Background and Purpose Tirilazad mesylate, a nonglucocorticoid 21-aminosteroid lipid peroxidation inhibitor, has shown promise as a neuroprotectant in experimental models of focal cerebral ischemia.
Methods To test whether early treatment with tirilazad, 6 mg/kg per day for 3 days, would improve functional outcome after acute human stroke, 27 North American centers conducted a prospective, randomized, double-blinded, vehicle-controlled trial in patients with acute stroke treated within 6 hours of onset. The primary outcome measures were disability as measured by the Glasgow Outcome Scale and activities of daily living by the Barthel Index determined 3 months after stroke.
Results From May 1993 through December 1994, 660 patients were randomized. The trial was prematurely terminated on the advice of an independent monitoring committee after review of outcome data at a preplanned interim analysis. In 556 fully eligible patients (276 tirilazad, 280 vehicle), the odds ratio of a favorable outcome in favor of tirilazad was 0.87 (95% confidence interval [CI], 0.60 to 1.25) for the Glasgow Outcome Scale and 0.87 (95% CI, 0.60 to 1.25) for the Barthel Index, after adjustment for imbalances between the groups in preexisting disability, prior stroke, and diabetes.
Conclusions These observations suggest that tirilazad, 6 mg/kg per day for 3 days administered beginning at a median of 4.3 hours after stroke, does not improve overall functional outcome.
Cerebrovascular disease, the third leading cause of death and a leading cause of disability in the United States, continues to be a major health concern.1 Ischemia accounts for approximately 80% of all strokes2 and is known to result in oxygen free radical–induced lipid peroxidation, which has been implicated as a contributor to ischemic cell death.3 4
Tirilazad mesylate is a nonglucocorticoid 21-aminosteroid that in vitro has shown activity in inhibiting lipid peroxidation.5 In animals treated within 15 minutes of temporary focal ischemia and within 10 minutes of permanent focal ischemia, there was a reduction in infarct volume compared with that in vehicle-treated animals.6 7 8 9 Human studies have demonstrated that doses up to 6.0 mg/kg per day are generally well tolerated in both volunteers10 11 and patients with acute ischemic stroke.12 The purpose of this study was to determine whether tirilazad given within 6 hours of onset of acute ischemic stroke results in sustained clinical benefit in overall functional outcome at 3 months.
Subjects and Methods
This was a multicenter, randomized, double-blinded, vehicle-controlled trial to evaluate the efficacy and safety of intravenous tirilazad mesylate in patients with acute ischemic stroke. On the basis of eligibility and exclusion criteria, patients for the trial were selected from all patients with acute ischemic stroke admitted to each of 27 participating North American centers (see “Appendix”). The protocol used for the trial was approved by the institutional review board of each participating center. The trial was overseen by an independent safety and monitoring committee appointed by the NINDS.
Eligible patients included those who had a serious neurological deficit due to focal ischemia, could be treated within 6 hours of stroke onset, were 18 years of age or older, were not pregnant if female, and in whom informed consent could be obtained. Subjects were excluded if they had sensory loss, ataxia, or dysarthria alone; coma due to mass effect by CT scan; severe hypertension (mean arterial pressure of >160 mm Hg); seizure at onset; stroke as a complication of a medical or surgical procedure (not including cardiac catheterization or cerebral angiography); hemorrhage on initial CT scan; or severe medical, neurological, or psychiatric illness. Randomization was performed separately for each participating center in blocks of four to ensure approximate balance in ancillary stroke treatments within each treatment group.
To expedite patient treatment, the initial dose of study drug was permitted before completion of the entire eligibility evaluation. After initial screening was performed, laboratory blood work drawn, and informed consent obtained, an initial dose of 150 mg tirilazad mesylate or matching vehicle was administered as a rapid intravenous infusion over 10 to 30 minutes. An emergent head CT scan without contrast was required before administration of subsequent doses. If complete evaluation (including laboratory work, CT scan, and clinical examination) obtained before the second dose was not exclusionary, then the patient was allowed to continue participation in the study. If for any reason the patient was found to be ineligible, subsequent treatment with study drug was terminated, and the patient was followed up for the duration of the study. Subsequent doses of 1.5 mg/kg every 6 hours for 11 additional doses (12 doses total, 6 mg/kg per day) were administered, and then treatment was discontinued.
Patients in the study were managed in an acute-care area in a contemporary fashion according to standard practice in each center. Treatment with corticosteroids and calcium channel blockers and any experimental stroke therapy (including thrombolytic therapy) was prohibited.
The primary outcome measures used in this trial included measures of activities of daily living (BI)13 and disability (GOS)14 obtained at 3 months after stroke. Additional key end points included neurological outcome as measured by the NIH Stroke Scale15 in fully eligible stroke patients and the volume of cerebral infarction measured by a 7- to 10-day follow-up head CT scan in a prospective random sample of 50% of fully eligible subjects. The degree of prestroke disability was estimated, using the GOS, according to the history. For this trial, favorable outcome on the BI was defined as a score of 60 or greater, with dead patients arbitrarily assigned a score of 0. The highest achievable score on the BI is 100; a score of 60 to 100 indicates a range of modest deficits in activities of daily living, whereas scores of 60 or less generally indicate the requirement of full-time nursing care. Favorable outcome on the GOS was defined as an outcome of either good recovery or moderate disability. The total NIH Stroke Scale score produces ordinal scores ranging from 0 (no neurological deficit) to 42 (maximal score or dead) based on the sum of ratings of 13 individual components of a standardized neurological examination. The volume of cerebral infarction was measured centrally by an investigator blinded to treatment group with computerized planimetric techniques.16 Ischemic stroke subtype was determined by the reporting investigators at 7 to 10 days after the entry stroke according to standard criteria.17
The primary win criterion for this trial required that there be a statistically significant (P<.05) benefit in favorable outcome in both the BI and GOS at 3 months in the tirilazad-treated group both for all randomized patients (intent-to-treat) and all fully eligible patients (patients with ischemic stroke meeting all entry criteria). On the assumption that up to 50% of randomized patients might have been excluded before the second dose and that tirilazad had no effect on the outcome of excluded patients, it was estimated that 1130 fully eligible patients (565 in each treatment group) would be necessary to detect an absolute 12-percentage-point improvement in favorable outcome among all randomized tirilazad-treated patients, with α=.05 and power of at least 80%. A prospective random audit of the primary outcome measures was performed in 20% of the fully eligible patients. The audit was performed by central registry staff via telephone contact with the subjects and/or the family within 30 days of the 3-month follow-up evaluation by the center.
A prespecified interim analysis was performed on all 500 patients enrolled in the trial by August 23, 1994. The data were reviewed by the independent Data and Safety Monitoring Committee. Although prespecified termination rules were to be used for both safety and efficacy, the committee also considered a futility analysis using methodology described by Choi and colleagues.18 With the partial data available, these techniques allowed for calculation of a conditional probability of success of finding a positive outcome in favor of tirilazad if the trial was allowed to continue to completion. On the basis of these considerations, on December 8, 1994, the enrollment was prematurely terminated on the recommendation of the Data and Safety Monitoring Committee. The results below describe the data from all patients enrolled in the trial through the date of termination and followed up for 3 months.
Both intent-to-treat and fully eligible analyses were performed. The last observation carried forward was used in the analyses. Comparisons of proportions of baseline factors and safety and efficacy end-point variables between treatment groups were made using a χ2 test for contingency tables. Continuous variables were compared between treatment groups using a one-way ANOVA approach. The NIH Stroke Scale at the baseline and the BI at 3 months were analyzed with a Kruskal-Wallis test. Mortality rates and curves were presented using the Kaplan-Meier product limit method, and the survival curve comparison between treatment groups was performed with the log-rank test. All of the tests were two sided, with a significance level of P=.05 for the baseline factors and mortality, P=.01 for medical events to account for multiple comparisons, and P=.00488 for the efficacy end points at the current sample size, although P=.04512 was to be used if the study went to completion.19 20
Logistic regression was used to adjust for the baseline imbalances between treatment groups for the primary efficacy analysis of GOS and BI at 3 months. The unbalanced factors in the model included prior stroke, diabetes, and prestroke disability. The vehicle group was considered as the reference group.
From May 1993 through December 1994, trial subjects were selected from a total of 3853 patients admitted within 12 hours of stroke onset registered in the combined stroke logs of the centers. The most frequent reasons for initial exclusion were time from stroke onset greater than 6 hours (36%), transient deficit (12%), severe complicating illness (9%), and hemorrhagic stroke (8%). A total of 660 patients (329 vehicle-treated and 331 tirilazad-treated) were randomized and included in the intent-to-treat analysis. Thirty patients (11 vehicle and 19 tirilazad) were excluded before dose administration. Of those who received treatment, 556 (280 vehicle and 276 tirilazad) were fully eligible and 104 (49 vehicle and 55 tirilazad) were subsequently excluded. The reasons for exclusion in each treatment group are detailed in Table 1⇓.
The two treatment groups had similar baseline characteristics (Table 2⇓) in both the randomized and fully eligible analyses, with the exception of the frequency of a history of previous stroke, diabetes mellitus, or prestroke disability, all of which were higher in the tirilazad group.
Compliance with the study protocol and data quality were excellent. A prospective random audit of 3-month outcome in 20% of the randomized subjects revealed a 96% agreement rate for favorable outcome on the GOS and 97% agreement for favorable outcome on the BI. There was no difference in the frequency of major protocol violations between groups (6% vehicle and 5% tirilazad). A total of 19 patients were lost to follow-up (9 vehicle and 10 tirilazad), 15 of whom were fully eligible (6 vehicle, 9 tirilazad). There was no significant difference in the proportion of patients evaluated at 91±15 days (3-month medical window) in each group (vehicle 89.6% and tirilazad 88.5%).
Table 3⇓ summarizes the 3-month outcome data for both the GOS and the BI. In both the randomized and the fully eligible groups, no statistically significant difference in the proportion of patients with favorable outcome by the GOS or BI was found. The odds ratio of a favorable outcome for fully eligible patients in the tirilazad group was 0.87 (95% CI, 0.60 to 1.25) for the GOS and 0.87 (95% CI, 0.60 to 1.25) for the BI after adjustment for imbalances between groups in preexisting disability, prior stroke, and diabetes mellitus. The results were similar among men and women (data not shown).
Median NIH Stroke Scale scores of fully eligible patients were not statistically different between the two groups at 7 to 10 days (vehicle: median=4, IR of 1 to 11; tirilazad: median=4, IR of 1 to 12) or at 3 months (vehicle: median=2, IR of 0 to 11; and tirilazad: median=3, IR of 0 to 13). Median CT infarct volumes also were not significantly different between the groups (vehicle: 35.4 cm3, IR of 4.8 to 126.2; tirilazad: 26.4 cm3, IR of 8.8 to 77.6). There were also no differences between groups regarding ancillary stroke treatment (eg, heparin, aspirin, surgery, and rehabilitation).
Of those who were fully eligible, 263 (93.9%) of the vehicle group and 252 (91.3%) of the tirilazad group completed the planned dosing schedule, which was defined as receiving at least 10 doses. Discontinuation of study medication due to a serious medical event or death occurred in 5 (1.8%) of the vehicle group and 12 (4.4%) of the tirilazad group. Crude mortality rates (for the 3-month medical window) were not statistically significantly different between the two groups (13.7% vehicle and 15.1% tirilazad) nor were estimated mortality rates (17% vehicle and 17% tirilazad) as determined by Kaplan-Meier survival estimates.
The most common serious medical events (ie, life-threatening or prolonging hospitalization) are summarized in Table 4⇓. None of the serious medical events were significantly more common in the tirilazad group. Infusion-site disorders were reported in 59% of tirilazad patients and 49% of vehicle patients (not significant). Study drug was prematurely terminated because of infusion-site disorders in 0.4% of tirilazad patients and none of vehicle patients. No significant differences between groups were detected in the proportion of reports of other adverse medical events, abnormal laboratory values, or vital signs.
At the prospectively planned interim analysis, the calculated conditional probability of success in favor of tirilazad in fully eligible subjects was .0006 if the trial was carried to completion. Further enrollment in the trial was therefore discontinued. The final data agreed with the interim results and suggest that tirilazad, 6 mg/kg per day administered for 3 days beginning a median of 4.3 hours after the onset of stroke, does not improve functional outcome at 3 months in patients with acute ischemic stroke.
No serious safety concerns were noted during this trial. Although mild-to-moderate injection-site complications were relatively frequent, they were easily managed, and overall the dose of 6 mg/kg per day of tirilazad was well tolerated when given through a peripheral line. There was no evidence of significant cardiotoxicity in the tirilazad-treated patients or any effect on level of consciousness, blood pressure, or laboratory assays.
The end points chosen for use in this trial, ie, favorable outcome by the GOS and BI, appear to have several advantageous features. First, measurements from both clinical scales were reliable in a population of acute stroke patients seen in late follow-up. The prospective, concurrent, independent audit of 3-month outcomes in this trial found agreement rates in excess of 95% for favorable outcome with both scales. Second, the concern regarding the requirement of positive results in favor of tirilazad for both scales seems to be minimized by the very high correlation between the measures (r=.88, Spearman's). A measure of confidence is provided for the results, since favorable outcome is assessed not only by a measure of global disability (the GOS) but also of activities of daily living (the BI). Finally, the approximately 70% favorable outcome rate observed in the vehicle group, despite enrollment of many patients with mild strokes in the trial, provides assurance that a significantly improved outcome, if present from an effective therapy, would be measurable. A 10-percentage-point improvement in favorable outcome would only raise the rate to 80%, a clinically reasonable outcome for an effective treatment.
This trial used potentially useful methodology for enhancing decision making regarding trial continuation in the setting of incomplete sample sizes.18 Although neither of the traditional (Lan-DeMets)20 boundaries for safety or efficacy were crossed, the very low likelihood of a positive outcome in favor of tirilazad if the trial was allowed to go to completion was influential in the Data and Safety Monitoring Committee's decision to recommend that the trial be discontinued. Similar approaches to the question of futility at interim end points may prove to be useful in other clinical stroke trials in the future.
Selected Abbreviations and Acronyms
|GOS||=||Glasgow Outcome Scale|
|NIH||=||National Institutes of Health|
|NINDS||=||National Institute of Neurological Disorders and Stroke|
University of Michigan (Ann Arbor), St Joseph Mercy Hospital, William Beaumont Hospital—Principal Investigators: Phillip Scott, MD; William Barsan, MD. Clinical Coordinator: Shirley Frederiksen, RN. Coinvestigators: Steven Kronick, MD; Brian J. Zink, MD; Robert M. Domeier, MD; James C. Mitchiner, MD; Frank P. Judge, MD; Robert J. Levy, MD; Anastasios Alexiou, MD; Hanna Reincke, MD; John D. Segall, MD; Brad Walters, MD; Robert Swor, DO; John Gilroy, MD; Mark Goetting, MD; Raymond Jackson, MD; Daniel Richardson, MD; Jim Cisek, MD; Julia Randall, MD; Steven Schecter, MD; Keith Wilkinson, MD; Bradford L. Walters, MD, FACEP.
Medical College of Georgia (Augusta)—Principal Investigator: Robert Adams, MD. Clinical Coordinator: Elizabeth Carl, CRA. Coinvestigators: Fenwick Nichols, MD; David Hess, MD; Brad Boop, MD.
Johns Hopkins Bayview Medical Center (Baltimore, Md)—Principal Investigator: Christopher Earley, MD. Clinical Coordinator: Donna Rae Smith, RN. Coinvestigators: Peter Kaplan, MD; Constance Johnson, MD; Christopher Morrow, MD; Elliott Frohman, MD; Neil Porter, MD; Kevin Flanigan, MD; Lewis Morganstern, MD; Neil Holland, MD; Alan Stein, MD; Eric Aldrich, MD; George Oyler, MD.
University of Alabama (Birmingham)—Principal Investigator: Edward Faught, MD. Clinical Coordinator: Vicki Mitchell, RN. Coinvestigators: Howard Liu, MD, PhD; Frank Thomas, MD; David Wenzel, MD; Badr Mustafa Dajani, MD; Julie Pan, MD; Robert Yapundich, MD; Yoshio Futatsugi, MD; Susan Geerlings, MD; Tal Moskowitz, MD; Anthony Nicholas, MD; John Brockington, MD; Anthony Collins, MD; J. Mark Bailey, DO, PhD; Anna Tseng, MD.
Massachusetts General Hospital (Boston)—Principal Investigator: Walter J. Koroshetz, MD. Clinical Coordinators: Ufuk Can, MD; Anna Felix, MD. Coinvestigators: M. Cudkowticz, MD; F. Buonanno, MD; L. Schwamm, MD; M. Elkind, MD; J.P. Kistler, MD; S. Finkelstein, MD; J. Cha, MD; S. Murphy, MD; H. Blumenfeld, MD; M. Lopez-Bresnahan, MD; U. Can, MD; K. Goslin, MD; S. Cramer, MD; N. Suwanwela, MD.
Northwestern University Medical School (Evanston, Ill), Evanston Hospital, Glenbrook Hospital—Principal Investigator: Daniel Homer, MD. Clinical Coordinator: Jackie Carpenter, RN.
Sinai Hospital at Baltimore, Md—Principal Investigator: Robert Wityk, MD. Clinical Coordinator: Nancy Michel, PA. Coinvestigators: S. Grufferman, MD; B. Litt, MD; H. Weiss, MD.
Wayne State University (Detroit, Mich), Detroit Receiving Hospital—Principal Investigators: Anne Guyot, MD; Patti Peterson, MD. Clinical Coordinators: Linda Tvardek, RN; Julie Schmidt, RN. Coinvestigators: Aashish Deshpande, MD; Walid Freij, MD; Balbir Gandhi, MD; Farah Minhas, MD; Jagdish Shah, MD; Cesar Zahka, MD.
University of Alberta (Edmonton, Canada), MacKenzie Health Science Center—Principal Investigator: Andrew Penn, MD. Clinical Coordinators: Judy Sherman, RN; Yu-Ling Li, RN. Coinvestigators: M.G. Elleker, MD; P. Stenerson, MD; H. Brooke, MD; Mohammed Al-Jumah, MD; Hassan Al-Ayafy, MD; Robert Pokroy, MD; Barbara Hoppe, MD.
Indiana University (Indianapolis), Wishard Memorial Hospital—Principal Investigators: Robert Pascuzzi, MD; Martin Farlow, MD. Clinical Coordinators: Debbie Rightmyer, RN; Marsha Bales, RN; Judy Caress, RN.
University of Kentucky (Lexington), VA Medical Center—Principal Investigator: Creed Pettigrew, MD. Clinical Coordinators: Charlotte Waugh, RN; Anna Rockich, RPH. Coinvestigators: Robert Fallis, MD; Alex Tikhtman, MD.
University of California at Los Angeles, University of California at Los Angeles Medical Center, Santa Monica Hospital—Principal Investigator: Sidney Starkman, MD. Clinical Coordinator: Glenn Schubert, MPH. Coinvestigators: B. Dobkin, MD; N. Martin, MD; J. Saver, MD.
Park Nicollet Medical Foundation (St Louis Park, Minn), Fairview Southdale Hospital, Methodist Hospital—Principal Investigator: Sandra Hanson, MD. Clincial Coordinator: Ann Weaver, RN. Coinvestigators: Karen Porth, MD; Rafael Magana, MD; John Davenport, MD; Frederick Taylor, MD; Danial Freking, MD; Deborah Olin Heros, MD; Eric Schnek, MD.
Medical College of Pennsylvania (Philadelphia)—Principal Investigator: Milton Alter, MD. Clinical Coordinators: Rodrigo Ribeiro, MD; Mary Lloyd, RN. Coinvestigators: Steven Scheiner, MD; Arthur Puff, MD; Sherry Boyle, MD; Neena Gupta, MD; Kellie White, MD; Sharon Carney, MD; Michael Moulton, MD; Samual LaCapra, MD; David Hassard, MD; S. Rizwan, MD; A. Shah, MD; Arthur Newmark, MD; Asha Gupta, MD; David Cone, MD; Iqbal Khan, MD; Beth Cohen, MD; Rosie Bopari, MD; John O'Connell, MD; Aatif Hussian, MD; Kishor Patil, MD; Jalil Shojari, MD; Rodrigo Ribeiro, MD.
Jefferson Medical College (Philadelphia, Pa), Thomas Jefferson University Hospital—Principal Investigators: Rodney Bell, MD; Daniel Gzech, MD. Clinical Coordinators: Toby Mazer, MPH; Jill Grothusen, RN. Coinvestigators: P. Reyes, MD; J. Arastu, MD; T. Strassburger, MD; C. Thomas, MD; R. Wolfe, MD; J. Fang, MD; M. Scavina, MD; W. Wolfe, MD; D. Zeidwerg, MD; J. Chavin, MD; O. Shachar, MD; L. Sandler, MD; D. McGarren, MD.
Pennsylvania Hospital (Philadelphia)—Principal Investigator: Dara G. Jamieson, MD. Clinical Coordinator: Concetta Gonnella, COA. Coinvestigators: Thomas M. Bosley, MD; Debra Ann Pollack, MD; John C. Andrefsky, MD; S. Hariharan, MD; Andrew Chang, MD; Marian P. Lamonte, MD; Joseph Champellone, MD; Henry C. Hooker, MD; Jonathan Fellus, MD; Veronica Sosa, MD; Stephanie Raaf, MD; Mark Friedman, MD.
Roanoke Neurological Associates, Community Hospital of Roanoke Valley, Roanoke Memorial Hospital (Va)—Principal Investigator: Gordon Burch, MD. Clinical Coordinators: Donna Atkins, RN; Candy Foley, RN. Coinvestigators: D. Bivins, MD; W. Elias, MD; D. Nolan, MD; M. Sisk, MD; J. Wilson, MD; A. Lloyd, MD; G. Stephens, MD; R. Surrusco, MD; C. Lothes, MD; W. Humphries, MD; S. Pastemak, MD; M. Donato, DO; E. Manetta, MD; J. Mitchell, MD; A. Briggs, MD; M. Rorrer, MD; P. Offermann, MD; W. Grover, MD; B. Bolton, MD.
University of California at San Diego, Veterans Administration Medical Center, Scripps Memorial Hospital—Principal Investigator: Patrick Lyden, MD. Clinical Coordinators: Stacy Lewis, RN; Karen Rapp, RN. Coinvestigators: M. Brody, MD; J. Rothrock, MD; C. Jackson, MD; P. Huott, MD; C. Kushida, MD; J. Liss, MD; R. Zweifer, MD; L. Caylor, MD; D. Phan, MD; Z. Mahdavi, MD; T. Tom, MD; H. Noack, MD; G. Forde, MD.
Lions Gate Hospital (North Vancouver, BC, Canada)—Principal Investigator: Donald Cameron, MD. Clinical Coordinator: Barbara Griesdale, RN. Coinvestigators: Vance Makin, MD; C.B. Bozek, MD.
Winchester Medical Center (Winchester, Va)—Principal Investigator: George Sheppard, MD. Clinical Coordinator: Sandra Massey, RN. Coinvestigators: David Zontine, MD; Neil Crowe, MD; Katherine Gustin, MD; Patrick Capone, MD.
Foothills Hospital (Calgary, Alberta, Canada)—Principal Investigator: Thomas E. Feasby, MD. Clinical Coordinator: Carolyn Robertson, RN.
Case Western Reserve University (Cleveland, Ohio), MetroHealth Medical Center—Principal Investigators: Mark Rorick, MD; Marc Winkelman, MD. Clinical Coordinator: Alice Liskay, RN, BSN. Coinvestigators: James Schmidley, MD; Monroe Cole, MD; Mohammed Al-Jaberi, MD; Angela Anagnos, MD; Mary Anderson, MD; Cynthia Bamford, MD; Eric Frederickson, MD; Jacob Gordon, MD; Steven Grosser, MD; Adriana Kori, MD; Andrew Kuntz, MD; Mohamed Murad, MD; Wassim Nasreddine, MD; Allen Pettee, MD; Naji Riachi, MD; Howard Schecht, MD; John Stahl, MD; Jason Soriano, MD; Joshua Sunshine, MD; Jose Suarez, MD; Joel Vandersluis, MD; Yahya Al-Lanham, MD; Amani Ramahi, MD.
Royal University Hospital (Saskatchewan, Canada)—Principal Investigator: Ashfaq Shuaib, MD. Clinical Coordinator: Edina Kadribasic, RN. Coinvestigator: Bradley Stewart, MD.
Hopital de Chicoutimi (Chicoutimi, Quebec, Canada)—Principal Investigator: Michel Beaudry, MD. Clinical Coordinator: Doris Boivin, RN.
St Alphonsus Medical Center (Boise, Idaho)—Principal Investigator: George Lyons, MD. Clinical Coordinator: Renae L. Dougal, RN.
Fairfax Hospital (Fairfax, Va)—Principal Investigator: James P. Simsarian, MD. Clinical Coordinator: Mary McGarvey, RN. Coinvestigators: D. Grass, MD; L. Sigmund, MD; R. Kurtzke, MD; L. Eberly, MD; D. Lipps, MD.
Hoosier Neurology Group, Methodist Hospital, Indianapolis, Ind—Principal Investigator: James T. Fesenmeier, MD. Clinical Coordinator: Kathy Viater, RN. Coinvestigators: R. Alonzo, MD; W. Cooper, MD; J. Scott, MD; P. Bustion, MD; J. Pappas, MD; M. Frazer, MD.
Virginia Neurological Institute, Neuroclinical Trials Center (Charlottesville, Va)—Principal Investigator: E. Clarke Haley, Jr, MD. Project Director: Wayne Alves, PhD. Coinvestigators: Neal F. Kassell, MD; Karen C. Johnston, MD; Gwen Ford, MD; Nina Solenski, MD.
Project Manager: Don L. Shreve, BBA. Project Clinical Coordinator: Sandra S. Wilkinson, RN, BSN. Clinical Coordinators: Stella Clements, RN; Elizabeth Cuccia, RN, MHM; Lori Elder, RN, BSN; Margaret Keller, RN, BSN; Rita Lackey, RN; Karen Mimms, RN; Pat Protzman, RN; Lynda Sparrow, RN, BSN. Data Manager: Angela Lightfoot, BS. Programming: A. Eugene Lightfoot, BS; Benedict E. Bocchicchio, MA; Patricia Halley, BS. Image Analysts: Angela Polin, BS; Richard Polin, MD. Senior Biostatistician: Lie-Ju Hwang, PhD. Statisticians: Mark C. Wolf, PhD; Laura L. Truskowski, MS. Data Technology: Carolyn Galbrieth, RN, BSN; Reginald Johnson; Sheila Johnson; Charlene Hill; Belinda Wilson; Annie Bartley; Gabriele Ford; Mike Rumfelt; Valerie Wingate; Mike Smith; Tracy Childress.
NINDS Data and Safety Monitoring Board
William J. Powers, MD (Chair), Washington University School of Medicine, St Louis, Mo; Michael Walker, MD (ex officio), Division of Stroke and Trauma, NINDS, Bethesda, Md; Joseph L. Fleiss, PhD, Columbia University, New York (NY); Michael Frankel, MD, Emory University, Atlanta, Ga; Roger P. Simon, MD, University of Pittsburgh (Pa).
Medical Officer, NINDS
John Marler, MD, Bethesda, Md.
RANTTAS Advisory Committee Members
Harold P. Adams, Jr, MD (Chair), University of Iowa Hospitals (Iowa City); Thomas G. Brott, MD, University of Cincinnati Medical Center (Ohio); Sung Choi, PhD, Medical College of Virginia (Richmond); John F. Kurtzke, MD, Veteran's Administration Hospital, Washington, DC; James C. Torner, PhD, University of Iowa (Iowa City).
The Upjohn Company, Kalamazoo, Mich
United States—Medical Clinical Monitor: Gary R. Peters, MD. Clinical Trials Specialists: Susan Eckert, RN; William J. Bryan, MS.
Canada—Clinical Research Director: Monica L. Bologa, MD. Clinical Trials Specialist: Denise Legace, RN.
Medical and Technical Research Associates Inc (MTRA), Boston, Mass
Clinical Projects Manager: Karen M. Brennan, RN, and staff.
This trial was supported by grants from the Upjohn Company (Kalamazoo, Mich) and the National Institutes of Health—National Institute of Neurological Disorders and Stroke (R01-NS31554).
The Investigators and Participating Centers are listed in the Appendix.
- Received April 26, 1996.
- Revision received May 31, 1996.
- Accepted June 4, 1996.
- Copyright © 1996 by American Heart Association
Wolf PA, Cobb JL, D'Agostino RB. Epidemiology of stroke. In: Barnett HJ, Mohr JP, Stein BM, Yatsu FM, eds. Stroke Pathophysiology, Diagnosis, and Management. New York, NY: Churchill Livingstone Inc; 1992:3-27.
Hall ED, McCall JM, Means ED. Therapeutic potential of the lazaroids (21-aminosteroids) in acute central nervous system trauma, ischemia and subarachnoid hemorrhage. Adv Pharmacol. 1994;28:221-267.
Silvia RC, Piercey MF, Hoffman WE, Chase RL, Tang AH, Brughler JM. U-74006F, an inhibitor of lipid peroxidation, protects against lesion development following experimental stroke in the cat: histologic and metabolic analysis. Soc Neurosci Symp. 1987;13:1499. Abstract.
Young W, Wofak JC, Decrescito V. Aminosteroid lipid peroxidation inhibitor reduces ion shifts and edema in the rat middle cerebral artery occlusion model of regional ischemia. Stroke. 1988;19:1013-1019.
Lythgoe W, Little RA, O'Shaughnessy CT, Steward MC. Effect of U74006F on oedema and infarct volumes following permanent occlusion of the middle cerebral artery in the rat. Br J Pharmacol. 1990;100:454P. Abstract.
STIPAS Investigators. Safety study of tirilazad mesylate in patients with acute ischemic stroke (STIPAS). Stroke. 1994;25:418-423.
Mahoney FT, Barthel DW. Functional evaluation: Barthel Index. Md Med J. 1965;14:61-65.
Brott T, Adams HP Jr, Olinger CP, Marler JR, Barsan WG, Biller J, Spilker J, Holleran R, Eberle R, Hertzberg V, Rorick M, Moomaw CJ, Walker M. Measurements of acute cerebral infarction: a clinical examination scale. Stroke. 1989;20:864-870.
Brott T, Marler JR, Olinger CP, Adams HP Jr, Tomsick T, Barsan WG, Biller J, Eberle R, Hertzberg V, Walker M. Measurements of acute cerebral infarction: lesion size by computed tomography. Stroke. 1989;20:871-875.
Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE III. Classification of subtype of acute ischemic stroke: definitions for use in a multicenter clinical trial, TOAST: Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993;24:35-41.
Reboussin DM, DeMets DL, Kim K, Lan KKG. Programs for computing group sequential bounds using the Lan-DeMets method. Biostatistics Technical Report No. 60. Washington, DC: George Washington University; June 22, 1992.