NEW ORLEANS—-The last decade has seen a number of drugs being developed with the promise of protecting the brain against the damaging consequences of ischemic injury. These neuroprotective agents, however, have yet to demonstrate significant efficacy in clinical trials, according to three separate research groups who presented their findings at the 25th International Stroke Conference.

None of the neuroprotectant drugs that were tried showed efficacy according to rigorous clinical standards, summarized Marc Mayberg, MD, Professor and Chairman, Department of Neurological Surgery at the Cleveland Clinic, Cleveland, Ohio. "I don't see it as a disappointment. I don't think we expect [Mark] McGwire to hit a home run every time he comes to the plate, and the same is true with stroke research," he said. The researchers discussed factors that may help explain the discrepancies between the laboratory and clinical findings, and all conceded that conclusions cannot be drawn at this time.

OF RATS AND MEN

Results of preliminary neuroprotectant experiments in animal models of ischemic injury have opened up a new approach in stroke damage control—the reduction or blockade of the cellular consequences of ischemic injury. Citicoline, in particular, has been shown to limit infarct volume in animal stroke models, according to Richard Gammans, PhD, of Interneuron Pharmaceuticals, Lexington, Massachusetts. Citicoline is thought to exert its neuroprotective effects through membrane repair and regeneration. Previous clinical studies, Dr. Gammans added, have suggested that citicoline treatment is well tolerated and may prove beneficial for stroke patients as well.

The largest citicoline clinical study to date, however, had disappointing results. The ECCO (Effects of Citicoline on Clinical Outcome) 2000 study, which was conducted at 125 participating centers throughout the United States and Canada, enrolled approximately 900 patients who presented with ischemic stroke referable to the middle cerebral artery distribution. All the patients (average age, 68) entered the study with baseline National Institutes of Health (NIH) Stroke Scale scores greater than 8 (average score, 14) and a prestroke Rankin Scale score of 1 or 0. Within 24 hours of stroke onset (mean time, 13 hours), the patients were randomized to receive a six-week treatment of either citicoline (1,000 mg/d) or placebo.

No differences were seen between the treatment and control groups with regard to the primary outcome, defined as the proportion of patients who improved at least seven points on their NIH Stroke Scale score by week 12. About half of the patients in both the citicoline group (52%) and placebo group (51%) achieved the primary end point, Dr. Gammans reported. Mortality rates, he continued, were no different between the two groups (17%).

Ad hoc analyses revealed a trend toward a favorable citicoline outcome. A slightly lower incidence of new strokes after the index event was found among citicoline patients, Dr. Gammans noted. Similarly, when scores from the NIH Stroke Scale, Rankin Scale, and Barthel Index were combined and analyzed, a 1.32 odds ratio was calculated in favor of citicoline treatment. These exploratory analyses suggest that citicoline may have moderate but significant effects that were not fully captured in this study, offered Dr. Gammans.

THE EARLIER, THE BETTER?

For many reasons, it is very difficult to get stroke patients to the hospital in time to give them thrombolytic therapy. "Fewer than 5% of patients who may otherwise qualify for [t-PA] make it to the hospital in time," Dr. Mayberg pointed out. Neuroprotectants offer a way to extend this window of time, he explained, by limiting the damaging cellular cascade that follows stroke.

The combination of thrombolysis with neuroprotection, because of different mechanisms, would be expected to show better results when used immediately after onset of focal ischemia, proposed James Grotta, MD, Professor of Neurology, University of Texas, Houston. Indeed, an experimental animal stroke study demonstrated extended benefits using a combination of diaspirin—cross-linked hemoglobin (DCLHb) with lubeluzole—a benzothiazole compound believed to exert neuroprotective effects.

The first clinical trial combining lubeluzole with t-PA, however, was terminated early by the sponsoring pharmaceutical company when findings from a concurrent lubeluzole monotherapy trial were negative. Definite conclusions cannot be drawn, Dr. Grotta said, since only 89 of the original 200 patients had enrolled in the combination study. However, "there was really not a signal, at least in these 89 patients, that outcome was better in the group that received lubeluzole and t-PA," he conceded.

"One of the thoughts when we went into this study was that it would be very difficult to enroll patients into a neuroprotective drug trial and give them t-PA at the same time," Dr. Grotta said. But in fact, many of the centers were capable of enrolling one patient every one or two months, he said. "The good news," he said, "is that we found such a study design is feasible—we can enroll patients into trials while at the same time treat."

Patients who qualified for and received t-PA within three hours of stroke onset were randomly allocated to receive either placebo or lubeluzole (7.5 mg IV over one hour, followed by a continuous five-day infusion of 10 mg/d). Infusion of the study medication was started before the end of the one-hour t-PA infusion, Dr. Grotta noted.

Most patients had either cardioembolic stroke (43%) or large-vessel strokes (45%), and the remaining 12% had small-vessel strokes. Before treatment, the mean NIH Stroke Scale scores were similar between the lubeluzole (14) and placebo patients (15).

No differences were found between treated and placebo patients with regard to the primary outcome, which was defined as the proportion of patients achieving a Barthel Index score of 70 or greater at three months. No differences between the two groups were seen on the NIH Stroke Scale or the Rankin Scale, Dr. Grotta added.

A lower rate of symptomatic hemorrhage was found among the combination group (4.8%) than in the control group, who received t-PA alone (14.9%). The mortality at three months was 29% in the combination group and 24% in the control group. Similar numbers of patients in both groups (approximately 20%) dropped out of the study because of adverse events. No conclusions can be drawn owing to the small sample size, Dr. Grotta reiterated; however, combination therapy is certainly worth additional study.

CLINICAL PROOF REMAINS ELUSIVE

Results from the GAIN (Glycine Antagonist in Neuroprotection) International trial, which included 1,788 stroke patients and the collaborative efforts of 173 investigators, were also disappointingly negative. Treatment with the neuroprotectant in question, GV150526, was no better than placebo with regard to Barthel Index scores, according to Kennedy Lees, MD, who is affiliated with the Department of Medicine and Therapeutics at the University of Glasgow, UK.

Like the other neuroprotectants, GV was found to be highly effective in experimental animal stroke models and was well tolerated in previous clinical trials. GV, which is a selective glycine site antagonist of the N-methyl-D-aspartate receptor, is believed to exert its neuroprotective effects by reducing glutamate excitotoxicity.

Patients were randomized to receive either placebo or a loading dose of 800 mg GV followed by 200 mg every 12 hours for three days. The doses used in this trial achieve plasma levels that exceed the putative neuroprotective concentration extrapolated from animal studies, Dr. Lees noted. Almost all the patients (99%) were treated within six hours of stroke onset, and a quarter of the patients were treated within the first four hours, Dr. Lees continued.

No differences were seen on the Barthel Index, NIH Stroke Scale, and Rankin Scale, Dr. Lees reported. There was no difference in the total number of adverse events in the first seven days or in final mortality. Minor changes in liver function tests were seen more in the GV-treated group (30%) than in the placebo group (9%); however, these were transient and asymptomatic, Dr. Lees noted.

The trial was well designed and well conducted and ran to completion. The GV-treated and placebo groups were well matched with regard to stroke severity, age, and other prognostic factors, Dr. Lees said. The results were quite consistent, and it was clear that the drug had no effect on stroke outcome in this trial. "All the factors we could possibly control for were controlled; but in spite of that, it did not work." All three presenters agreed that it is just a matter of time before neuroprotectants will become an integral part of stroke treatment. Although animals are different from humans, "at some point in time, at some level, [animal data] should be translated into benefit for patients," Dr. Grotta concluded.

NR

—Shauna Kubose
Senior Associate Editor

Suggested Reading
Clark WM, Williams BJ, Selzer KA, et al. A randomized efficacy trial of citicoline in patients with acute ischemic stroke. Stroke.1999;30:2592-2597.
Grotta J. Lubeluzole treatment of acute ischemic stroke. The US and Canadian Lubeluzole Ischemic Stroke Study Group. Stroke. 1997;28:2338-2346.
Phase II studies of the glycine antagonist GV150526 in acute stroke: the North American experience. The North American Glycine Antagonist in Neuroprotection (GAIN) Investigators. Stroke. 2000;31:358-365.

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