NXY-059 for the treatment of acute ischemic stroke.

BACKGROUND: The free-radical-trapping agent NXY-059 showed promise as a neuroprotectant in the Stroke-Acute Ischemic NXY Treatment I (SAINT I) trial, reducing disability when given to patients who had acute ischemic stroke. We sought confirmation of efficacy in a second, larger trial. METHODS: We enrolled 3306 patients with acute ischemic stroke in a randomized, double-blind trial to receive a 72-hour infusion of intravenous NXY-059 or placebo within 6 hours after the onset of stroke symptoms. Our primary end point was the distribution of disability scores on the modified Rankin scale at 90 days. We examined scores on neurologic and activities-of-daily-living scales as secondary end points. We also tested the hypothesis that NXY-059 would reduce alteplase-related intracranial hemorrhages. RESULTS: The efficacy analysis was based on 3195 patients. Prognostic factors were well balanced between the treatment groups. Mortality was equal in the two groups, and adverse-event rates were similar. The distribution of scores on the modified Rankin scale did not differ between the group treated with NXY-059 (1588 patients) and the placebo group (1607 patients; P=0.33 by the Cochran-Mantel-Haenszel test; odds ratio for limiting disability, 0.94; 95% confidence interval [CI], 0.83 to 1.06). Analysis of categorized scores on the modified Rankin scale confirmed the lack of benefit: the odds ratio for trichotomization into modified Rankin scale scores of 0 to 1 versus 2 to 3 versus 4 to 6 was 0.92 (95% CI, 0.80 to 1.06). There was no evidence of efficacy for any of the secondary end points. Among patients treated with alteplase, there was no difference between the NXY-059 group and the placebo group in the frequency of symptomatic or asymptomatic hemorrhage. CONCLUSIONS: NXY-059 is ineffective for the treatment of acute ischemic stroke within 6 hours after the onset of symptoms. (ClinicalTrials.gov number, NCT00061022 [ClinicalTrials.gov].)

Hyperfibrinogenemia and functional outcome from acute ischemic stroke.

BACKGROUND AND PURPOSE: Epidemiological studies have found strong correlations between elevated plasma fibrinogen levels and both ischemic stroke incidence and stroke mortality. Little is known about the influence of fibrinogen levels on functional stroke outcome. METHODS: Placebo data from the Stroke Treatment with Ancrod Trial (STAT) and European Stroke Treatment with Ancrod Trial (ESTAT) were analyzed. Fibrinogen levels were determined within 3 hours (STAT) or 6 hours (ESTAT) of stroke onset and at preset intervals throughout 5 days of intravenous infusions. Barthel Index scores at 90 days quantified functional outcomes. The association between initial fibrinogen levels and functional outcomes was evaluated using a multiple logistic regression analysis. RESULTS: Fibrinogen levels increased gradually over the first 24 hours from a pretreatment median value of 340 mg/dL to a 24-hour median value of 376 mg/dL. In a univariate analysis, the proportion of patients with good functional outcome decreased with increasing quartiles of initial fibrinogen levels in both STAT (36.0% to 26.2%) and ESTAT (53.8% to 24.8%). In a multifactorial analysis, the same trend was observed. Patients with initial fibrinogen levels <450 mg/dL had better outcomes in both studies; the difference (42.0% versus 21.6%) was significant in ESTAT (P=0.0006), even when corrected for age and initial stroke severity. CONCLUSIONS: The independent association of higher initial fibrinogen levels with poor outcome needs to be verified using a larger acute stroke dataset. Even in the present small populations, the apparent association of these 2 variables suggests that treatments designed to reduce fibrinogen levels could potentially be important in treating acute ischemic stroke.

Ancrod in acute ischemic stroke: results of 500 subjects beginning treatment within 6 hours of stroke onset in the ancrod stroke program.

BACKGROUND AND PURPOSE: Previous studies of multiple-day dosing with the defibrinogenating agent, ancrod, in acute ischemic stroke yielded conflicting results but suggested that a brief dosing regimen might improve efficacy and safety. The Ancrod Stroke Program was designed to test this concept in subjects beginning ancrod or placebo within 6 hours of the onset of acute ischemic stroke. METHODS: Five hundred subjects with acute ischemic stroke who could begin receiving study material within 6 hours of symptom onset were infused intravenously with either ancrod (0.167 IU/kg per hour) or placebo over 2 or 3 hours. The primary efficacy outcome was a dichotomized, modified Rankin score at 90 days with less stringent cut-points for higher prestroke modified Rankin score and pretreatment NIHSS total score ("responder analysis"). Safety variables included mortality, major bleeding, and intracranial hemorrhage. RESULTS: Although the desired changes in fibrinogen level were seen in >90% of ancrod subjects, interim analysis for futility led to the study being halted for lack of efficacy. Positive responder status in the interim dataset was seen in 39.6% of ancrod subjects and 37.2% of placebo subjects (P=0.47). Ninety-day mortality did not differ between the 2 groups (ancrod, 15.6%; placebo, 14.1%; P=0.32), and the incidence of symptomatic intracranial hemorrhage within the first 72 hours, although not significantly different in ancrod compared to placebo subjects (P=0.19), was approximately twice as high (3.9% vs 2.0%; P=0.19). CONCLUSIONS: These results demonstrate that intravenous ancrod starting within 6 hours after symptom onset in a broad selection of subjects with ischemic stroke did not improve their outcome and revealed a trend to increased bleeding despite successful efforts to achieve rapid initial defibrinogenation and avoid prolonged hypofibrinogenemia.

NXY-059 for acute ischemic stroke.

BACKGROUND: NXY-059 is a free-radical-trapping agent that is neuroprotective in animal models of stroke. We tested whether it would reduce disability in humans after acute ischemic stroke. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 1722 patients with acute ischemic stroke who were randomly assigned to receive a 72-hour infusion of placebo or intravenous NXY-059 within 6 hours after the onset of the stroke. The primary outcome was disability at 90 days, as measured according to scores on the modified Rankin scale for disability (range, 0 to 5, with 0 indicating no residual symptoms and 5 indicating bedbound, requiring constant care). RESULTS: Among the 1699 subjects included in the efficacy analysis, NXY-059 significantly improved the overall distribution of scores on the modified Rankin scale, as compared with placebo (P=0.038 by the Cochran-Mantel-Haenszel test). The common odds ratio for improvement across all categories of the scale was 1.20 (95 percent confidence interval, 1.01 to 1.42). Mortality and rates of serious and nonserious adverse events were each similar in the two groups. NXY-059 did not improve neurologic functioning as measured according to the National Institutes of Health Stroke Scale (NIHSS): the difference between the two groups in the change from baseline scores was 0.1 point (95 percent confidence interval, -1.4 to 1.1; P=0.86). Likewise, no improvement was observed according to the Barthel index (P=0.14). In a post hoc analysis of patients who also received alteplase, NXY-059 was associated with a lower incidence of any hemorrhagic transformation (P=0.001) and symptomatic intracranial hemorrhage (P=0.036). CONCLUSIONS: The administration of NXY-059 within six hours after the onset of acute ischemic stroke significantly improved the primary outcome (reduced disability at 90 days), but it did not significantly improve other outcome measures, including neurologic functioning as measured by the NIHSS score. Additional research is needed to confirm whether NXY-059 is beneficial in ischemic stroke. (ClinicalTrials.gov number, NCT00119626.).

Ancrod for acute ischemic stroke: a new dosing regimen derived from analysis of prior ancrod stroke studies.

BACKGROUND: Ancrod, a fibrinogen-reducing agent, has been evaluated as treatment beginning within 3 or 6 hours of onset of acute ischemic stroke with inconsistent results. The data sets from these studies provide an opportunity to determine whether ancrod-related variables are associated with efficacy and safety. OBJECTIVE: This post hoc analysis of data from the Stroke Treatment with Ancrod Trial (STAT) analyzed ancrod-related variables as potential determinants of efficacy or safety. The resulting hypotheses were then tested in the European STAT (ESTAT) database. METHODS: The relationships between ancrod-related variables and the outcomes of efficacy and symptomatic intracranial hemorrhage (ICH) were analyzed using a 3-stage multivariate process. RESULTS: Good clinical outcome at 3 months based on the Barthel Index occurred almost twice as often in rapid defibrinogenators (>or=30 mg/dL/h) (52%) as in slow defibrinogenators (26%), with no increase in mortality or symptomatic ICH. Compared with a 20.7% incidence of symptomatic ICH in patients with mean post-9-hour fibrinogen levels less than or equal to 60 mg/dL, symptomatic ICH incidence was 0.8% in those with mean levels greater than 60 mg/dL (with no loss of efficacy). There were no symptomatic ICHs among 220 North American patients with mean levels greater than 70 mg/dL. It was hypothesized that an initial controlled rapid ancrod infusion with mean post-9-hour fibrinogen levels greater than 70 mg/dL would yield superior efficacy and safety. Such ESTAT patients had statistically significant efficacy versus placebo and a marked reduction in the incidence of symptomatic ICH versus patients taking ancrod with lower maintenance fibrinogen levels. CONCLUSION: Modifications to ancrod dosing may substantially improve efficacy while reducing the rate of symptomatic ICH.

Safety and tolerability of NXY-059 for acute intracerebral hemorrhage: the CHANT Trial.

BACKGROUND AND PURPOSE: NXY-059 is a free radical-trapping neuroprotectant developed for use in acute ischemic stroke. To facilitate prompt administration of treatment, potentially before neuroimaging, we investigated the safety of NXY-059 in patients with intracerebral hemorrhage (ICH). METHODS: We randomized 607 patients within 6 hours of acute ICH to receive 2270 mg intravenous NXY-059 over 1 hour and then up to 960 mg/h over 71 hours, or matching placebo, in addition to standard care. The primary outcome was safety: the mortality and the frequency of adverse events, and the change from baseline for a variety of serum, imaging, and electrophysiological measurements. We also studied the overall distribution of disability scores on the modified Rankin Scale (mRS) and the Barthel index. RESULTS: We treated 300 patients with NXY-059 and 303 with placebo. Treatment groups were well matched for prognostic variables including Glasgow Coma Scale, risk factors, and age. The mean National Institute of Health Stroke Scale score on admission was 14 in both groups. The baseline hemorrhage volume was 22.4+/-20.1 mL in the NXY-059 group and 23.3+/-22.8 mL in the placebo group (mean+/-SD). Most hemorrhages were related to hypertension or anticoagulant use. Mortality was similar in both groups: 20.3% for NXY-059 and 19.8% for placebo-treated patients. The proportion of patients who experienced an adverse event was the same for both groups, whereas for serious adverse events the proportion was slightly higher in the NXY-059 group. However, no pattern emerged to indicate a safety concern. Serum potassium fell transiently in both groups, lower in the NXY-059 group. There were no differences in 3-month function, disability, or neurological deficit scores. The odds ratio for an improved outcome in 3-month mRS scores in the NXY-059 group was 1.01 (95% CI 0.75, 1.35). CONCLUSIONS: NXY-059 given within 6 hours of acute ICH has a good safety and tolerability profile, with no adverse effect on important clinical outcomes.

Efficacy of zolmitriptan nasal spray in adolescent migraine.

OBJECTIVE: The goal was to evaluate the efficacy and tolerability of zolmitriptan nasal spray in the treatment of adolescent migraine. METHODS: The "Double-Diamond" study used a novel, single-blind, "placebo challenge" in a multicenter, randomized, double-blind, placebo-controlled, 2-way, 2-attack, crossover design. A total of 248 US adolescent patients (12-17 years of age) with an established diagnosis of migraine, with or without aura, were enrolled. A single-blind placebo challenge was used for each migraine attack. No additional medications were taken if a headache response to the initial placebo treatment was achieved at 15 minutes; if migraine intensity remained moderate or severe, then patients treated the attack with zolmitriptan (5 mg) nasal spray or placebo according to a randomized, crossover schedule (double-blind). The primary efficacy variable was headache response at 1 hour after treatment. A comprehensive range of secondary end points included sustained headache response at 2 hours. RESULTS: A total of 171 patients (mean age: 14.2 years; 57.3% female) treated > or = 1 attack with study medication (intention-to-treat population). The onset of significant pain relief was apparent 15 minutes after treatment with zolmitriptan nasal spray. At 1 hour after the dose, zolmitriptan nasal spray produced a higher headache response rate than did placebo (58.1% vs 43.3%). Zolmitriptan nasal spray was also significantly superior to placebo in improvement in pain intensity, pain-free rates, sustained resolution of headache, and resolution of associated migraine symptoms. Return to normal activities was also consistently faster with zolmitriptan nasal spray than with placebo, with less use of any escape medication. Treatment with zolmitriptan nasal spray was well tolerated. CONCLUSIONS: This novel, placebo-challenge study demonstrated that zolmitriptan nasal spray was well tolerated and provided fast and significantly effective relief of migraine symptoms in the acute treatment of adolescent migraine.