Additional outcomes and subgroup analyses of NXY-059 for acute ischemic stroke in the SAINT I trial.
ABSTRACT NXY-059 is a free radical-trapping neuroprotectant demonstrated to reduce disability from ischemic stroke. We conducted analyses on additional end points and sensitivity analyses to confirm our findings.
We randomized 1722 patients with acute ischemic stroke to a 72-hour infusion of placebo or intravenous NXY-059 within 6 hours of stroke onset. The primary outcome was disability at 90 days, as measured by the modified Rankin Scale (mRS), a 6-point scale ranging from 0 (no residual symptoms) to 5 (bed-bound, requiring constant care). Additional and exploratory analyses included mRS at 7 and 30 days; subgroup interactions with final mRS; assessments of activities of daily living by Barthel index; and National Institutes of Health Stroke Scale (NIHSS) neurological scores at 7 and 90 days.
NXY-059 significantly improved the distribution of the mRS disability score compared with placebo at 7, 30, and 90 days (Cochran-Mantel-Haenszel test P=0.002, 0.004, 0.038, respectively; 90-day common odds ratio 1.20; 95% CI, 1.01 to 1.42). The benefit was not attributable to any specific baseline characteristic, stratification variable or subgroup interaction. Neurological scores were improved at 7 days (odds ratio [OR], 1.46; 95% CI, 1.13, 1.89; P=0.003) and the Barthel index was improved at 7 and 30 days (OR, 1.55; 95% CI, 1.22, 1.98; P<0.0001; OR, 1.27; 95% CI, 1.01, 1.59; P=0.02).
NXY-059 within 6 hours of acute ischemic stroke significantly reduced disability. Benefit on neurological scores and activities of daily living was detectable early but not significant at 90 days; however, our trial was underpowered to measure effects on the neurological examination. The benefit on disability is not confounded by interactions and is supported by other outcome measures.
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ABSTRACT: After the onset of brain ischemia, a series of events leads ultimately to the death of neurons. Many molecules can be pharmacologically targeted to protect neurons during these events, which include glutamate release, glutamate receptor activation, excitotoxicity, Ca2+ influx into cells, mitochondrial dysfunction, activation of intracellular enzymes, free radical production, nitric oxide production, and inflammation. There have been a number of attempts to develop neuroprotectants for brain ischemia, but many of these attempts have failed. It was reported that cyclosporin A (CsA) dramatically ameliorates neuronal cell damage during ischemia. Some researchers consider ischemic cell death as a unique process that is distinct from both apoptosis and necrosis, and suggested that mitochondrial dysfunction and Δψ collapse are key steps for ischemic cell death. It was also suggested that CsA has a unique neuroprotective effect that is related to mitochondrial dysfunction. Here, I will exhibit examples of neuroprotectants that are now being developed or in clinical trials, and will discuss previous researches about the mechanism underlying the unique CsA action. I will then introduce the results of our cDNA subtraction experiment with or without CsA administration in the rat brain, along with our hypothesis about the mechanism underlying CsA's effect on transcriptional regulation.Brain sciences. 01/2013; 3(3):1325-56.
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ABSTRACT: BACKGROUND: The neurotrophic drug Cerebrolysin accelerated recovery and prevented acute neuronal damage in preclinical models of ischaemia. Previous clinical trials support therapeutic effects in stroke patients. The study investigated whether the combination with alteplase and Cerebrolysin is safe and can further reduce disability after acute ischaemic stroke. METHODS: This placebo-controlled, double-blind trial involved 119 patients with acute ischaemic hemispheric stroke, randomly assigned to a combined treatment with alteplase plus Cerebrolysin or placebo (administered 1 h after thrombolytic treatment) starting within three-hours after onset of symptoms. A daily i.v. infusion of 30 ml Cerebrolysin or placebo was given for 10 consecutive days. Primary outcome was the modified Rankin Scale at day 90. A sequential design with interim analyses was applied. RESULTS: The third interim analysis did not show a benefit in the modified Rankin Scale for Cerebrolysin on day 90 compared to placebo and the study was stopped. The National Institutes of Health Stroke Scale responder analysis (secondary outcome measure) showed significantly more patients with an improvement of 6 or more points (or a total score of 0 or 1) after two-, five-, 10, and 30 days in the Cerebrolysin group. Similar trends were observed for the modified Rankin Scale responder analysis without achieving statistical significance. There was no difference between treatment groups regarding adverse events. CONCLUSIONS: The combination of Cerebrolysin with recombinant tissue-Plasminogen Activator is safe for treatment of acute ischaemic stroke but did not improve outcome at day 90. During the treatment period with Cerebrolysin (10 days), significantly more patients had a favourable response in neurological outcome measures (National Institutes of Health Stroke Scale) as compared to the placebo group.International Journal of Stroke 09/2012; · 4.03 Impact Factor
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ABSTRACT: Schlaganfälle gehören zu den häufigsten Erkrankungen dieser Zeit. Die zahlreichen negativen klinischen Studien mit neuroprotektiven Substanzen führten zur Einführung von Empfehlungen der Stroke Therapy Academic Industry Roundtable (STAIR) für die präklinische und klinische Entwicklungsphase. Als Folge dieser verbesserten neuen Entwicklungen zeigte die erstmalig positive klinische Studie mit dem Radikalfänger NXY-059 ein ermutigendes Ergebnis (SAINTI), das sich allerdings in einer Folgestudie (SAINTII) nicht bestätigen ließ. In diesem Artikel analysieren wir kritisch die präklinische und klinische Entwicklung von Neuroprotektiva für die Schlaganfallbehandlung am Beispiel von NXY-059 und geben Empfehlungen für die mögliche zukünftige Entwicklung neuroprotektiver Substanzen. Stroke remains one of the most urgent medical problems of our times. The failure of most neuroprotective drugs in clinical trials led to the initiation of the Stroke Therapy Academic Industry Roundtable guidelines. Due to this improvement, the positive clinical trial results with the free radical scavenger NXY-059 (SAINTI) was encouraging. However, the subsequent SAINTII trial did not confirm these results. In this article we critically review the history of preclinical and clinical trials based on experience of NXY-059 development and present recommendations for potential future preclinical and clinical development of neuroprotective stroke therapy.Der Nervenarzt 01/2008; 79(2):218-224. · 0.80 Impact Factor