SAINT I
NXY-059 for Acute Ischemic Stroke (Stroke-Acute Ischemic NXY Treatment I)
Clinical Question
Does NXY-059, a free-radical-trapping neuroprotectant, reduce disability when given within 6 hours of acute ischemic stroke onset?
Study Overview
Objective
To determine 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
- NXY-059 significantly improved the distribution of modified Rankin scale scores at 90 days vs placebo (P=0.038; common OR 1.20, 95% CI 1.01-1.42)
- No improvement in neurologic functioning by NIHSS (between-group difference 0.1 point, 95% CI -1.4 to 1.1; P=0.86)
- No improvement on Barthel index (P=0.14)
- Mortality and adverse event rates similar between groups
- Post hoc analysis in alteplase-treated patients: NXY-059 associated with lower any hemorrhagic transformation (P=0.001) and symptomatic ICH (P=0.036)
Intervention
72-hour IV infusion of NXY-059 (initial 2270 mg/hr for 1 hour, then 480-960 mg/hr for 71 hours, targeting plasma concentration of 260 µmol/L) vs placebo, started within 6 hours of stroke onset.
Patients per Arm
NXY-059 n=850; Placebo n=849
Bottom Line
NXY-059 administered within 6 hours of acute ischemic stroke onset significantly improved the primary outcome of disability at 90 days on the modified Rankin scale, but failed to improve neurologic functioning (NIHSS) or other secondary outcomes; additional research was needed to confirm benefit.
Major Points
- NXY-059 significantly improved the distribution of modified Rankin scale scores at 90 days vs placebo (P=0.038; common OR 1.20, 95% CI 1.01-1.42)
- Benefit was consistent at 7 and 30 days (OR 1.31 and 1.27 respectively)
- Among survivors, functional outcome on mRS was significantly improved (P=0.007)
- Coprimary neurologic outcome (NIHSS change from baseline) showed NO benefit (between-group difference 0.1 point; P=0.86)
- Barthel index showed no significant improvement (P=0.14)
- Complete neurologic recovery (NIHSS 0) more common with NXY-059: 21.9% vs 17.3% (OR 1.39, 95% CI 1.08-1.79; P=0.01) — post hoc
- Excellent neurologic outcome (NIHSS 0 or 1): 33.1% vs 30.9% (OR 1.13, 95% CI 0.90-1.41; P=0.28) — not statistically significant
- Mortality and adverse event rates similar between groups (mortality 17.0% NXY-059 vs 16.6% placebo, P=0.89)
- Post hoc in alteplase subgroup: NXY-059 associated with lower any hemorrhagic transformation (P=0.001) and symptomatic ICH (2.5% vs 6.4%, P=0.036)
- Discordance between mRS benefit and NIHSS lack of benefit raised questions about the validity of the primary finding
Design
Study Type: Randomized, double-blind, placebo-controlled trial
Randomization: 1
Blinding: Double-blind (vials visually identical; no laboratory test or adverse event known to distinguish study drug from placebo). Apart from 11 documented cases, investigators and assessors were unaware of treatment assignments throughout the trial until the database was locked.
Allocation: Central interactive voice-response system with dynamic algorithm; stratified by country, NIHSS at baseline, side of cerebral infarct, and intention to treat with alteplase
Enrollment Period: May 2003 through November 2004
Follow-up Duration: 90 days
Centers: 158
Countries: Multinational trial across 24 countries (individual countries not enumerated in the publication)
Sample Size: 1722
Analyzed: 1699
Analysis: Intention-to-treat. Primary end point analyzed across full mRS distribution using Cochran-Mantel-Haenszel test, adjusted for stratification variables (NIHSS, side of infarct, alteplase use), using modified ridit scores. Proportional-odds logistic regression for common odds ratio. Hierarchical testing of outcomes.
Power Calculation: Sample size chosen to provide 90% power to detect a common odds ratio for reduction of disability at 90 days of 1.3
Registration: ClinicalTrials.gov NCT00119626
Inclusion Criteria
- Age ≥18 years
- Conscious
- Clinical diagnosis of acute stroke commencing within 6 hours before study entry
- Limb weakness
- NIHSS score ≥6
Exclusion Criteria
- Specific exclusion criteria not detailed in the primary publication. Note: patients with an estimated creatinine clearance below 30 ml/min were withdrawn from study treatment (not an enrollment exclusion).
Arms
| Field | NXY-059 | Control |
|---|---|---|
| N | 850 | 849 |
| Intervention | IV infusion of NXY-059 initiated within 6 hours of stroke onset; initial rate 2270 mg/hr for 1 hour, then 480-960 mg/hr for further 71 hours, targeting plasma concentration of 260 µmol/L; rate adjusted by estimated creatinine clearance | IV infusion of matching placebo (visually identical vials) initiated within 6 hours of stroke onset |
| Duration | 72 hours | 72 hours |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Disability at 90 days, measured by distribution of scores on the modified Rankin scale (range 0-5) | Primary | Placebo distribution on mRS | NXY-059 distribution on mRS (improved) | 1.2 | 0.038 (Cochran-Mantel-Haenszel) |
| Change from baseline NIHSS score (coprimary neurologic end point) | Secondary | 0.86 | |||
| Barthel index at 90 days (dichotomized ≥95) | Secondary | 40.8% | 43.3% | 0.14 | |
| mRS distribution at 7 days | Secondary | 1.31 | |||
| mRS distribution at 30 days | Secondary | 1.27 | |||
| Functional outcome on mRS among survivors | Secondary | 0.007 (Cochran-Mantel-Haenszel) | |||
| Recovery of ability to walk (mRS ≤3) | Secondary | 0.02 | |||
| Complete cure (mRS 0) | Secondary | 0.003 | |||
| Stroke Impact Scale (SIS) | Secondary | 63.4 ± 1.1 | 66.2 ± 1.1 | 0.08 | |
| EuroQoL EQ-5D (weighted index) | Secondary | 0.43 ± 0.013 | 0.47 ± 0.013 | 0.06 | |
| EuroQoL EQ-5D (VAS) | Secondary | 62.0 ± 0.9 | 64.5 ± 0.9 | 0.05 | |
| Complete neurologic recovery (NIHSS 0) — post hoc | Secondary | 17.3% | 21.9% | 1.39 | 0.01 |
| Excellent neurologic outcome (NIHSS 0 or 1) — post hoc | Secondary | 30.9% | 33.1% | 1.13 | 0.28 |
| Post hoc nonparametric NIHSS analysis (Cochran-Mantel-Haenszel) | Secondary | 0.10 | |||
| Mortality at 90 days | Safety | 141/847 (16.6%) | 146/858 (17.0%) | 0.89 (log-rank test) | |
| Serious adverse events (number of patients) | Safety | 313/847 | 295/858 | ||
| Any adverse events (number of patients) | Safety | 670/847 | 662/858 | ||
| Discontinuation of treatment due to adverse events | Safety | 60 | 45 | ||
| Hypokalemia during infusion | Safety | 4.4% | 6.4% | ||
| Symptomatic intracranial hemorrhage in alteplase-treated patients (post hoc) | Safety | 16/249 (6.4%) | 6/240 (2.5%) | 0.036 | |
| Asymptomatic intracranial hemorrhage in alteplase-treated patients (post hoc) | Safety | 52/249 (20.9%) | 31/240 (12.9%) | ||
| Any hemorrhagic transformation in alteplase-treated patients (post hoc) | Safety | 0.001 | |||
| Adverse | 0.89 | ||||
| Adverse | Event: Any adverse event · Placebo (n=847): 670 · NXY-059 (n=858): 662 | ||||
| Adverse | Event: Serious adverse event · Placebo (n=847): 313 · NXY-059 (n=858): 295 | ||||
| Adverse | Event: Discontinuation due to adverse event · Placebo (n=847): 60 · NXY-059 (n=858): 45 | ||||
| Adverse | Event: Hypokalemia during infusion · Placebo: 4.4% · NXY-059: 6.4% | ||||
| Adverse | 0.036 | ||||
| Adverse | Event: Asymptomatic ICH (alteplase subgroup, post hoc) · Placebo (n=249): 52 (20.9%) · NXY-059 (n=240): 31 (12.9%) | ||||
Subgroup Analysis
Post hoc analysis of patients who also received alteplase showed NXY-059 was associated with a lower incidence of any hemorrhagic transformation (P=0.001) and symptomatic intracranial hemorrhage (P=0.036). In the per-protocol population (n=1525), the modified Rankin scale benefit was maintained (P=0.028). No significant interaction with stroke severity, alteplase use, or time from onset to treatment (P=0.72, 0.93, 0.92 respectively).
Criticisms
- Discordance between mRS benefit and NIHSS lack of benefit raised concerns about the consistency of the neuroprotective signal
- Primary outcome P-value (0.038) was marginally significant
- Reliance on a shift analysis of the full mRS distribution rather than a clinically intuitive dichotomous outcome
- Many post hoc analyses, including the alteplase-interaction findings on hemorrhagic transformation
- The favorable hemorrhagic transformation finding in the alteplase subgroup was post hoc and exploratory
- Subsequent SAINT II trial failed to replicate the primary efficacy finding
Funding
AstraZeneca (sponsor responsible for operational aspects, data collection, storage, and analysis according to approved study plan)
Based on: SAINT I (New England Journal of Medicine, 2006)
Authors: Lees KR, Zivin JA, Ashwood T, ..., for the SAINT I Trial Investigators
Citation: N Engl J Med 2006;354:588-600
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