AXIOMATIC-SSP
Safety and efficacy of factor XIa inhibition with milvexian for secondary stroke prevention (AXIOMATIC-SSP): a phase 2, international, randomised, double-blind, placebo-controlled, dose-finding trial
Clinical Question
Does factor XIa inhibition with milvexian reduce ischemic stroke or covert brain infarcts without increasing bleeding risk in patients with acute non-cardioembolic stroke or TIA?
Bottom Line
Milvexian did not demonstrate a clear dose-response benefit for the composite outcome of symptomatic stroke or covert infarcts, but some doses showed a reduction in symptomatic stroke without increasing major bleeding.
Major Points
- Largest phase 2 trial of FXIa inhibition in non-cardioembolic stroke
- No dose-response effect for the primary composite outcome
- Symptomatic stroke was numerically reduced in all but highest dose group
- No increase in intracranial hemorrhage or fatal bleeding across doses
- Major GI bleeding slightly higher with doses ≥50 mg BID
- Findings support moving 25–100 mg BID doses to phase 3 testing
Design
Study Type: Phase 2, randomised, double-blind, placebo-controlled, dose-finding
Randomization: 1
Blinding: Double-blind
Enrollment Period: Jan 2019 – Dec 2021
Follow-up Duration: 90 days
Centers: 367
Countries: Argentina, Austria, Belgium, Brazil, Canada, Chile, Denmark, Finland, France, Germany, Greece, Hungary, Israel, Italy, Japan, Mexico, Norway, Poland, Russia, South Korea, Spain, Sweden, Switzerland, UK, USA, Netherlands, Others
Sample Size: 2366
Analysis: MCP-MOD for dose-response; ITT and per-protocol analyses
Inclusion Criteria
- Age ≥40 years
- Non-cardioembolic ischemic stroke (NIHSS ≤7)
- High-risk TIA (ABCD2 ≥6 or motor deficit)
- Symptom onset <48 hours
- Imaging evidence of atherosclerosis
Exclusion Criteria
- Hemorrhage history or contraindications to anticoagulation
- eGFR <15 mL/min/1.73m²
- Active liver disease
- Need for anticoagulants or strong CYP3A4/P-gp modulators
- Use of dual antiplatelet therapy >21 days
Arms
| Field | Control | Milvexian 25 mg once daily | Milvexian 25 mg twice daily | Milvexian 50 mg twice daily | Milvexian 100 mg twice daily | Milvexian 200 mg twice daily |
|---|---|---|---|---|---|---|
| Intervention | Placebo + ASA 100 mg/day + Clopidogrel 75 mg/day (21 days) | Milvexian 25 mg QD + standard DAPT | Milvexian 25 mg BID + standard DAPT | Milvexian 50 mg BID + standard DAPT | Milvexian 100 mg BID + standard DAPT | Milvexian 200 mg BID + standard DAPT |
| Duration | 90 days | 90 days | 90 days | 90 days | 90 days | 90 days |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Composite of symptomatic ischemic stroke or new covert brain infarct by day 90 | Primary | 17% | 14–16% (no dose-response) | 1.00% | NS across all models |
| Symptomatic stroke: reduced in all but 200 mg BID group | Secondary | Placebo: 38/691 (5%) | 25 mg QD: 15/328 (5%) RR 1.26 (0.20-5.73); 25 mg BID: 12/318 (4%) RR 1.30 (0.21-5.92); 50 mg BID: 13/328 (4%) RR 0.84 (0.11-4.26); 100 mg BID: 11/310 (4%) RR 2.23 (0.61-8.12); 200 mg BID: 27/351 (8%) RR 1.57 (0.36-6.51) | Doses 25-100 mg BID showed numerically fewer ischaemic strokes than placebo; 200 mg BID had more events | Not significant (CIs cross 1; no formal hypothesis testing for individual doses) |
| No difference in covert infarcts | Secondary | Placebo: 66/625 (11%) | 25 mg QD: 35/308 (11%) RR 0.98 (0.72-1.33); 25 mg BID: 41/287 (14%) RR 1.11 (0.82-1.50); 50 mg BID: 30/306 (10%) RR 0.84 (0.61-1.17); 100 mg BID: 30/277 (11%) RR 0.89 (0.64-1.24); 200 mg BID: 25/317 (8%) RR 0.99 (0.73-1.34) | No significant treatment effect across doses | |
| No significant difference in MI or all-cause death | Secondary | Placebo composite (non-fatal stroke + non-fatal MI + all-cause death): 42/691 (6%); MI 2/691 (<1%); all-cause death 5/691 (1%) | Composite: 25 mg QD 17/328 (5%) RR 0.85 (0.49-1.47); 25 mg BID 15/318 (5%) RR 0.78 (0.44-1.38); 50 mg BID 16/328 (5%) RR 0.80 (0.46-1.41); 100 mg BID 16/310 (5%) RR 0.85 (0.49-1.49); 200 mg BID 33/351 (9%) RR 1.55 (1.00-2.40). MI: 1/328, 2/318, 1/328, 2/310, 3/351. All-cause death: 3/328, 3/318, 2/328, 5/310, 4/351 | No significant differences | |
| Major Bleeding | Adverse | 1–2% across groups, no fatal events | |||
| Intracranial Hemorrhage | Adverse | <1% | |||
| GI Bleeding | Adverse | ↑ at ≥50 mg BID doses | |||
| Renal Events | Adverse | ↑ at 200 mg BID |
Subgroup Analysis
No significant heterogeneity by age, sex, or qualifying event
Criticisms
- No dose-response for primary efficacy
- MRI-detected covert infarcts may not correlate with clinical benefit
- Potential signal of harm at highest dose (200 mg BID)
- Study underpowered to detect rare safety signals
Funding
Bristol Myers Squibb and Janssen Research & Development
Based on: AXIOMATIC-SSP (Lancet Neurology, 2024)
Authors: Sharma M, Molina CA, Toyoda K, ..., Czlonkowska A
Citation: Lancet Neurol. 2024 Jan;23(1):46–59. doi:10.1016/S1474-4422(23)00403-9
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