Background and Purpose Lubeluzole is a novel benzothiazole compound that has shown neuroprotective activity in preclinical models of ischemic stroke. The present multicenter, double-blind, placebo-controlled study was conducted to assess the efficacy and safety of lubeluzole in the treatment of ischemic stroke.
Methods Seven hundred twenty-one patients with clinical symptoms of acute ischemic stroke were randomized to receive either lubeluzole (7.5 mg over 1 hour, followed by a continuous daily infusion of 10 mg for up to 5 days) or placebo. Treatment was initiated within 6 hours of symptom onset. Mortality at 12 weeks was the primary efficacy end point. Secondary efficacy end points included neurological recovery (based on the National Institutes of Health Stroke Scale [NIHSS]), functional status (based on the Barthel Index), and level of disability (based on the Rankin Scale). Safety assessments included standard and continuous electrocardiographic monitoring, physical examination, measurements of vital signs, clinical laboratory evaluation, and adverse events reports.
Results The overall mortality rate at 12 weeks for lubeluzole-treated patients was 20.7% compared to 25.2% for placebo-treated patients (NS). Controlling for relevant covariates, the degree of neurological recovery (NIHSS) at week 12 significantly favored lubeluzole over placebo (P=.033). Lubeluzole treatment similarly resulted in significantly greater improvements in functional status (Barthel Index) (P=.038) and overall disability (Rankin Scale) (P=.034) after 12 weeks. A global test statistic confirmed that lubeluzole-treated patients had a more favorable clinical outcome at 12 weeks (P=.041). The safety profile of lubeluzole resembled that of placebo.
Conclusions Treatment with lubeluzole within 6 hours of the onset of ischemic stroke had a nonsignificant effect on mortality and resulted in improved clinical outcome compared with placebo, with no safety concerns.
Until recently, the treatment of acute ischemic stroke has been primarily limited to supportive medical care to optimize cerebral perfusion and oxygenation and to avoid complications. New insights into the pathophysiology of ischemic stroke have led to the development of agents that protect neuronal tissue against the toxic effects of ischemia. Lubeluzole (Prosynap, Janssen) is a new benzothiazole compound that has shown promise in preclinical models of ischemia. These studies have revealed that when administered intravenously up to 6 hours after either photochemically induced thrombotic cerebral infarcts or after middle cerebral artery occlusion in rats, lubeluzole reduced neuronal damage and lesion volume,1 2 possibly by preventing an increase in extracellular glutamate in the penumbra3 and by normalizing the excitability of neurons in this region.4 In addition, experiments with cultured embryonic hippocampal neurons indicate that the drug inhibits glutamate-induced nitric oxide–related neurotoxicity.5 6
No major toxicity issues were identified with lubeluzole in animal studies or in phase-I clinical studies at the recommended dosage of 10 mg per day. In a phase-II, multicenter, double-blind, placebo-controlled trial involving 232 patients (193 with ischemic stroke), lubeluzole, administered intravenously within 6 hours of stroke onset at a dosage regimen of 7.5 mg during the first hour followed by 10 mg per day for 5 days, was safe and effective, resulting in a statistically significant reduction in mortality compared with placebo.7 Although phase-I studies identified QTc interval prolongation with increasing lubeluzole concentrations, evident with intravenous infusion at doses of 20 to 25 mg of lubeluzole,8 in this phase-II study QTc interval changes were similar in the lubeluzole and placebo groups. Based on these positive results, further study of lubeluzole was warranted. The present trial was designed to evaluate the efficacy and safety of lubeluzole, administered within 6 hours of stroke onset, in a large population of ischemic stroke patients.
Subjects and Methods
The target population was patients at least 18 years of age who presented with substantial neurological deficit within 6 hours of the onset of an acute cerebral hemispheric ischemic stroke. They had to be alert or arousable to minor stimulation, exhibit a significant motor deficit of the arm or leg, and have a total National Institutes of Health Stroke Scale (NIHSS) score of >7 at baseline. All patients or their legal representatives provided written informed consent before participating. Women of childbearing potential must have had a negative pregnancy test prior to entry.
Patients were ineligible if their baseline CT scan was inconsistent with the diagnosis of acute cerebral infarction or if they had experienced a previous stroke with residual functional impairment. Patients with a life-threatening concurrent illness, overt heart failure, myocardial infarction within the previous 6 weeks, electrocardiographic (ECG) findings of serious ventricular arrhythmia, second or third degree atrioventricular block, or a QT interval >450 msec were excluded. Medications known to prolong the QT interval (eg, quinidine), potassium-wasting diuretics without special measures to prevent hypokalemia, and other experimental stroke medications were prohibited. Anticoagulants and antiplatelet agents were allowed as clinically indicated.
Classification of ischemic stroke subtypes, which included small-vessel occlusive, large-vessel occlusive, and cardioembolic, was based on the TOAST (Trial of Org 10172 in Acute Stroke Treatment) criteria.9 Patients were included whatever the subtype as long as they met entry criteria.
This was a multicenter, randomized, placebo-controlled, double-blind, parallel-group trial. Institutional Review Board approval was obtained at each of the 83 US and Canadian study centers. Patients were randomized to receive intravenous treatment with lubeluzole or placebo. Lubeluzole was given as a loading dose of 7.5 mg during the first hour, followed by a continuous daily infusion of 10 mg. Study medication was administered until complete neurological recovery, as measured by a score of 0 on the NIHSS, or for a maximum of 5 days and 1 hour. Patients were evaluated for 12 weeks from the start of treatment.
Baseline assessments included a medical history and neurological evaluations, including a Clinical Global Impression (CGI) of Stroke rating of mild, moderate, or severe. Mortality was followed over the entire 12 weeks. Neurological status was assessed using the NIHSS before beginning study treatment, daily on treatment days 2 to 5, and at weeks 4 and 12 after the start of treatment. The NIHSS10 is a 42-point scale that quantifies neurological deficits in 12 areas; normal function without deficit is given a score of 0. Functional status, assessed using the Barthel Index,11 and residual disability, evaluated using the Rankin Scale,12 were measured at baseline, at the end of study treatment, and at weeks 4 and 12. The Barthel Index evaluates 10 activities of daily living; patients able to complete all activities independently are given a score of 100. Using the Rankin Scale, the patient is assigned a score of 0 (no symptoms present) to 5 (severe disability requiring constant nursing and attention).
Multiple safety assessments were made at specified times throughout study drug administration and follow-up. A physical examination, which included collection of blood and urine samples for clinical laboratory evaluation, was performed at baseline and at the end of treatment. A CT scan of the brain was performed either before or up to 3 hours after the start of study treatment in the United States and up to 24 hours after the start of medication in Canada. Additional CT scans were obtained between days 4 and 7 and at week 4. Continuous ECG monitoring was initiated prior to the start of study treatment and continued throughout the treatment period and for an additional 48 hours after treatment in the majority of patients. Blood pressure and heart rate were measured, and 12-lead ECGs were performed at the end of the loading dose, at 6 and 12 hours after the start of study medication, daily during the treatment period, and at the end of treatment. Adverse event reports were recorded throughout the study. All adverse events were based on the clinical judgment of the principle investigator at each study site. Serious cardiac arrhythmia (ventricular fibrillation, torsade de pointes, sustained ventricular tachycardia), QT >550 milliseconds, or clinically significant heart failure mandated discontinuation of study drug.
Patients were randomized by blocks of four for each study center location. Sample size (300 ischemic stroke patients per group) was based on the phase-II trial of lubeluzole.7 The study was powered (80% power, 2 sided α=.05) to detect a difference between 14% and 23.5% in 3-month mortality. We anticipated that 17% of randomized patients would not have ischemic stroke.
The efficacy end points, all evaluated at week 12, were defined a priori as follows:
Primary Efficacy End Point.
Secondary Efficacy End Points.
(1) Survival time.
(2) Neurological recovery. Based on the total NIHSS score, which could range from 0 to 34 (for patients who died, a score of 34 was used). (Note: Item 12, distal motor function, was not included in the total score.10 ) Only the weaker limb and weaker leg were graded for items 5 and 6, respectively.
(3) Functional status. Based on the total Barthel Index score represented in three categories: “independent or mildly dependent” (score of ≥75), “moderately or severely dependent” (score of <75), and “dead.”
(4) Level of disability. Based on the modified Rankin Scale score represented in three categories: “no symptoms to slight disability” (score of 0, 1, or 2), “moderate to severe disability” (score of 3, 4, or 5), and “dead.”
Analyses of the efficacy end points were based on week 12 data from two protocol-specified target populations: (1) all randomized patients who received study medication (all patients) and (2) patients with ischemic stroke confirmed by the baseline CT scan (ischemic stroke population). The week 12 time point was defined as 84 days (with the exception of mortality and survival time).
Patients lost to follow-up were omitted from the analyses of time points after they were lost (observed case analysis). Patients who died were given the worst possible score on all outcome measures.
Safety analyses were based on data from all randomized patients.
Mortality was analyzed using a logistic regression approach for the logit model. Continuous efficacy parameters (total Barthel score and changes from baseline in NIHSS score) were analyzed with use of an analysis of covariance on the rank-transformed data. The Wilcoxon signed rank test was used for within-treatment group comparisons (baseline versus each visit) of the total NIHSS score. Functional status and Rankin Scale scores were analyzed with a logistic regression approach for the cumulative logit model. Survival time was analyzed with the Cox regression.
In addition to these per-protocol analyses, data were also analyzed with age, stroke severity, and study center location as covariates because of their possible confounding effect on outcome and statistical design.
Treatment differences in the proportion of patients exhibiting a favorable outcome (ie, scores of ≥75 on the Barthel Index, ≤7 on the NIHSS, and ≤2 on the Rankin Scale) were compared using a global statistic (Wald test) derived from a general linear model with logit-link function, computed with the use of generalized estimating equations. When the global test statistic was significant, logistic regression models for each outcome measure were used to evaluate treatment differences. The global test was the same as that published in the NINDS rt-PA study.13
Demographics and baseline characteristics were compared using a two-way ANOVA for continuous variables (eg, age, body weight, and inclusion time) and the Cochran-Mantel-Haenszel test for general associations for nominal categoric variables (eg, race, sex, and CGI). A paired Student’s t test was used to analyze changes from baseline for each ECG interval, blood pressure, and heart rate in each treatment group; an ANOVA was used to evaluate between-group differences in observed changes in these parameters. Fisher’s exact test was used to evaluate differences in the number of adverse events in each group.
Data are expressed as mean±SD unless otherwise stated. All tests were two-sided, and statistical significance was defined as P≤.05. All data were compiled and analyzed in-house at Janssen Research Foundation, Beerse, Belgium. Data for each center were monitored by an independent auditing agency. Investigators, monitors and all Janssen personnel, including statisticians, remained blinded to treatment groups until all patients completed follow-up and the database was finalized.
A total of 721 patients were enrolled in the trial and randomized to treatment with lubeluzole (n=368) or placebo (n=353). The two treatment groups were similar with respect to all demographics and baseline disease characteristics (Table 1⇓). The interval between stroke onset and initiation of therapy averaged 4.7 hours (range, 1.3 to 7.4 hours) and did not differ between the two treatment groups. The overall mean duration of treatment was 4.4±1.4 days, with a range of 18 minutes to 5.8 days in the lubeluzole group and 42 minutes to 6.0 days in the placebo group. Of the 721 randomized patients (all-patient population), 700 had an ischemic stroke as confirmed by the baseline CT scan (ischemic stroke population); 13 had hemorrhagic stroke, 3 had functional-psychogenic reaction, 2 had brain tumors, 1 had migraine syndrome, 1 had possible multiple sclerosis, and 1 had dystrophic calcification. Approximately 50 percent of all the strokes were categorized as severe on the CGI.
Approximately 20% of the patients in both treatment groups withdrew prematurely from either the treatment period or the follow-up period (Table 2⇓). A total of 145 patients (72 lubeluzole, 73 placebo) did not receive all 5 days of medication, with the most common reason being adverse experience(s) (38 lubeluzole, 42 placebo). A total of 684 patients entered the follow-up period; 152 (72 lubeluzole, 80 placebo) did not finish this phase of the trial.
Mortality Rate and Survival Time
In the all-patient population, 76 (20.7%) of the 368 patients in the lubeluzole group died during the 12 weeks of the study compared with 89 (25.2%) of the 353 patients in the placebo group (NS) (Table 3⇓). When the analysis was restricted to patients with an ischemic stroke, mortality was 20.9% with lubeluzole and 25.4% with placebo. Throughout the trial, lubeluzole treatment was associated with a 32% reduction in the odds of dying compared with the placebo group (estimated odds ratio [OR], 0.68; 95% confidence interval [CI], 0.46 to 1.02; all-patient population). Age and stroke severity (determined by CGI) were highly correlated with mortality (P=.0002 and P=.0001, respectively). Therefore, along with study center location, data were also analyzed using these variables as covariates (Table 3⇓).
A difference in mortality between lubeluzole and placebo (all patients) was observed shortly after treatment and was consistently favorable for lubeluzole throughout the observation period (Fig 1⇓). Survival time in the lubeluzole group was enhanced, although it did not reach statistical significance (P=.077; Cox regression).
Lubeluzole treatment was associated with statistically significant improvements in neurological recovery, functional status, and residual disability compared with placebo when controlling for relevant covariates. Significant neurological recovery, as revealed by NIHSS scores, began on day 2 in both treatment groups (all patients), but improvement continued through week 12 in the lubeluzole group (Fig 2⇓). At week 12, the change from baseline in total NIHSS score statistically favored lubeluzole over placebo (P=.033).
The functional status assessment, based on the total Barthel Index score and mortality, indicated that more patients in the lubeluzole group (46.8%) were independent or mildly dependent at week 12 compared with the placebo group (40.1%) (Table 3⇑; Fig 3⇓). This difference in functional status between the two groups was statistically significant in favor of lubeluzole (P=0.038; estimated OR, 0.73; 95% CI, 0.54 to 0.98).
Analysis of the degree of disability, as tested with the modified Rankin Scale and mortality, also showed a statistically significant difference between the two groups at week 12 (P=.034; estimated odds OR, 0.72, 95% CI, 0.54 to 0.98). In the lubeluzole group, fewer patients died, about the same number had moderate to severe disability, and more had no symptoms or slight disability (Table 3⇑; Fig 3⇑).
The global test statistic indicated that the odds of a favorable outcome were 38% higher (P=.041) in patients treated with lubeluzole than those treated with placebo (OR, 1.38; 95% CI, 1.01 to 1.88) (Table 4⇓). In the ischemic stroke population, the small-vessel occlusive type of stroke was associated with the lowest mortality rate in both treatment groups and the greatest percentage of patients with a favorable outcome on neurological recovery, functional status, and residual disability (Table 5⇓). Cardioembolic-type stroke was associated with the worst prognosis. A greater percentage of patients treated with lubeluzole achieved a favorable outcome on all parameters in the three subtypes of stroke: small-vessel occlusive, large-vessel occlusive, and cardioembolic.
Incidence of Adverse Events
All 721 patients who received study medication were included in the safety analyses. The causes of death during the treatment period plus 2 days and the entire study were similar in both groups (Table 6⇓). The number of cardiac-related deaths was similar between the two groups during the treatment plus 2 days. There were 165 deaths during the 12 weeks of the study. The most common category was stroke related. There were no differences between treatment groups.
A total of 330 (89.7%) lubeluzole-treated and 311 (88.1%) placebo-treated patients reported adverse events during treatment plus the 2-day post treatment period, whereas 348 (94.6%) of lubeluzole-treated and 333 (94.3%) of placebo-treated patients did so during the entire length of the trial. The most common adverse events, seen in >10% of patients in either treatment group during the first week or the entire trial, are given in order of decreasing incidence, based on the entire trial (Table 7⇓). The types and incidence of the majority of adverse events were similar in both groups, with the exception of a statistically greater incidence of headache (first week and entire trial) and peripheral edema (first week) in the lubeluzole group.
Lubeluzole had no effect on blood pressure or heart rate, and there were no apparent differences between the two treatment groups with respect to clinical laboratory parameters.
Incidence of Cardiac-Related Complications
Cardiac-related adverse events consisted of 3 World Health Organization system-organ classes: heart rate and rhythm disorders; cardiovascular disorders; and myocardial, endocardial, pericardial, and valve disorders. The difference in the incidence rates of these cardiovascular events was not statistically significant in the two treatment groups (46.2% and 43.6% in the lubeluzole- and placebo-treated groups, respectively) during treatment plus the 2-day posttreatment period, as shown in Table 8⇓. Serious heart-rate and rhythm disorders, including cardiac arrest, torsades de pointes, and ventricular fibrillation or their combination, were noted in 8 patients in each treatment group.
A standard 12-lead ECG was performed at baseline; at 1, 6, and 12 hours after the onset of treatment; daily during treatment; and at the end of the treatment period. Compared with baseline values, an increase in QTc interval was observed in both treatment groups during the first 24 to 48 hours. The mean change in QTc in the lubeluzole group (18.6±1.7 msec) was significant only on the first day of treatment, 1 hour after the start of the infusion, compared with that in the placebo group (5.7±1.7 msec) (P<.001). By 6 hours after the initiation of treatment and for the rest of the treatment period, the difference in QTc interval prolongation did not differ significantly between the two groups. The number of patients with QTc intervals greater than 500 msec differed significantly between the two groups only at 1 hour after the start of the infusion of the medication (Table 9⇓).
In this trial with 721 patients, using a 6-hour inclusion window, lubeluzole was associated with a trend toward a reduction in mortality and produced statistically significant improvements in neurological recovery, functional status, and global disability 3 months after stroke. The effect of lubeluzole on mortality (our primary end point) did not reach conventional levels of statistical significance. Based on pilot data,7 we overestimated the impact of lubeluzole treatment on mortality, and consequently the study was powered to identify only a very large treatment effect. To date, no stroke therapy (including FDA-approved rt-PA) has been found to have a significantly favorable effect on mortality.
The prespecified secondary end points were improved functional recovery, neurological recovery, and level of handicap as measured by the Barthel Index, NIHSS, and Rankin Scale, respectively. Compared with patients given placebo and controlling for important covariates, those treated with lubeluzole were 32% less likely (OR, 0.68) to die and 38% more likely (OR, 1.38) to have a favorable outcome on each efficacy scale—the NIHSS, the Barthel Index, and the modified Rankin Scale. The estimated OR of 1.38 for a favorable outcome had a 95% CI of 1.01 to 1.88, which means that the chance of a positive outcome due to lubeluzole could be in the interval of 1% to 88% in 19 of 20 cases treated. A 7% absolute increase in favorable outcome observed on these three scales indicates that 7 additional patients of 100 would be left independent or only mildly dependent 3 months after their stroke with lubeluzole therapy. A similar pattern of results was observed when the analyses were restricted only to those patients with an ischemic stroke. Therefore, lubeluzole is the first neuroprotective drug associated with improved outcome by a double-blind, placebo-controlled trial in a large population of ischemic stroke patients. These beneficial effects are consistent with the neuroprotective activity of lubeluzole shown in preclinical models.14 Lubeluzole has been shown to interfere with key biochemical mechanisms that lead to irreversible tissue damage in the penumbra.
Analysis of data from randomized clinical trials should be protected from giving substantially biased estimates by adjusting on very strong prognostic variables, even if they are balanced across treatment groups. Recent research, including the NINDS rt-PA trial, have identified age and stroke severity as important independent and interacting predictors of outcome. Therefore, results were analyzed per protocol and also using age and stroke severity (and study center location) as covariates in outcome analyses.
The favorable therapeutic benefits of lubeluzole were not achieved at the expense of patient safety. Headache was more frequent with lubeluzole in pilot data7 and in the present study. With the exception of headache and peripheral edema, the overall adverse events and the cardiac-related events were similar in terms of both the types of complaints and their reported frequency in the two treatment groups. The primary causes of death were similarly balanced in the two groups of patients and were most often related to the stroke itself. Lubeluzole had no discernible effect on blood pressure, heart rate, or clinical laboratory parameters.
Since plasma level–related QTc prolongation was observed with lubeluzole in phase-I studies, considerable care was taken to monitor cardiac function in the current trial. Extensive ECG monitoring revealed significant differences between the two groups only on the first day, at 1 hour after the start of the infusion, which did not appear to have any serious clinical consequences. The overall incidence of cardiovascular events was similar in the two treatment groups; of particular interest is the similar occurrence of serious ventricular tachyarrhythmias or cardiac arrest in the two patient populations.
The availability of an effective neuroprotective treatment, such as lubeluzole, with a 6-hour window for administration, no need for a CT scan prior to treatment, and a favorable safety profile, could be expected to increase the overall number of stroke patients with favorable long-term outcome. In addition, the potential concomitant use of a neuroprotective agent, such as lubeluzole, with the first approved therapy for stroke, the thrombolytic agent rt-PA, warrants further consideration as a promising treatment protocol. Such combination therapy may prove very beneficial in the treatment of ischemic stroke because the two agents have different mechanisms of action in the ischemic cascade.
In conclusion, treatment with lubeluzole within 6 hours of the onset of ischemic stroke resulted in improved clinical outcome at 3 months with no safety concerns.
The following principal investigators participated in the study:
D. Barbut, Cornell Medical Center–New York Hospital, New York, NY; V. Bates, Millard Filmore Hospital, Buffalo, NY; J. Belden, Maine Medical Center, Portland, ME; R. Bell, Thomas Jefferson University Hospital, Philadelphia, Pa; J. Biller, Indiana University Medical Center, Indianapolis, Ind; J. Bounds, Luther Hospital, Eau Claire, Wis; S. Braheny, Sharp Grossmont Hospital, La Mesa, Calif; A. Bruno, Indiana University Medical Center, Indianapolis, Ind; K. Burkhart, Milton S. Hershey Medical Center, Hershey, Pa; N.R. Cooke, Sacred Heart Medical Center, Spokane, Wash; P. Cullis, Macomb Hospital Center, Warren, Mich; J. Duff, Cox Medical Center, Springfield, Mo; D. Dulli, University of Wisconsin Hospital & Clinics, Madison, Wis; M. Fisher, Los Angeles County & USC Medical Center, Los Angeles, Calif; M. Franklin, St Anthony’s Hospital, St. Petersburg, Fla; K. Gaines, Baptist Memorial Hospital, Memphis, Tenn; F. Gengo, Millard Filmore Hospital, Buffalo, NY; J. Gezon, Salt Lake Regional Medical Center, Salt Lake City, Utah; T. Giancarlo, St. John Hospital & Medical Center, Detroit, Mich; P. Green, Borgress Medical Center, Kalamazoo, Mich; A. Grindal, Sarasota Memorial Hospital, Sarasota, Fla; J. Grotta, University of Texas Health Science Center, Houston, Tex; J.K. Harris, St Mary’s Hospital, Richmond, Va; C. Helgason, University of Illinois at Chicago, Chicago, Ill; B.A. Hendin, Good Samaritan Regional Medical Center, Phoenix, Ariz; D. Heiselman, Akron General Medical Center, Akron, Ohio; J. Hormes, Kennestone Hospital, Marietta, Ga; G. Howell, Munroe Regional Medical Center, Ocala, Fla; T.-L. Hwang, Richland Memorial Hospital, Columbia, SC; M. Jacoby, Mercy Hospital, Des Moines, Iowa; D.G. Jamieson, Pennsylvania Hospital, Philadelphia, Pa; T. Kent, The University of Texas, Galveston, Tex; P. Kershaw, Southampton Hospital, Southampton, NY; L.J. Kinsella, Mt. Sinai Medical Center, Cleveland, Ohio; S.A. Kulick, Staten Island University Hospital, Staten Island, NY; D. Landis, University Hospitals of Cleveland, Cleveland, Ohio; I. Lawver, Dekalb Medical Center, Decatur, Ga; D. Lefkowitz, Bowman Gray/North Carolina Baptist Hospital, Winston-Salem, NC; K. Levin, The Valley Hospital, Ridgewood, NJ; S. Mallenbaum, Virginia Beach General Hospital, Virginia Beach, Va; L.C. Marmion, Butterworth Hospital, Grand Rapids, Mich; G. Marshall, St Mary’s Hospital, Russellville, AR; F.E. McGee, St Mary’s Hospital, Richmond, Va; G. McIntosh, Poudre Valley Hospital, Fort Collins, Colo; J. Mikszewski, Arlington Hospital, Arlington, Va; T. Mirsen, Cooper Hospital/University Medical Center, Camden, NJ; M. Mordes, Saint Joseph Medical Center, Towson, Md; S. Nadis, MacNeal Hospital, Berwyn, Ill; K. Ng, Munroe Regional Medical Center, Ocala, Fla; M. Pessin, New England Medical Center, Boston, Mass; S. Pulst, Cedars-Sinai Medical Center, Los Angeles, Calif; B. Richardson, Alta Bates Medical Center, Berkeley, Calif; M. Rorick, Hartford Research Group, Cincinnati, Ohio; H. Rothschild, Medical Center of Louisiana—Charity Hospital, New Orleans, La; J. Ryals, Parkview Episcopal Medical Center, Pueblo, Colo; M. Rymer, Center for Clinical Neurologic Studies, Kansas City, Mo; R. Sacco, Columbia Presbyterian Medical Center, New York, NY; A. Sama, North Shore University Hospital, Manhasset, NY; D.P. Saur, Overlook Hospital, Summit, NJ; M. Sauter, Westmoreland Regional Hospital, Greensburg, Pa; M.R. Schwartz, Christ Hospital and Medical Center, Oak Lawn, Ill; C. Sheppard, Akron General Medical Center, Akron, Ohio; R. Singer, Westside Regional Medical Center, Plantation, Fla; D.B. Smith, Columbia Swedish Medical Center, Englewood, CO; S. Spencer, Mary Greeley Medical Center, Ames, Iowa; A. Spiegel, Mease Hospital Dunedin, Dunedin, Fla; D. Stein, Sharp Memorial Hospital, San Diego, Calif; S. Thurston, St Mary’s Hospital, Richmond, Va; R. Tieszen, Carraway Methodist Medical Center, Birmingham, Ala; H.M. Todd, North Broward Medical Center, Pompano Beach, Fla; B. Tolge, Ellis Hospital, Schenectady, NY; R. Troiano, Virginia Beach General Hospital, Virginia Beach, Va; M. Tuchman, Palm Beach Gardens Medical Center, Palm Beach Gardens, Fla; F. Vroom, Tallahassee Memorial Regional Medical Center, Tallahassee, Fla; P.A. Walicke, Piedmont Hospital, Atlanta, Ga; W.S. Wiggins, Doylestown Hospital, Doylestown, Pa; B. Woods, Central Texas VA Health Care Center, Temple, Tex.
R. Arts, Royal Victoria Hospital, Barrie, Ontario; N. Bayer, St Michael’s Hospital, Toronto, Ontario; M. Beaudry, Hôpital de Chicoutimi, Chicoutimi, Quebec; S. Bekhor, St Mary’s Hospital Centre, Montreal, Quebec; A. Kertesz, St Joseph’s Hospital, London, Ontario; G. Klein, Rockyview General Hospital, Calgary, Alberta; L. Lebrun, Hôpital St-Luc, Montreal, Quebec; J. Maher, Health Sciences Center, Winnipeg, Manitoba; G. Mohr, Sir Mortimer B. Davis–Jewish General Hospital, Montreal, Quebec; T.P. Seland, Kelowna General Hospital, Kelowna, British Columbia; D. Simard, Hôpital de l’Enfant-Jesus, Quebec City, Quebec; P. Stenerson, University of Alberta, Edmonton, Alberta.
Safety Oversight Committee
H. Adams, University of Iowa, Iowa City, Iowa; C. Hsu, Washington University School of Medicine, St. Louis, Mo; J. Norris, Sunnybrook Hospital, Toronto, Ontario; J. Rothrock, University of South Alabama Medical Center, Mobile, Ala; B. Singh, VA Medical Center West Los Angeles, Los Angeles, Calif; J. Torner, University of Iowa, Iowa City, Iowa.
J. Grotta, University of Texas Health Science Center, Houston, Tex; W. Hacke, University of Heidelberg, Heidelberg, Germany; L. Hantson, Janssen Pharmaceutica, Titusville, NJ.
The author would like to thank Shiferaw G. Mariam, PhD, and Yuh-Wen Soo, PhD, from Janssen Pharmaceutica for statistical assistance and to recognize the contribution of all co-investigators, nurse coordinators, and participating patients and families.
This trial was sponsored by the Janssen Research Foundation, Beerse, Belgium.
↵1 The investigators of the study group are listed in the Appendix.
- Received September 9, 1997.
- Revision received October 13, 1997.
- Accepted October 13, 1997.
- Copyright © 1997 by American Heart Association
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