Context: Tissue plasminogen activator is the only thrombolytic agent approved in the United States for treatment of acute ischemic stroke, and has limitations. Aptiganel hydrochloride is a novel and selective ligand for the ion-channel site of the N-methyl-D-aspartate receptor-channel complex and a promising neuroprotective agent in animal models of focal brain ischemia.
Objective: To determine whether aptiganel improves the clinical outcome for acute ischemic stroke patients.
Design: Nested phase 2/phase 3 randomized controlled trial conducted between July 1996 and September 1997.
Setting: One hundred fifty-six medical centers in the United States, Canada, Australia, South Africa, England, and Scotland.
Participants: A total of 628 patients with hemispheric ischemic stroke (50.3% male; mean age, 71.5 years).
Interventions: Patients were randomly assigned within 6 hours of stroke to receive 1 of 3 treatment regimens: high-dose aptiganel (5-mg bolus followed by 0.75 mg/h for 12 hours; n = 214); low-dose aptiganel (3-mg bolus followed by 0.5 mg/h for 12 hours; n = 200); or placebo (n = 214).
Main outcome measures: The primary efficacy end point was the Modified Rankin Scale score at 90 days after stroke onset. Secondary end points included mortality and change in National Institutes of Health (NIH) Stroke Scale score at 7 days after stroke.
Results: The trial was suspended by the sponsor and the independent data and safety monitoring board because of both a lack of efficacy and a potential imbalance in mortality. There was no improvement in outcome for either aptiganel (low-dose or high-dose) group compared with the placebo group at 90 days (median Modified Rankin Scale score for all 3 treatment groups = 3; P =.31). At 7 days, placebo-treated patients exhibited slightly greater neurological improvement on the NIH Stroke Scale than high-dose aptiganel patients (mean improvement for placebo group, -0.8 points vs for high-dose aptiganel, 0.9 points; P =.04). The mortality rate at 120 days in patients treated with high-dose aptiganel was higher than that in patients who received placebo (26.3% vs 19.2%; P =.06). Mortality in the low-dose aptiganel group was 22.5% (P =.39 vs placebo).
Conclusions: Aptiganel was not efficacious in patients with acute ischemic stroke at either of the tested doses, and m ay be harmful. The larger proportion of patients with favorable outcomes and lower mortality rate in the placebo group suggest that glutamate blockade with aptiganel may have detrimental effects in an undifferentiated population of stroke patients.