NXY-059 Ineffective in Acute Ischemic Stroke: SAINT II Published

Susan Jeffrey

August 10, 2007

August 10, 2007 — Disappointing results of the Stroke Acute Ischemic NXY-059 Trial (SAINT II), a randomized study of the investigational neuroprotectant NXY-059 ( Cerovive, AstraZeneca), show no effect of treatment vs placebo in patients with acute ischemic stroke, despite the promising results from SAINT I, a previous trial of the same agent.

The results are published in the August 9 issue of the New England Journal of Medicine.

"I think the field has taken a big hit here, because we hoped that we were going to be able to confirm the first result, but we have not done so," Kennedy R. Lees, MD, from the University of Glasgow and the Acute Stroke Unit, Western Infirmary, in Scotland, and chair of the study's steering committee, told Medscape. "It's not the end of the world, but it is desperately disappointing for the patients."

Lessons Learned

NXY-059 is a free-radical–trapping agent that had been shown to be neuroprotective in animal models of stroke. SAINT I, published last year (Lees KR et al. N Engl J Med. 2006; 354:588-600), was a randomized trial that showed treatment with NXY-059 within 6 hours of ischemic stroke significantly improved the primary outcome of reduced disability at 90 days, although treatment did not have a significant effect on other outcomes, including neurologic function on the National Institutes of Health Stroke Scale (NIHSS).

An intriguing finding from a post hoc analysis of SAINT I was that, among patients who received tPA, treatment with NXY-059 was associated with a lower incidence of hemorrhagic transformation ( P = .001) and of symptomatic intracranial hemorrhage ( P = .036).

The SAINT I trial marked the first time that a neuroprotective strategy had shown benefit in a large clinical trial, despite excellent results with many such agents in animal models of stroke. After SAINT I, the enrollment in SAINT II was increased to 3200 from 1700 to raise its statistical power.

In all, 3306 patients with acute ischemic stroke were randomized to receive a 72-hour infusion of intravenous NXY-059 or placebo within 6 hours after onset of stroke symptoms. The primary end point of interest was the distribution of disability scores on the modified Rankin scale (mRS) at 90 days.

Of those randomized, 3195 patients received the study drug (n = 1588) or placebo (n = 1607) and formed the basis of the efficacy analysis. Prognostic factors were well balanced between the groups, the authors note.

There were 267 deaths in each group, and adverse event rates were similar. In the end, though, the distribution of scores on the mRS did not differ between the groups ( P = .33 by the Cochran-Mantel-Haenszel test; odds ratio for limiting disability, 0.94 [95% CI, 0.83 – 1.06]).

Modified Rankin Scale Scores at 90 days With NXY-059 vs Placebo

mRS score
NXY-059 (% of Patients)
Placebo (% of Patients)
0
9.8
10.3
1
17.6
18.4
2
14.0
14.7
3
14.7
15.0
4
17.8
17.4
5 or death
26.1
24.2


When they divided scores on the mRS into 3 categories, 0 – 1 vs 2 – 3 vs 4 – 6, there was still no benefit seen with treatment (odds ratio, 0.92 [95% CI, 0.80 – 1.06). There were no differences either on secondary end points of scores on neurologic and activities-of-daily-living scales.

Finally, they also tested the hypothesis, generated from the findings of SAINT I, that NXY-059 would reduce alteplase-related intracranial hemorrhages. However, among patients treated with alteplase in SAINT II, there was no difference between groups in the frequency of symptomatic or asymptomatic hemorrhage.

Dr. Lees pointed out that evaluation of this kind of agent is still hampered by differences in how outcomes are assessed: outcomes for stroke patients can be judged as slightly different, for example, between raters, and many factors not associated with the drug may also affect the outcome. However, although there is still a planned analysis of these data combining SAINT I and SAINT II to increase the statistical power even more, there are no plans to continue further investigation with this agent.

"With current knowledge, this drug doesn't look good enough to be going on at the moment," Dr. Lees said. In October 2006, when the results of the SAINT II trial were first known, AstraZeneca announced that the company did not plan to pursue investigation of this drug.

Dr. Lees praised the New England Journal for publishing this negative follow-up to the positive findings of the SAINT I trial. "Journals are sometimes criticized for not taking negative or neutral papers, so it was right for them to take this," he said. "It was important to get this published, and I hope in the future that we're going to get something that will be more successful."

The Importance of Confirmation

Asked to comment on the SAINT II results, Philip Gorelick, MD, from the University of Illinois College of Medicine at Chicago, told Medscape that he had been excited and hopeful at the results of SAINT I, but the results from this confirmation trial with more than 3300 patients has, like other neuroprotective trials before it, shown no effect of this agent.

"The trialists and AstraZeneca should be congratulated for carrying out a rigorous study and for following the Stroke Therapy Academic Industrial Roundtable criteria for doing a study, bringing it from basic science to the clinical arena," he said. "They did everything right, followed the criteria, and had a negative study.

"Everybody's wondering why," he added, "and I think the authors did a very credible job of looking at the pros and cons of this." They suggest that the positive results of SAINT I may simply have been the play of chance and could not be replicated in the much larger SAINT II trial.

"All of the neuroprotectants have failed, unfortunately, and this is another one that's been shot down, although very carefully studied, very carefully engineered in terms of the study design," Dr. Gorelick said. "My suspicion is that the complexities of the ischemic cascade for acute stroke are such that we're probably going to need to have a cocktail approach to solve this problem; that monotherapy may not be the way to go; and that there are so many mechanisms that may need to be inhibited in acute ischemic stroke that polytherapy may turn out to be the answer down the road."

Other stroke experts echoed this disappointment. The result from SAINT II "is obviously disappointing but not entirely unexpected," Larry B. Goldstein, MD, director of the Duke Center for Cerebrovascular Disease at Duke University Medical Center, in Durham, North Carolina, and current president of the American Heart Association Mid-Atlantic Affiliate, told Medscape. "It also points out that findings from a single trial of a putative new therapy need to be confirmed in a second trial."

Ralph L. Sacco, MD, from the Miller School of Medicine, University of Miami, Florida, also characterized the news as disappointing, both for the field of acute stroke therapy and in particular the concept of neuroprotection. "We were cautiously optimistic after SAINT I but knew that a larger trial was required to substantiate the findings," he told Medscape. "I still remain optimistic that the right drug, in the right stroke patient, using a sensitive outcome, will show benefits in a neuroprotection trial, but the stakes remain high."

The SAINT trials were sponsored by AstraZeneca. Dr. Lees reports receiving fees and expenses from AstraZeneca for steering committee work and lectures. Disclosures for other coauthors appear in the paper.

N Engl J Med. 2007;357:562-571. Abstract

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