SAINT I
(2006)Objective
To evaluate whether NXY-059, a free-radical–trapping neuroprotective agent, reduces disability in patients with acute ischemic stroke when administered within 6 hours of symptom onset.
Study Summary
• 3.7% more patients recovered ability to walk (mRS ≤3; P=0.02) and 4.4% more were completely cured (mRS 0; P=0.003) with NXY-059
• NXY-059 did not improve neurologic function on NIHSS (difference 0.1 points, 95% CI −1.4 to 1.1; P=0.86) or Barthel index (P=0.14)
• Post hoc analysis in alteplase-treated patients: NXY-059 reduced hemorrhagic transformation (P=0.001) and symptomatic ICH (P=0.036)
• Mortality and adverse event rates were similar between groups
Intervention
72-hour IV infusion of NXY-059 (initial rate 2270 mg/hr for 1 hour, then 480–960 mg/hr adjusted for renal function, targeting plasma concentration 260 µmol/L) versus visually identical placebo, initiated within 6 hours of stroke onset
Inclusion Criteria
Conscious patients ≥18 years with clinical diagnosis of acute ischemic stroke within 6 hours of onset, limb weakness, and NIHSS score ≥6
Study Design
Arms: NXY-059 72-hour IV infusion (n=850) vs Placebo (n=849)
Patients per Arm: 850 (NXY-059) vs 849 (placebo) in efficacy analysis
Outcome
• 3.7% more patients achieved mRS ≤3 (P=0.02); 4.4% more achieved mRS 0 (P=0.003)
• No significant improvement in NIHSS (P=0.86) or Barthel index (P=0.14)
• Post hoc in alteplase subgroup: lower hemorrhagic transformation (P=0.001) and symptomatic ICH (P=0.036) with NXY-059
Bottom Line
NXY-059 met its primary endpoint of improving mRS distribution at 90 days, but failed to improve NIHSS or Barthel index; the modest effect size and mixed secondary results required a confirmatory trial before any clinical adoption could be considered.
Major Points
- NXY-059 significantly improved the primary outcome — distribution of mRS scores at 90 days — compared with placebo (OR 1.20, 95% CI 1.01–1.42; P=0.038)
- 3.7% more patients recovered ability to walk (mRS ≤3; P=0.02) and 4.4% more were completely cured (mRS 0; P=0.003) with NXY-059
- NXY-059 did not improve the secondary neurologic endpoint: mean NIHSS change from baseline differed by only 0.1 point (95% CI −1.4 to 1.1; P=0.86); nonparametric post hoc analysis also non-significant (P=0.10)
- Barthel index at 90 days was not significantly improved (P=0.14)
- Post hoc analysis in alteplase-treated patients showed lower rates of any hemorrhagic transformation (P=0.001) and symptomatic ICH (P=0.036) with NXY-059
- Mortality and serious/nonserious adverse event rates were similar between groups, supporting an acceptable safety profile
- Per-protocol analysis (n=1525) confirmed primary endpoint benefit (P=0.028); consistent improvement also seen at 7 days (OR 1.31, 95% CI 1.09–1.57) and 30 days (OR 1.27, 95% CI 1.07–1.52)
Study Design
- Study Type
- Randomized, double-blind, placebo-controlled trial
- Randomization
- Yes
- Blinding
- Double-blind (vials visually identical; investigators and assessors unaware of allocation until database lock; 11 documented unblinding exceptions)
- Sample Size
- 1722
- Follow-up
- 90 days
- Centers
- 158
Primary Outcome
Definition: Distribution of scores on the modified Rankin Scale (mRS; 0–5, with 5 = bedbound requiring constant care) at 90 days, analyzed across the full score distribution using the Cochran–Mantel–Haenszel test with modified ridit scores
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Placebo mRS distribution at 90 days | NXY-059 mRS distribution at 90 days — improved across all cut points | 1.2 (1.01 to 1.42) | 0.038 |
Limitations & Criticisms
- Primary endpoint (mRS distribution) was met, but coprimary/secondary neurologic endpoints (NIHSS, Barthel) were not significant — raises questions about clinical meaningfulness of the mRS improvement alone
- Effect size was modest (OR 1.20), and the trial was powered to detect OR 1.3; the lower bound of the CI barely exceeded 1.0
- Hierarchical testing structure was pre-specified, but the coprimary label for NIHSS created interpretive ambiguity around what constituted trial success
- Hemorrhagic transformation benefit in alteplase patients was entirely post hoc, limiting causal inference and generalizability
- Three AstraZeneca employees were co-authors, and AstraZeneca handled all operational aspects of the trial including data collection, storage, and analysis
- Enrollment across 158 centers in 24 countries introduced potential heterogeneity in stroke care standards and rehabilitation practices
Citation
Lees KR, et al. NXY-059 for Acute Ischemic Stroke. N Engl J Med. 2006;354(6):588-600.