

GiACTA

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

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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