ACTISAVE
(2026)Objective
To evaluate the efficacy and safety of glenzocimab, a platelet glycoprotein VI antagonist, as add-on therapy to intravenous thrombolysis with or without mechanical thrombectomy in patients with acute ischemic stroke.
Study Summary
• No statistically significant difference in any secondary outcomes
• No major safety signals: any ICH occurred in 28.6% (glenzocimab) vs 29.9% (placebo)
• ACTISAVE failed to confirm a beneficial effect of glenzocimab on mRS in acute ischemic stroke
Intervention
Glenzocimab 1000 mg IV (6-hour infusion: ¼ dose over 15 min, ¾ over 5h45min) administered within 2 hours of thrombolysis initiation, vs matching placebo, added to standard IV thrombolysis (alteplase or tenecteplase) ± mechanical thrombectomy.
Inclusion Criteria
Adults ≥18 years with acute ischemic stroke (anterior or posterior circulation), treated within 4.5 hours of symptom onset with IV thrombolysis (alteplase or tenecteplase), prethrombolysis NIHSS ≥6 (≥4 before protocol amendment), eligible for mechanical thrombectomy if large vessel occlusion present.
Study Design
Arms: Glenzocimab 1000 mg IV (n=211) vs Placebo (n=208) in FAS (as randomized), both added to IV thrombolysis ± mechanical thrombectomy
Patients per Arm: FAS (randomized and treated): 419 (glenzocimab 211, placebo 208); Safety Set: 421 (glenzocimab 210, placebo 211, including 2 nonrandomized treated patients); 438 enrolled, 436 randomized (1:1)
Outcome
• No statistically significant difference in key secondary outcome (mRS 0-2 at day 90)
• No significant differences in mortality, mRS shift, NIHSS, or quality of life
• Safety: any ICH 28.6% glenzocimab vs 29.9% placebo — no major safety signals
Bottom Line
ACTISAVE failed to confirm a beneficial effect of glenzocimab on functional outcomes in acute ischemic stroke patients treated with IV thrombolysis ± mechanical thrombectomy. There was no significant reduction in poor outcome (mRS 4-6) and no significant benefit on secondary outcomes, although safety was acceptable with no increase in ICH.
Major Points
- Phase 2/3 international RCT (54 centers, 10 countries) of glenzocimab 1000 mg IV vs placebo added to IV thrombolysis ± mechanical thrombectomy in 419 randomized-and-treated AIS patients (FAS: 211 glenzocimab, 208 placebo)
- Primary outcome (mRS 4-6 at day 90): 21.6% glenzocimab vs 15.3% placebo (OR 1.51, 95% CI 0.90-2.54; P=0.120) — numerically worse with glenzocimab, not statistically significant
- No statistically significant difference in key secondary outcome (mRS 0-2 at day 90) or any other secondary outcome
- No major safety signals: any ICH 28.6% glenzocimab vs 29.9% placebo
- Mechanical thrombectomy was performed in 36% of patients; thrombolysis given at median 2.3 hours post-onset; study drug initiated median 1.2 hours after thrombolysis
- Trial does not support efficacy of glenzocimab as add-on to thrombolysis in AIS, contradicting earlier ACTIMIS signals
Study Design
- Study Type
- Phase 2/3 international, randomized, double-blind, placebo-controlled, parallel-group trial
- Randomization
- Yes
- Blinding
- Quadruple masking (patient, caregiver, outcome assessor, investigator)
- Sample Size
- 438
- Follow-up
- 90 days
- Centers
- 54
- Countries
- Belgium, Czech Republic, Denmark, France, Germany, Israel, Slovakia, Spain, United Kingdom, United States
Primary Outcome
Definition: Poor functional outcome defined as mRS score 4-6 (vs 0-3)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 15.3% | 21.6% | 1.51 (0.90-2.54) | 0.120 |
Limitations & Criticisms
- Primary endpoint changed during conduct from ordinal mRS shift to binary mRS 4-6 vs 0-3, with sample size reduced from 1000 to 400 evaluable patients
- Numerically higher rate of poor outcome in the glenzocimab arm (21.6% vs 15.3%) raises concern despite non-significance
- Failed to replicate the favorable mortality and ICH signals seen in the smaller ACTIMIS phase 1b/2a trial
- Study drug administered up to 2 hours after thrombolysis initiation — potentially too late for platelet GPVI inhibition to affect outcomes
- Imbalance in baseline characteristics (diabetes, NIHSS) within the mechanical thrombectomy subgroup, plus lower post-MT recanalization (eTICI) with glenzocimab, may have contributed to worse mRS outcomes in that subgroup
Citation
Stroke. 2026;57:1116-1125. DOI: 10.1161/strokeaha.125.052935