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SAINT I

NXY-059 for Acute Ischemic Stroke (Stroke-Acute Ischemic NXY Treatment I)

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Year of Publication: 2006

Authors: Lees KR, Zivin JA, Ashwood T, ..., for the SAINT I Trial Investigators

Journal: New England Journal of Medicine

Citation: N Engl J Med 2006;354:588-600

Link: https://doi.org/10.1056/nejmoa052980

Clinical Question

Does NXY-059, a free-radical-trapping neuroprotectant, reduce disability when given within 6 hours of acute ischemic stroke onset?

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).

Baseline Characteristics

Characteristic	Placebo (n=847)	NXY-059 (n=858)
Mean Age (yr)	68.5	68.4
Male %	55.7	55.4
Mean Time from Onset to Treatment (hr:min)	3:47	3:45
Mean NIHSS Score	12.5	12.6
Treated with Alteplase (%)	29.4	28
Hypertension (%)	69.1	68.9
Previous Stroke (%)	16.6	14.6
Previous TIA (%)	9.9	11.1
Ischemic Heart Disease (%)	33.5	32.1
Atrial Fibrillation (%)	31.8	28
Diabetes Mellitus (%)	21.5	18.8
Antiplatelet Use (%)	32.2	28
Cardioembolic Stroke (%)	44.9	42.1

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

Content summarized and formatted by NeuroTrials.ai.

SAINT I

(2006)

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.

Inclusion Criteria

Age ≥18 years, conscious, clinical diagnosis of acute ischemic stroke within 6 hours of onset, limb weakness, NIHSS score ≥6.

Study Design

Arms: NXY-059 IV infusion x 72h (n=850) vs Placebo IV infusion x 72h (n=849)

Patients per Arm: NXY-059 n=850; Placebo n=849

Outcome

• Primary: Modified Rankin scale distribution at 90 days improved with NXY-059 (P=0.038; common OR 1.20, 95% CI 1.01-1.42)
• 3.7% more patients recovered ability to walk (mRS ≤3; P=0.02)
• 4.4% more patients completely cured (mRS 0; P=0.003)
• NIHSS change from baseline: no significant difference (P=0.86)
• Barthel index: no significant difference (P=0.14)
• Complete neurologic recovery (NIHSS 0): 21.9% NXY-059 vs 17.3% placebo (OR 1.39, 95% CI 1.08-1.79; P=0.01)

Bottom Line

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

Study Design

Study Type: Randomized, double-blind, placebo-controlled trial
Randomization: Yes
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.
Sample Size: 1722
Follow-up: 90 days
Centers: 158
Countries: Multinational trial across 24 countries (individual countries not enumerated in the publication)

Primary Outcome

Definition: Disability at 90 days, measured by distribution of scores on the modified Rankin scale (range 0-5)

Control	Intervention	HR/OR	P-value
Placebo distribution on mRS	NXY-059 distribution on mRS (improved)	1.2 (1.01 to 1.42)	0.038 (Cochran-Mantel-Haenszel)

Limitations & 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

Citation

N Engl J Med 2006;354:588-600

View Original Publication →

SAINT I

NXY-059 for Acute Ischemic Stroke (Stroke-Acute Ischemic NXY Treatment I)

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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