Phase II studies of the glycine antagonist GV150526 in acute stroke - The North American experience

Background and Purpose-GV150526, a selective glycine site antagonist, reduc es infarct volume in rats with focal cerebral ischemia. Safety and efficacy in humans with acute stroke are being investigated, We sought to further e xplore the safety. pharmacokinetics, and preliminary outcome of GV150526 tr eatment in patients with a clinical diagnosis of acute stroke. Methods-Two trials were conducted in North America. The North American Glyc ine Antagonist in Neuroprotection trial (GAIN 1) (GLYA2001; United States o nly) was designed as a sequential dose escalation study. GAIN 2 (GLYA2005; United States and Canada) was designed to further assess the safety of the highest dose tolerated in GAIN 1. Both trials were randomized (2:1), double -blind, and placebo controlled, Treatment was started within 12 hours of sy mptom onset; patients with both ischemic stroke and primary intracerebral h emorrhage were included in both trials. Results-The dose escalation study (GAIN 1) completed 3 dosing tiers. Enroll ment was suspended before escalation to the fourth tier because of laborato ry reports of transiently elevated bilirubin levels in a concurrent Europea n study that employed the dose targeted for this tier. After review by an i ndependent safety committee of the worldwide safety data, the second study (GAIN 2) commenced. One hundred nine patients were randomized and dosed wit h study drug, either an 800-mg loading dose followed by 200 mg every 12 hou rs for 3 days of GV150526 or placebo. The incidence of serious adverse even ts was similar in the drug and placebo groups. Mild irritation at the infus ion site and symptoms suggestive of mild and reversible altered mentation w ere reported more frequently in the GV150526 group than in the placebo grou p. Hyperbilirubinemia was reported in 6% of GV150526-treated patients compa red with 3% of placebo-treated patients. Outcome at 4 weeks after stroke wa s better in GV150526-treated patients, but the studies were not powered to show statistical significance, and the baseline neurological deficits in th e GV150526-treated patients were less severe. Conclusions-These preliminary studies suggest that GV150526 is well tolerat ed by patients with suspected acute stroke. Further pivotal studies testing the efficacy and safety of GV150526 in acute stroke are ongoing.