SAINT II
(2007)Objective
To confirm whether the free-radical–trapping neuroprotectant NXY-059, given within 6 hours of acute ischemic stroke onset, reduces disability at 90 days, following a promising signal from the SAINT I trial.
Study Summary
• Trichotomized mRS analysis confirmed no benefit (OR 0.92, 95% CI 0.80–1.06)
• No benefit on any secondary end point (NIHSS, Barthel index at 90 days)
• No reduction in alteplase-related symptomatic or asymptomatic intracranial hemorrhage
• Mortality was equal in both groups (267 deaths each arm); adverse event rates were similar
• NXY-059 is ineffective for the treatment of acute ischemic stroke
Intervention
IV NXY-059 72-hour infusion (initial rate 2270 mg/hr then 480–960 mg/hr for 71 hours, adjusted for creatinine clearance, targeting plasma unbound concentration of 260 µmol/L) vs matching placebo, started within 6 hours of stroke onset
Inclusion Criteria
Age ≥18; clinical diagnosis of acute ischemic stroke within 6 hours of onset; NIHSS ≥6 with ≥2 points for limb weakness
Study Design
Arms: NXY-059 (n=1588 efficacy analysis) vs Placebo (n=1607 efficacy analysis)
Patients per Arm: NXY-059: 1588; Placebo: 1607 (efficacy analysis); 3306 total randomized
Outcome
• Trichotomized mRS (0–1 vs 2–3 vs 4–6): OR 0.92 (95% CI 0.80–1.06), no benefit
• Secondary outcomes (NIHSS, Barthel index): No evidence of efficacy for NXY-059
• Alteplase subgroup: No reduction in symptomatic or asymptomatic ICH with NXY-059
• Mortality equal; adverse events similar between arms
Bottom Line
NXY-059 is definitively ineffective for the treatment of acute ischemic stroke within 6 hours of symptom onset; it should not be used as a neuroprotective agent in this setting, and its null result underscores the persistent translational gap between animal model neuroprotection and human clinical benefit.
Major Points
- NXY-059 did not reduce disability: mRS distribution at 90 days showed no significant difference vs placebo (P = 0.33; OR for limiting disability 0.94, 95% CI 0.83–1.06).
- Trichotomized mRS analysis (0–1 vs 2–3 vs 4–6) confirmed no benefit (OR 0.92, 95% CI 0.80–1.06).
- No benefit was observed on any secondary end point, including NIHSS and Barthel index at 90 days.
- Among the ~44% of patients receiving concomitant alteplase, NXY-059 did not reduce the frequency of symptomatic or asymptomatic intracranial hemorrhage.
- Mortality was equal in both groups (267 deaths per arm); adverse event rates were similar.
- Target plasma concentrations of NXY-059 were achieved in 96.6% of treated patients, ruling out pharmacokinetic failure as an explanation for the null result.
- SAINT II (n=3306, 362 centers, 31 countries) was robustly powered and confirmed that the positive SAINT I signal was not reproducible.
- This trial is a landmark example of the failure to translate neuroprotective efficacy from animal stroke models to human clinical benefit.
Study Design
- Study Type
- Randomized, double-blind, placebo-controlled trial
- Randomization
- Yes
- Blinding
- Double-blind
- Sample Size
- 3306
- Follow-up
- 90 days
- Centers
- 362
- Countries
- 31 countries across Europe, North America, and Australia (individual countries not listed in source text)
Primary Outcome
Definition: Distribution of scores on the modified Rankin scale (mRS, range 0–5 with deceased patients scored 5) at 90 days, analyzed across the whole distribution using the Cochran–Mantel–Haenszel test with modified ridit scores, adjusted for stratification variables
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Placebo (n=1607): 1313 assessed at day 90, 267 died (mRS assigned 5), 27 lost to follow-up with last observation carried forward | NXY-059 (n=1588): 1279 assessed at day 90, 267 died (mRS assigned 5), 42 lost to follow-up with last observation carried forward | 0.94 (0.83 to 1.06) | 0.33 |
Limitations & Criticisms
- The positive SAINT I result was not reproducible in a much larger, better-powered replication — raising the possibility that the original finding was a false positive driven by smaller sample size.
- Despite robust pharmacokinetic confirmation (96.6% of patients achieving ≥150 µmol/L, well above neuroprotective animal model thresholds), no clinical benefit emerged, indicating the drug-target mechanism itself may not translate to human stroke.
- The trial highlights the ongoing translational failure in stroke neuroprotection: dozens of agents that worked in animal models have failed in human trials, pointing to fundamental differences in the models.
- Enrollment spanned 31 countries and 362 centers, introducing heterogeneity in care practices; however, prognostic factors were well balanced and the result was uniformly null.
Citation
N Engl J Med 2007;357:562-71