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(Stroke. 2000;31:358.)
© 2000 American Heart Association, Inc.
Original Contributions |
Phase II Studies of the Glycine Antagonist GV150526 in Acute Stroke
The North American Experience
Presented in part at the 23rd American Heart Association International Joint Conference on Stroke and Cerebral Circulation, Orlando, Fla, February 5–7, 1998.
Correspondence to E. Clarke Haley, Jr, MD, Department of Neurology, Box 394, University of Virginia Health System, Charlottesville, VA 22908. E-mail ech{at}virginia.edu
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionAppendix 1References |
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Background and Purpose—GV150526, a selective glycine site antagonist, reduces infarct volume in rats with focal cerebral ischemia. Safety and efficacy in humans with acute stroke are being investigated. We sought to further explore the safety, pharmacokinetics, and preliminary outcome of GV150526 treatment in patients with a clinical diagnosis of acute stroke.
Methods—Two trials were conducted in North America. The North American Glycine Antagonist in Neuroprotection trial (GAIN 1) (GLYA2001; United States only) 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 symptom onset; patients with both ischemic stroke and primary intracerebral hemorrhage were included in both trials.
Results—The dose escalation study (GAIN 1) completed 3 dosing tiers. Enrollment was suspended before escalation to the fourth tier because of laboratory reports of transiently elevated bilirubin levels in a concurrent European study that employed the dose targeted for this tier. After review by an independent safety committee of the worldwide safety data, the second study (GAIN 2) commenced. One hundred nine patients were randomized and dosed with study drug, either an 800-mg loading dose followed by 200 mg every 12 hours for 3 days of GV150526 or placebo. The incidence of serious adverse events was similar in the drug and placebo groups. Mild irritation at the infusion site and symptoms suggestive of mild and reversible altered mentation were reported more frequently in the GV150526 group than in the placebo group. Hyperbilirubinemia was reported in 6% of GV150526-treated patients compared with 3% of placebo-treated patients. Outcome at 4 weeks after stroke was better in GV150526-treated patients, but the studies were not powered to show statistical significance, and the baseline neurological deficits in the GV150526-treated patients were less severe.
Conclusions—These preliminary studies suggest that GV150526 is well tolerated by patients with suspected acute stroke. Further pivotal studies testing the efficacy and safety of GV150526 in acute stroke are ongoing.
Key Words: cerebral infarction • glutamate antagonists • neuroprotection • stroke, acute • stroke therapy
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAppendix 1References |
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Development of an effective neuroprotective agent for the treatment of acute ischemic stroke remains problematic. While many treatments appear promising in laboratory studies, none has been definitively shown to result in improved outcome in human trials. One promising avenue of research has been the development of agents targeted to blocking the excitotoxic effects of glutamate in the ischemic cascade, specifically at the N-methyl-D-aspartate (NMDA) receptor.1 Unfortunately, a number of promising NMDA antagonist drugs have not been well tolerated by patients with acute stroke2 3 4 and therefore have been abandoned.
An alternative to blocking the glutamate site of the NMDA receptor is to block the glycine site. Glycine is an obligatory coagonist with glutamate of the NMDA receptor. A compound, GV150526, was developed as a highly selective antagonist at the glycine site of neurons and in animal models was associated with substantially fewer behavioral side effects than either the competitive or noncompetitive NMDA antagonists.5 Moreover, studies in both transient and permanent middle cerebral artery occlusion in rats suggested that GV150526 reduced infarct volume even if treatment was delayed for 6 hours after onset of ischemia.6 Preliminary studies in human volunteers as well as ischemic stroke patients suggested that the drug was well tolerated at several doses.7
The present studies were designed to test the safety and pharmacokinetics of a new, more concentrated formulation of GV150526 in patients with a clinical diagnosis of acute ischemic stroke managed in North American centers. The purpose was to develop sufficient experience with the compound in ischemic stroke patients to warrant carrying it forward into pivotal phase III efficacy studies.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAppendix 1References |
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Two sequential phase II trials were performed in North America: the North American Glycine Antagonist in Neuroprotection trial (GAIN 1) (GLYA2001) and GAIN 2 (GLYA2005). The protocols used for each study were reviewed and approved by the institutional review board at each participating center. A third trial,8 reported elsewhere, was conducted concurrently in Europe. GAIN 1 was a randomized, double-blind, placebo-controlled, sequential dose escalation trial conducted at 19 centers in the United States. Eligible patients were 18 years of age or older; had symptoms and signs consistent with acute stroke; could begin treatment within 12 hours of stroke onset; and had no previous functional disability (defined as a Modified Rankin score of
1). Patients with either
ischemic stroke or intraparenchymal hemorrhage were
eligible. Patients were excluded if they were stuporous or comatose;
had another serious medical, neurological, or psychiatric illness that
was likely to confound the study; had a history of epilepsy or a
seizure at onset; had a subarachnoid hemorrhage; had a
prior stroke within the previous 3 months; had only sensory loss,
dysarthria, or facial weakness; had evidence of acute myocardial
infarction or severe congestive heart failure; had known liver or renal
disease; had hypertensive encephalopathy; had received >1 g of aspirin
within the previous 24 hours; were pregnant women; had been treated
with another investigational drug or device within 3 months or had
previous exposure to GV150526; or were judged to be unable or unwilling
to comply with the protocol.
After informed consent was obtained, eligible patients were randomly
assigned through a central randomization service to receive either
GV150526 or placebo in a 2:1 ratio according to a computer-generated
randomization code. Table 1
displays the
doses planned for the study and the number of patients planned for the
study at each dose. Doses were selected to test the tolerability of a
loading dose followed by a maintenance regimen calculated to
achieve blood levels of GV150526 
10 µg/mL for a duration of 3 days.
The safety experience from each dosage tier was reviewed by an
independent Data and Safety Monitoring Committee (DSMC) after target
enrollment in each tier was reached. During the time that data were
being collated for review by the DSMC, enrollment was allowed to
continue at the same dosage tier, but the DSMC was required to approve
all increases in study drug dosage, ie, advancement to the next dosing
tier.
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Study drug was mixed in 5% dextrose and water and administered intravenously as 400 mg/250 mL of study drug. Study pharmacists were unblinded to treatment allocation, but infusions were delivered in a blinded and masked fashion, and all protocol assessments were performed by personnel not involved with administering study drug infusions.
The patients were all managed in an acute care area, where frequent vital signs and neurological checks were performed. Concomitant medications and measures for stroke treatment, including intravenous tissue plasminogen activator, anticoagulants, antiplatelet agents, blood pressure modification, and rehabilitation, were allowed at the discretion of the treating investigator. No other experimental therapies for acute stroke (eg, intra-arterial thrombolysis, other putative neuroprotectant drugs) were allowed.
Safety measures included laboratory blood work (serum chemistries, liver and renal function tests, and hematology), and urinalysis collected at entry, day 4, day 7 (or hospital discharge, whichever came sooner), and at week 4; 12-lead ECG at baseline and daily during study drug administration; and continuous surveillance for adverse medical events. Adverse events were defined as any untoward medical occurrence with a patient (either clinical or a clinically significant laboratory abnormality alone) whether or not it was considered drug related. An adverse event was considered serious if it was fatal or immediately life-threatening, permanently disabling, cancer, a congenital anomaly in the offspring of a subject who received study drug, required or prolonged hospitalization, or resulted from an overdose of study drug.
These studies were not powered to detect treatment differences for efficacy parameters. However, several clinical measures commonly performed in clinical stroke trials were obtained in study subjects to pilot their feasibility for future studies of GV150526. They included the National Institutes of Health (NIH) Stroke Scale,9 the Barthel Index of Activities of Daily Living,10 and the modified Rankin Scale11 obtained at day 7 (or discharge, whichever was sooner) and week 4. A head CT scan was required on day 3 to day 5 to assist with stroke diagnosis and subtype classification according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria.12 Laboratory blood work and urinalyses, ECGs, and protocol CT scans were each evaluated by central laboratories blinded to treatment allocation.
The blood sampling strategy for the pharmacokinetics in both studies was based on a population pharmacokinetics model, thereby reducing the number of blood samples required per patient. Population pharmacokinetic analysis was performed with nonlinear mixed effect modeling (NONMEM Version V).13 Samples were obtained at the end of the loading dose, at the end of maintenance doses, and in the interdose intervals. Results from 105 patients from both the North American and European phase II studies in ischemic and hemorrhagic stroke patients were combined to generate a preliminary predicted concentration-time profile for an 800-mg loading dose and 200-mg maintenance dose every 12 hours for 5 doses of GV150526. The concentration results from the final North American phase II studies were then compared with the predicted concentration profile.
GAIN 2 was also a randomized, double-blind, placebo-controlled clinical trial designed to develop additional safety and pharmacokinetic experience with GV150526 at the highest well-tolerated dose chosen from the GAIN 1 experience. One hundred patients, again randomized in a 2:1 ratio of GV150526 to placebo according to a computer-generated randomization code, were planned for enrollment. The protocol and entry criteria were virtually identical to GAIN 1, except that the exclusion for recent stroke was eliminated. Participation was expanded to 33 centers (24 in the United States and 9 in Canada). Data collection methods for safety, pharmacokinetics, and outcome were identical. The head CT scan between day 3 and day 5 was eliminated, and a baseline scan before or within 12 hours of initiation of treatment was required.
Additionally, 11 more patients were enrolled in a substudy examining diffusion-weighted MRI techniques as adjunctive outcomes. These patients were randomized in a 1:1 ratio and are included in the main safety and outcome analyses. The details and results of the MRI studies have been reported separately.14
No prespecified outcome hypotheses were generated since the studies were not powered to detect differences in outcome. Data from adverse event reporting and laboratory studies were tabulated and compared within each dosage tier for GAIN 1, but because of the small sample size and low power for detecting potentially important differences, an exploratory analysis was conducted that combined the placebo groups from each dose tier and compared rates of adverse events with GV150526-treated patients. A final exploratory analysis was conducted combining all patients with ischemic stroke treated with the 800-mg loading dose plus 200-mg maintenance dose for 5 doses from both studies, since this was the dose chosen to be carried forward in additional studies. This was compared with placebo patients pooled across both studies. Safety in patients with hemorrhagic stroke was analyzed separately in the exploratory analyses.
Because of the absence of prespecified hypotheses and the exploratory nature of the multiple comparisons, no level for statistical significance was set. Probability values <0.05 are noted for referential purposes only.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAppendix 1References |
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From July 11, 1996, to October 30, 1996, 59 patients were randomized in GAIN 1. Three patients did not receive study drug and therefore were excluded from the analyses. One patient assigned to receive placebo in dose tier 2 actually received GV150526, 800 mg; this patient was analyzed with the GV150526 group since the study was primarily a safety study and outcome analyses were exploratory. Table 1
shows the distribution of patients within
the first 3 dosage tiers, and Table 2
shows their baseline characteristics. GAIN 1 was terminated after
enrollment in the third dose tier was complete, when reports of
asymptomatic and reversible hyperbilirubinemia from the
European study testing the dosage planned for the fourth dosage tier
were examined. Table 3 depicts selected
safety data acquired in tiers 1 to 3. No episodes of either clinical
jaundice or elevated bilirubin were seen in the patients receiving the
800-mg loading dose followed by five 200-mg maintenance doses.
This dose was therefore chosen for further study in GAIN 2.
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From April 28, 1997, to October 31, 1997, 110 patients were randomized
in GAIN 2. One patient was randomized but not treated and therefore was
excluded from the analyses. Table 2 shows the baseline
characteristics of the patients in GAIN 2.
Table 3 illustrates key safety data observed in this trial.
There was no excess of reports of adverse effects on blood pressure,
heart rate or rhythm, or seizures in GV150526-treated patients. The
incidence of hyperbilirubinemia, defined as an elevation >1.67 times
the upper limit of normal, was slightly greater in the GV150526 group.
Peak bilirubin concentrations were on day 3, and elevated levels
returned to normal by day 7. No clinical sequelae were reported, and no
associated rise in liver enzymes was seen. Additionally, no clinically
significant differences in liver enzyme measurements were seen between
treatment groups, even in the absence of hyperbilirubinemia. Local
injection site reactions and events suggestive of altered mentation
(ie, agitation, confusion, paranoia, behavioral disorders,
aggression/hostility, and hypnagogic effects) were observed more
frequently in the GV150526 group. None of these events was considered
serious, and all were reversible. The fluid volume required was well
tolerated in both the drug and placebo groups. Mortality was similar in
the 2 groups.
GV150526 concentration data were available from 89 patients who
received the 800-mg loading dose followed by 200 mg every 12 hours for
5 doses (Figure ). The observed plasma
concentrations were consistent with the concentration profile
predicted using preliminary data. In the vast majority of patients,
trough blood levels remained above the putative neuroprotective
concentration (10 µg/mL) for the duration of the 3-day treatment
period.
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There were no clinically significant differences in the administration of concomitant stroke treatments between the groups. Approximately 10% of patients in both GV150526-treated and placebo-treated groups received recombinant tissue plasminogen activator, approximately 50% of patients received heparin (either subcutaneous or intravenous), 60% received aspirin or ticlopidine, and approximately 33% received warfarin.
Finally, the results of the pooled exploratory analyses of the
baseline characteristics and the safety and outcome experience with the
800-mg loading dose plus 200 mg every 12 hours for 5 doses are shown in
Tables 4, 5, and 6.
In addition to median scores for the Barthel Index, Rankin Scale, and
NIH Stroke Scale, the proportions of patients with nearly complete
independence (Barthel score of 95 to 100), assisted independence
(Barthel score 60 to 90), and severe dependence or death (Barthel score
0 to 55 or death) are shown. The baseline NIH Stroke Scale score
was lower (better) in the GV150526-treated patients, with an
approximate balance of the other baseline characteristics. The pooled
safety experience demonstrated an excess of drug infusion site
disorders (P<0.05) and suggested a slight excess of reports
suggestive of transient altered mentation (P>0.05) in
patients treated with GV150526. These events were mild to moderate in
severity, and none were reported to be serious. The proportions of
altered mentation events thought to be possibly attributable to study
drug were similar in both the GV150526 (5%) and placebo (4%)
groups.
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Ischemic stroke patients treated with GV150526 had better outcomes at 4 weeks than patients treated with placebo, but the studies were not powered to show statistical significance, and the baseline stroke scale scores in the GV150526-treated patients were less severe. The number of patients studied with intracranial hemorrhage (total n=12) was too small to make any meaningful statements (data not shown).
Analysis of the serial ECG data disclosed no evidence of drug-related arrhythmia or prolongation of the QT interval. No clinically significant differences were seen in the results of laboratory blood work or urinalyses (data not shown).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAppendix 1References |
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These data suggest that in North American centers, intravenous GV150526 at doses up to and including an 800-mg loading dose followed by a 200-mg maintenance dose every 12 hours for 5 doses is well tolerated by patients with ischemic stroke. The characteristics of the patients enrolled in both trials are similar to those of stroke patients in general.15 No conclusions can be drawn regarding efficacy because the trials were too small to detect potentially meaningful clinical differences, the baseline NIH Stroke Scale scores were better in GV150526-treated patients, and the end point was at 4 weeks instead of 3 to 6 months. However, no trend for harm was observed, and the observations may be regarded as encouraging for future studies.
Only mild side effects from GV150526 dosing are suggested by this experience. Asymptomatic elevations in bilirubin were observed at an incidence of 6% in the pooled experience at the 800-mg/200-mg dosage regimen and were not associated with rises in other liver enzymes or reticulocyte counts. Free GV150526 may compete with bilirubin for glucuronidation in the liver and may account for the apparent dose-related incidence of this finding. No evidence of a direct hepatotoxic effect has been developed from these or other studies. Mild injection site reactions were reported at a higher frequency in patients receiving GV150526 than in placebo, but the overall rate was low (<20%), and no patient had to discontinue study drug because of an injection site reaction. In contrast to the direct NMDA antagonists,2 3 4 GV150526 dosing was not associated with clinically limiting reports of psychotomimetic side effects, hypotension, or seizures.
The pharmacokinetic profile obtained from 3 days of dosing of GV150526
with the 800-mg/200-mg regimen supports that this fixed-dose regimen
provides levels at or above the targeted neuroprotective concentration
and therefore is appropriate for carrying forward into more definitive
efficacy studies. Extrapolation from studies of focal brain
ischemia in rodents, with interspecies differences in protein
binding of GV150526 taken into account, suggests that a blood level
10 µg/mL may be neuroprotective in humans. The 800-mg/200-mg
regimen produced sustained levels exceeding this target for the
duration of the 3-day dosing period. Furthermore, blood levels >100
µg/mL, a level above which protein binding of GV150526 becomes
saturated, were of short duration.
Intravenous administration of GV150526 required coadministration of modest amounts of dextrose and water (approximately 500 mL over 4 hours for the loading dose, then 125 mL every 12 hours for 5 doses). In some experimental models of focal cerebral ischemia, hyperglycemia has been shown to increase infarct size.16 In human stroke, hyperglycemia on admission has been associated with poorer outcomes,17 but whether treatment or prevention of hyperglycemia after admission results in improved outcome has not been established. In the present studies, treatment-emergent elevations in blood glucose (ie, those that occurred after treatment with study drug began) were observed in only 2% of patients, suggesting that the administration of the approximately 60 g of dextrose over 3 days was well tolerated. In terms of the fluid volume, the 5% incidence of congestive heart failure reported in these trials is well within the rates reported from other studies.18 Precautions were taken to exclude patients with severe heart failure from GAIN 1 and GAIN 2.
These trials, as with all phase II trials, have limitations, and caution should be used in interpreting the results. The number of patients studied, even with both trials combined, was small. The sample size provides only approximately 50% power for detecting an absolute 20% difference in rates of prespecified adverse events. Since smaller differences may be potentially clinically important, continued vigilance regarding safety in future larger trials will be mandatory.
This experience provides supportive data for further studies of GV150526 in patients with acute stroke. The compound appears to have an excellent preliminary safety profile in patients with ischemic stroke, and since it may have no apparent immediate effects on either cardiovascular or neurological status, it could potentially be administered emergently before head CT scan is performed. Thus, further evidence of the safety of GV150526 in patients with intracerebral hemorrhage would be valuable. Pivotal phase III trials to establish the safety and efficacy of GV150526 in patients with acute stroke are ongoing in North America, Europe, and Australasia.
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Acknowledgments |
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These studies (GLYA2001, GLYA2005) were funded by Glaxo Wellcome, Inc.
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Footnotes |
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Each of the investigators on the Writing Committee received research support from Glaxo Wellcome for conducting the phase II studies and is continuing to receive research support for conducting the phase III study currently in progress. Additionally, Drs Haley and Sacco have consulting agreements with Glaxo Wellcome as members of the Steering Committee for the phase III study. Dr Snipes, a member of the Writing Committee, is an employee of Glaxo Wellcome and holds stock in the company.
1 A list of all GAIN study participants is given in the Appendix.
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Appendix 1 |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAppendix 1References |
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Participating Centers
Boston Medical Center, Boston, Mass: Principal Investigator: Viken Babikian, MD; Coordinator: Eloise Licata-Gehr, RN, MS; Sub-Investigator: Lemore N. Joseph, MD. Saint John Regional Hospital, Saint John, New Brunswick, Canada: Principal Investigator: Peter Bailey, MD; Coordinator: Rosemary Boyle; Sub-Investigators: A. MacDougall, MD; G. MacLean, MD; W.B. Wheelock, MD; G. Kolyvas, MD. Parkview Memorial Hospital, Fort Wayne, Ind: Principal Investigator: Thomas Banas, MD; Coordinator: Mary Ann Wissman, RN, BSN; Sub-Investigators: James D. Heckaman; Mark A. Porter, MD; Madhav H. Bhat, MD; Paul E. Later, MD; Stanley D. Wissman, MD; C. Joe Ottinger, MD; James C. Stevens, MC, ACP; Robert Plant, PharmD; Fen Lee Chang, MD. Palms of Pasedena, St Petersburg, Fla: Principal Investigator: Joel Beatty, MD; Coordinator: Theresa W. Beatty, MSN; Sub-Investigators: Steven B. Cohen; Alberto B. Vasquez, MD; David W. Schmidt, MD; Theresa Beatty, MSW; Todd Allen. Charles Lemoyne Hospital, Greenfield Park, Quebec, Canada: Principal Investigator: Andre Bellavance, MD, PhD; Coordinator: Luce Hebert, RN; Sub-Investigators: L. Berger, MD; R. Filatrault, MD; Z. Nasredding, MD; A.G. Trottier, MD; M. Duplessis, MD; F. Grand Maison, MD; S. Ninkovic, MD. Good Samaritan & St Mary’s, West Palm Beach, Fla: Principal Investigator: Bruce Berman, MD; Coordinator: Mari Yipelkonen; Sub-Investigators: Barry M. Miskin, MD, FACS; Stephen A. Shaivitz, MD; Daniel Rowe; Lloyd Elliot Reich. University of of Texas Health Sciences Center, San Antonio, Tex: Principal Investigator: Oscar Benavente, MD; Coordinator: Glennda Bruce, RN, MSN; Sub-Investigators: Diane Solomen, MD; David Sherman, MD; Robert Hart, MD; Merrill Kanter-Carolin, MD; Daniel R. Lalonde, MD; Diane Rogers, RN; Glennda Bruce, RN, MSN; Ann Leonard, RN, BSN. University of Cincinnati Hospital, Cincinnati, Ohio: Principal Investigator: Thomas Brott, MD; Coordinator: Judith Spilker, RN; Sub-Investigators: Joseph Broderick, RN; Rashmi Kothari, MD; Arthur Pancioli, MD; Laura Sauerbeck, RN; Rosie Miller, RN. Oregon Health Sciences Center, Portland VA Medical Center, Portland, Ore: Principal Investigator: Wayne M. Clark, MD; Coordinators: Sandy McClurksey Deely, RN; Suzie Fisher, RN; Sub-Investigators: Helmi Lutsep, MD; Joseph Quinn, MD; Jacqueline Crawford, MD; Robert Egan, MD; Gary Nesbit, MD; AbdulKader Al-Azzaz, MD. Johns Hopkins Bayview, Baltimore, Md: Principal Investigator: Christopher Earley, MD; Coordinator: Melanie Herr, RN; Sub-Investigators: Hubert Michel, MD; Gretchen Dike, MD; Nicholas Maragakis, MD; Michael Polydefkis, MD; Kathryn Wagner, MD; Michael Wang, MD; Renata Rusa, MD; Charlotte Jones, MD; Douglas Kerr, MD; Lauren Moo, MD; Carlos Pardo, MD; Isaac Silverman, MD; Joseph Hoffman, DO; Ellen Diebert, MD; Hyder Jinnah, MD; Jennifer York, MD; Ahmet Hoke, MD; Francisco Vega-Bermudez, MD; Ann Comi, MD; Argye Hillis, MD; Jeremy Rich, MD. St Joseph Health Care, Kansas City, Mo: Principal Investigator: John Ervin, MD; Coordinator: Carlene Bryan; Sub-Investigators: Arthur A. Allen, MD; Gordon B. Kelley, MD; Michael F. Perll, MD; Mark S. Box, MD; Luis H. Robles, MD; Jay S. Zwibelman, MD; Donald K. Hopewell, MD; Michael E. Ryan, MD; Robert T. Wendland, MD. University Medical Center, Tucson, Ariz: Principal Investigator: William Feinberg, MD; Bruce Coull, MD; Coordinator: Diane Rose-Taylor, RN; Sub-Investigators: Geoffrey Ahern, MD; L. Roderick Anderson, MD; Samuel Keim, MD; Scott Sherman, MD; Diane Rose-Taylor, RN, CCRN. University of Virginia Health System, Charlottesville, Va: Principal Investigator: E. Clarke Haley, Jr, MD; Coordinators: Angel Morris, RN; Karen Ahern, RN; Sub-Investigators: Karen Johnston, MD; Nina Solenski, MD; Bart Nathan, MD; Thomas Bleck, MD; Brad Worrall, MD; Dave Leszczyszyn, MD; Mitzi Hemstreet, MD; James Kiely, MD; Ted Burns, MD; Caroline Klein, MD; Wayne Cail, MD; Steven Huff, MD; Jennifer Quinn, MD; Robert Armstrong, MD; Javier Provencio, MD; Robb Snider, MD; Jay Van Gerpen, MD. Barnes-Jewish Hospital, St Louis, Mo: Principal Investigator: Chung Hsu, MD; Coordinators: Laurie Duke, RN; Gerry Banet RN, BSN; Sub-Investigators: John Choi, MD; Jin-Moo Lee, MD; Ted Lowenkopf, MD. Royal Columbia Hospital, St Louis, Mo: Principal Investigator: Grant Innes, MD; Coordinator: Cathy Metcalf; Sub-Investigators: P. Huang, MD; C. Rumball, MD; B. Miller, MD; J. Haegert, MD; A. Holmes, MD; B. Oldring, MD; J. MacNab, MD; R. Grosch, MD; B. Deady, MD; R. Street, MD; R. O’Brien, MD; L. Vertesi, MD; G. Erhardt, MD; J. Finkler, MD; C. Tessler, MD; S. Glazer, MD; R. Noseworthy, MD; M. Knazen, MD; P. MacDonald, MD; A. Smyth, MD. Tampa Bay Medical Research, Inc, Clearwater, Fla: Principal Investigator: Jeffrey Karp, MD; Coordinator: Barbara Phillips, RN; Sub-Investigators: Allan Spiegel, MD; Steven C. Bowman, MD; James P. Hampsey, MD; Mohsen W. Habib, RPh; Terry Schroeder, RN; Kim Stopnytsky, LPN, CCRC. St Joseph’s Health Center, London, Ontario, Canada: Principal Investigator: Andrew Kertecz, MD; Coordinator: Shirley Piotrowski; Sub-Investigator: Paul Cooper, MD. UCSD Medical Center, San Diego, Calif: Principal Investigator: Patrick Lyden, MD; Coordinator: Karen Rapp, RN, BSN, CCRN; Sub-Investigators: Christy Jackson, MD; Ronald Ellis, MD, PhD; Howard Noack, MD; Marwan Sabbagh, MD; Douglas Galasko, MD, PhD; Karen Rapp, RN; Nancy Kelly, RN; Janet Werner, RN; Cherylee Chang, MD. University of North Carolina Hospitals, Chapel Hill, NC: Principal Investigator: Dexter Tony Morris, MD; Coordinator: Susan Pusek; Sub-Investigators: Albert Hinn, MD; John Ma, MD; Estrada Bernard, MD. Neurological Investigation, Halifax, Nova Scotia, Canada: Principal Investigator: Stephen Phillips, MBBS, FRCPC; Coordinator: Yvette Reidy, RN; Sub-Investigators: G. Gubitz, MD; F. Tanha, MD; R. Leckey, MD; J. Ansell, MD; S. Darvesh, MD; E. Aguilar, MD. Buffalo General Hospital, Buffalo, NY: Principal Investigator: Patrick Pullicino, MD; Coordinator: Sandra Starr, RN; Sub-Investigator: Frederick E. Munschauer, III, MD. Memorial Regional Hospital, Hollywood, Fla: Principal Investigator: David B. Ross, MD; Coordinator: Deborrah Norris, CRC; Sub-Investigators: Jeff Steinberg, MD; Bruce Zaret, MD; Mayur Maniar, MD; Deborrah Norris, CRC. Columbia Presbyterian Medical Center, New York, NY: Principal Investigator: Ralph L. Sacco, MS, MD; Coordinators: Bernadette Boden-Albala, MPH; Marta Jimenez, MD; Sub-Investigators: J.P. Mohr, MD; Douglas Kargman, MD; Randolph Marshall, MD; Mitchell S. Elkind, MD; Kirk Roberts, MD; Robert Gan, MD; Neal Shipley, MD; Sami Aboumatar, MD; Robert Greene, MD. Royal University Hospital, Saskatoon, Canada: Principal Investigator: A. Shuaib, MD; Coordinator: E. Kadribasic, RN; Subinvestigators: M. Keegan, MD; B. Stewart, MD; K. Khaan, MD. George Washington University, Washington, DC: Principal Investigator: Ashfaq Shuaib, MD; Coordinator: Traci Renee Dean, RN; Sub-Investigators: Perry Richardson, MD; Mohammed Moussavian, MD; Wiaam Faloriji, MD; Mark Johnson, MD; Zachary Levin, MD. University of Florida Health Science Center, Jacksonville, Fla: Principal Investigator: Scott Silliman, MD; Coordinator: Paula S. Fuqua, PharmD; Sub-Investigators: Alan Berger, MD; Souhel Najjar, MD; Ronald Schwartz, MD. University of Texas Health Sciences Center, San Antonio, Tex: Principal Investigator: Diane H. Solomon, MD; Coordinator: Lori Limon, RN; Sub-Investigators: Robert G. Hart, MD; David G. Sherman, MD; Merrill C. Kanter Carolin, MD; Daniel Roger Lalonde, MD; Oscar Benavente, MD. UCLA Medical Center, Los Angeles, Calif: Principal Investigator: Sidney Starkman, MD; Coordinator: Glen B. Schubert, MPH; Sub-Investigators: Bruce Dobkin, MD; Jeffrey Saver, MD; Paul Vespa, MD; Jeffry Alger, PhD. Hospital Maissoneuve, Rosemont, Montreal, Canada: Principal Investigator: Jeanne Teitelbaum, MD; Coordinator: Nicole Lachance; Sub-Investigators: A. Robillard, MD; J. Lachapelle, MD; J. Boileau, MD; S. Rousseau, MD; L. Roy, MD; P. Laplante, MD. Richmond Memorial Hospital, Chippenham Medical Center, Richmond, Va: Principal Investigator: Stephen Thurston, MD; Coordinator: Janet R. McGee; Mary Ann Lutz, RN, CNS; Sub-Investigators: F.E. McGee, MD; J.K. Harris, MD; R.J. White, MD; J.M. O’Bannon, MD; J.J. Brush, MD; R.J. Cohen, MD; T.A. Smith, MD; S.A. Mathé, MD; S.F. Karner, MD; A.K. Worthington, MD; Jane G. Deel, RN. Stanford Universtiy Medical Center, Palo Alto, Calif: Principal Investigator: David Tong, MD; Coordinator: Nanette Hock, RN, MS; Sub-Investigators: Gregory Albers, MD; Michael O’Brien, MD; Andrew Woofenden, MD; Midori Yenari, MD; Susan Freyberg, RN, MS; Grayce Guro, RN; Nanette Hock, RN, MS. Mt Sinai Medical Center, New York, NY: Principal Investigator: Stanley Tuhrim, MD; Coordinator: Sandra Augustine, RN; Sub-Investigators: Jesse Weinberger, MD; Deborah Horowitz, MD; Kara Sheinart, MD; Walter Schonewille, MD; Scott Atlas, MD. Pasqua Hospital, Regina, Saskatchewan, Canada: Principal Investigator: Felix Veloso, MD; Coordinator: Marilyn Reid; Sub-Investigators: K. Adaikari, MD; V. Gebhardt, MD; C.P.V. Nair, MD. OSF Saint Francis Medical Center and Methodist Hospital, Peoria, Ill: Principal Investigator: David Wang, DO; Coordinator: David Vrabel; Sub-Investigators: John McLean, MD; Jai Kumar, MD; Dennis Garwacki, MD; Michelle Roda, DO; Edward Hui, MD, PhD; Jenny Coyner, CTC; David Vrabel, CRC; Deb Honings, RN; Jean Rose, RN, CNRN, MS; Robert Sladana, Pharm D, MS. University of Pittsburgh, Pittsburgh, Pa: Principal Investigator: Larry Wechsler, MD; Coordinator: Laurel Yasko, RN; Sub-Investigators: Laurie Knepper, MD; Lori Massaro, CRNP; Steven Graham, MD; Gregory Larkin, MD; Thomas Ulicny, MD; Howard Yonas, MD; Carol Barch, RN, CRNP; Hartwell Lin, MD; Eric Brader, MD; Kent Berkey, MD; Jennifer Ludovici, RN; Anthony Kaufmann, MD; Sharon De Cesare; Alan Hodgdon, MD; Bruce MacLeod, MD; Dan Thompson, MD; Sue Piatkowski, RN; Kevin O’Toole, MD; Laurel Yasko, RN; Kaveh Ilkhanipour, MD; Rich Maenza, MD; Susan Mathias, CRNP; Keith Thulborn, MD; Charles Jungreis, MD; Pamela Cockley, RN; Guy Corsello, MD; Cheryl Ammon, RN; Aamir Rasheed, MD. Moncton Hospital, Moncton, New Brunswick, Canada: Principal Investigator: Lyle Weston, MD; Coordinator: Giselle Bourque; Sub-Investigators: David Silverberg, MD; Byrne Harper, MD; Dale Robinson, MD; Michael MacEachern, MD. Sentara Norfolk General Hospital, Norfolk, Va: Principal Investigator: Armistead D. Williams, MD; Coordinator: Robin Roth, RN, BSN; Sub-Investigators: Marcus Rice, MD; Joseph Hogan, MD; Thomas R. Pellegrino, MD; Marie T. Holland, MD; Robert J. Lanoue, MD; Anne Redding, MD; Joseph Handler, MD.
Neuroclinical Trials Center–Data Management Center: Principal Investigator: E. Clarke Haley, Jr, MD; Project Manager: Wayne M. Alves, PhD; Monitors: Lori Elder, RN, BSN; Karen Davenport, RN, BSN; Kathlkeen McClure, RN, CCRA; Sharon Knowlton, RN, BA; Elizabeth Cuccia, RN, MHM; Kay Maupin, RN, BSN; Administration: Melissa Lotts.
Central Laboratories: Covance–Hematology and Blood Chemistry: Mark Hund, Kimberly Shelleck, Tara Szewc; UVA Neuroclinical Trials Center–Central CT Laboratory: Wayne Cail, MD, CT Director; Duke University–ECG Laboratory: Galen Wagner, MD; Kathy Gates, RN.
Manuscript Writing Committee: Christopher Earley, MD, PhD; E. Clarke Haley, Jr, MD; Karen C. Johnston, MD; Ralph L. Sacco, MD; Ashfaq Schuaib, MD; Rose Snipes, MD; David Z. Wang, DO.
Data Safety Monitoring Committee: Lawrence M. Brass, MD, Chair; William R. Clark, PhD; James C. Grotta, MD; Michael Harrison, MD; Neil McIntyre, MD.
Consulting Hepatologist: Hyman Zimmerman, MD.
Sponsor: Glaxo Wellcome; Medical Director: Rose Snipes, MD; Study Team Leader: David Watson, MS; Project Manager: Paul Ordronneau, PhD; Clinical Pharmacology: Frank Hoke, PhD; Statistical Support: Wen Jen Ko, PhD. Monitors: Linda Clayton, PharmD; Lori Enney-O’Mara; Joel Johnson, PharmD; Connie Orander. Administration: Bari Card; Sylvia Green.
Received August 3, 1999; revision received October 19, 1999; accepted October 27, 1999.
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