Phase IIB/III Trial of Tenecteplase in Acute Ischemic Stroke
Results of a Prematurely Terminated Randomized Clinical Trial
Background and Purpose— Intravenous alteplase (rtPA) remains the only approved treatment for acute ischemic stroke, but its use remains limited. In a previous pilot dose-escalation study, intravenous tenecteplase showed promise as a potentially safer alternative. Therefore, a Phase IIB clinical trial was begun to (1) choose a best dose of tenecteplase to carry forward; and (2) to provide evidence for either promise or futility of further testing of tenecteplase versus rtPA. If promise was established, then the trial would continue as a Phase III efficacy trial comparing the selected tenecteplase dose to standard rtPA.
Methods— The trial began as a small, multicenter, randomized, double-blind, controlled clinical trial comparing 0.1, 0.25, and 0.4 mg/kg tenecteplase with standard 0.9 mg/kg rtPA in patients with acute stroke within 3 hours of onset. An adaptive sequential design used an early (24-hour) assessment of major neurological improvement balanced against occurrence of symptomatic intracranial hemorrhage to choose a “best” dose of tenecteplase to carry forward. Once a “best” dose was established, the trial was to continue until at least 100 pairs of the selected tenecteplase dose versus standard rtPA could be compared by 3-month outcome using the modified Rankin Scale in an interim analysis. Decision rules were devised to yield a clear recommendation to either stop for futility or to continue into Phase III.
Results— The trial was prematurely terminated for slow enrollment after only 112 patients had been randomized at 8 clinical centers between 2006 and 2008. The 0.4-mg/kg dose was discarded as inferior after only 73 patients were randomized, but the selection procedure was still unable to distinguish between 0.1 mg/kg and 0.25 mg/kg as a propitious dose at the time the trial was stopped. There were no statistically persuasive differences in 3-month outcomes between the remaining tenecteplase groups and rtPA. Symptomatic intracranial hemorrhage rates were highest in the discarded 0.4-mg/kg tenecteplase group and lowest (0 of 31) in the 0.1-mg/kg tenecteplase group. Neither promise nor futility could be established.
Conclusion— This prematurely terminated trial has demonstrated the potential efficiency of a novel design in selecting a propitious dose for future study of a new thrombolytic agent for acute stroke. Given the truncation of the trial, no convincing conclusions can be made about the promise of future study of tenecteplase in acute stroke.
To date, the only approved treatment for acute ischemic stroke is intravenous recombinant tissue plasminogen activator (alteplase, rtPA). Despite extensive efforts, implementation of this treatment has been limited, largely because of the narrow time limits within which treatment must be delivered, but also due to concerns regarding adverse bleeding risk.1 Development of an alternative thrombolytic therapy that might be easier and safer to administer could lead to wider acceptance and use of thrombolytic therapy for stroke.
Tenecteplase is a modified version of rtPA that is more fibrin-specific and has a longer half-life and can thus be administered as an intravenous bolus. It has been approved for use in myocardial infarction, in which it is associated with fewer systemic bleeding complications than alteplase.2 A dose-escalation safety study of tenecteplase in patients with acute ischemic stroke observed no symptomatic intracranial hemorrhages (ICHs) among 75 patients treated with doses ranging from 0.1 mg/kg to 0.4 mg/kg.3 Although 3-month outcomes were similar to patients treated with alteplase in the National Institute of Neurological Diseases and Stroke rtPA Stroke Trial, the results at 24 hours indicated that there may be important differences in the clinical activity of the tested doses. The proportion of patients with major neurological improvement at 24 hours was an absolute 20% higher in the 0.1-mg/kg group than at the highest safe dose tested, 0.4 mg/kg, suggesting the possibility of an inverse dose response. Further dose comparisons were considered prudent.
Based on these encouraging results, we designed an innovative, seamless, Phase IIB/III, randomized, multicenter, double-blind trial of intravenous tenecteplase versus standard-dose rtPA in patients with acute ischemic stroke within 3 hours of onset. We report here the results of the trial, which was prematurely terminated during Phase IIB due to slower than expected enrollment.
Phase IIB of the trial had 2 goals: (1) to use an efficient statistical strategy to select a “best” dose of tenecteplase for acute stroke using an early (24-hour) clinical outcome; and (2) to decide whether further comparison of these interventions was promising or futile by comparing the selected tenecteplase dose with standard-dose rtPA using safety and longer-term (3-month) efficacy outcomes. If tenecteplase proved promising, then Phase III provided for a pivotal randomized trial comparing the selected tenecteplase dose with rtPA for 3-month clinical outcome.
A complete description of the design will be published elsewhere. Summarizing the major features, the dose-selection component of Phase IIB compared 3 tenecteplase doses: 0.1 mg/kg, 0.25 mg/kg, and 0.4 mg/kg. A rapid-response outcome score was assigned at 24 hours as follows. Patient status was scored: 0 (worst), 1, or 2 (best) on a composite measure that balanced Major Neurological Improvement (MNI)4 against risk of symptomatic ICH. A symptomatic ICH was scored 0. MNI, defined as a ≥8-point improvement compared with baseline, or a score of 0, on the National Institutes of Health Stroke Scale5 at 24 hours, was scored 2. A patient without either symptomatic ICH or MNI, or with both, was scored 1. Inferior dose arms were to be eliminated by a sequential selection procedure. Patients were randomized within sites to quadruplets—1 of the 3 tenecteplase doses or rtPA—but only the triplet tenecteplase arms were involved in the selection procedure. (The patients receiving rtPA provided concurrent randomized controls for later comparisons of 3-month outcome with the selected tenecteplase dose.) Whenever a tenecteplase triplet completed 24-hour follow-up, the cumulative sum of the scores for each of the tenecteplase doses on the rapid-response outcome was calculated. A dose was eliminated when this cumulative score first fell 6 points behind the cumulative score of the leading dose. This criterion provided a probability of at least 80% of correctly selecting the best tenecteplase dose if the true absolute difference between it and the 2 inferior doses was ≥10% on MNI given a symptomatic ICH probability of 0.06 for each dose. Given the selection procedure, the sample size for Phase IIB was variable. The distribution of the number of patients needed was relatively narrow with a mean of 278 and a SD of 50. A maximum sample size of 600 patients for the Phase IIB portion was pre-established.
Once the tenecteplase dose was selected, randomization between that dose and rtPA controls was to continue until at least 100 patients in each group had been randomized. At that point, an interim analysis would be performed. To avoid the low statistical power of a traditional hypothesis test with 100 patients in each group, we prespecified clinically meaningful decision rules that would lead to a clear recommendation to consider the preliminary results either sufficiently or insufficiently promising to continue. These rules combined symptomatic ICH rates at 24 hours and rates of poor outcome at 3 months using the primary outcome measure for Phase III. This was the modified Rankin Scale,6 trichotomized into the ordered categories “good” (Rankin=0 or 1), “intermediate” (Rankin=2 or 3), or “poor” (Rankin=4, 5, or 6 [death]). For example, if the selected dose of tenecteplase showed a lower symptomatic ICH rate than rtPA, defined as at least 2 fewer symptomatic ICHs, we would declare it promising if the observed proportion of patients with poor 3-month outcome was less than or equal to that of rtPA (Scenario 1). In Scenario 2, if the rate of symptomatic ICH within 24 hours for tenecteplase was effectively the same (ie, ±1) as that for rtPA, then the proportion of poor outcomes on the 3-month Rankin Scale would have needed to be at least 8 percentage points lower than that of patients with rtPA for further study of tenecteplase to be declared promising. Additionally, if the proportion of good outcomes for tenecteplase was significantly less than the proportion of good outcomes with rtPA at the nominal 2-tailed 0.001 level in either scenario, then further study of tenecteplase would be declared futile. If the selected tenecteplase dose had ≥2 symptomatic ICHs than rtPA at the interim analysis, then the research would stop. Simulations showed that the operating characteristics of these decision rules, taken together, may be regarded as a second “selection procedure.” That is, there was a calculated >85% probability of correct selection (either continue or discontinue) using the design parameters.
If Phase IIB showed promise, Phase III would continue the trial with additional clinical sites to test 2 coprimary null hypotheses comparing tenecteplase and rtPA on the trichotomized 3-month Rankin: (1) the proportion of poor outcomes with tenecteplase treatment at the selected dose does not differ from the proportion of poor outcomes with rtPA treatment; and (2) the proportion of good outcomes with tenecteplase treatment at the selected dose does not differ from the proportion of good outcomes with rtPA treatment.
Each hypothesis was to be tested at α=0.025, 2-tailed, using the site-stratified Mantel-Haenszel 1 degree of freedom procedure with ½ continuity correction. The planned sample size was 1908 (954 per group). This provided 90% power to detect a ≥8% reduction in poor outcome without a reduction in good outcome or 89% power to detect an 8% increase in good outcome without an increase in poor outcome.
The premature termination of the trial precluded the planned comparisons of the selected dose of tenecteplase to rtPA for promise or futility as well as the full Phase III trial. A new “postspecified” analysis plan was developed by the investigators and approved by the trial Data and Safety Monitoring Board after the termination but before breaking the blind and before analysis of any efficacy data. The analysis plan compared the proportions of the 3 tenecteplase groups separately and combined with the rtPA group, first on the good outcome (Rankin 0 to 1) and then on the poor outcome (Rankin 4 to 6) using Mantel-Haenszel tests. Given the fact that the original analysis plan was not followed and that the presented analysis is exploratory, nominal probability values were calculated without taking into account the multiple comparisons; no prespecified level of significance was set. All outcome analyses are by treatment assignment (intent-to-treat).
The protocol and consent forms were reviewed and approved by the Institutional Review Board of each participating institution. Eligible patients were aged ≥18 years with serious neurological deficits believed to be on the basis of acute focal cerebral ischemia and who were otherwise suitable for treatment with intravenous rtPA within 3 hours of stroke onset using contemporary guidelines.7 After informed consent was obtained, a web-based randomization method provided a treatment assignment to an unblinded investigative pharmacist at the site, who then prepared 0.1 mg/kg, 0.25 mg/kg, or 0.4 mg/kg of tenecteplase to be administered in 10 mL of normal saline as a bolus followed by 90 mL of normal saline administered over 1 hour or 0.9 mg/kg of rtPA with 10% of the total dose administered in 10 mL as a bolus followed by the remaining 90% in 90 mL of normal saline administered over 1 hour. Treating physicians, staff, and investigators as well as trial patients remained blinded to the identity of the study drug throughout. A baseline National Institutes of Health Stroke Scale was performed immediately before initiation of the study drug in each patient to confirm continued eligibility in the trial. Patients whose deficits had cleared or who had become otherwise ineligible in the interval between treatment assignment and actual treatment were considered to be “enrolled” but were not “randomized” or included in the analyses. Reasons for exclusion of enrolled but not randomized patients were recorded.
Randomized patients were managed in an intensive care or acute stroke unit for 24 hours after treatment using standard guidelines for postthrombolytic stroke treatment. A follow-up National Institutes of Health Stroke Scale examination was performed at 24±2 hours after stroke onset, and a noncontrast head CT scan was performed at 48±6 hours after treatment to assess for asymptomatic intracranial bleeding. If neurological worsening occurred, then a head CT scan was performed and the primary and contributing causes of the neurological worsening were recorded. Neurological worsening was defined as any clinically significant neurological change (appearance of a new deficit or worsening of previous deficits) that persisted for >8 hours. All CT scans (both baseline and follow-up) were sent to the Clinical Coordinating Center for interpretation blinded to treatment assignment by a study neuroradiologist who independently judged whether the scan depicted ICH. If hemorrhage was present on any follow-up scan, the entire case was referred to an independent blinded clinical neurologist who adjudicated whether the hemorrhage was symptomatic or asymptomatic. A symptomatic ICH was defined as any clinically important neurological worsening (ie, meeting neurological worsening criteria, see previously) attributable to new hemorrhage seen on a follow-up head CT scan. Confluent hematoma occupying greater than one third of the infarct volume and exerting space-occupying effects and intraventricular or subarachnoid extension of blood were considered strongly, but the decisions of the neurological adjudicator were final. Symptomatic ICHs that became symptomatic within 24 hours of treatment were considered potentially attributable to the study drug.
Safety was overseen by an independent Medical Monitor and Data and Safety Monitoring Board. The Data and Safety Monitoring Board was also charged with reviewing the progress of the selection procedure, protecting the integrity of the trial, and reviewing the results of the analysis for promise or futility.
From March 2006 through December 2008, 112 patients were randomized into the trial at 10 hospitals in 8 clinical centers (see the Appendix). One patient was randomized to rtPA but received 0.25 mg/kg tenecteplase, and 1 was randomized to 0.25 mg/kg tenecteplase but received 0.7 mg/kg tenecteplase. The remaining 110 patients received the assigned medication and dose. Seventeen additional patients received a provisional treatment assignment but were excluded before final eligibility determination. Seven became ineligible because of deficit resolution; drug was not available in time for 8; and 2 withdrew consent before treatment.
Table 1 shows the baseline characteristics and ischemic stroke subtypes (by TOAST criteria8 at 7 to 10 days following the entry stroke) by treatment group. The patients randomized to rtPA were older and had more severe stroke deficits at baseline than patients in the tenecteplase groups. Four patients (2 in the 0.1 mg/kg tenecteplase group, and 2 in the rtPA group) were determined to have had conversion disorders, hyperglycemia, or migraine as the cause of their acute neurological deficits. All 4 had complete resolution of their acute deficits.
The results of the tenecteplase dose selection procedure are depicted in the Figure. The 0.4-mg/kg dose fell 6 points behind the leading dose (0.25 mg/kg) after 14 triplets of patients on tenecteplase completed 24-hour follow-up. The 0.4-mg/kg dose was therefore eliminated and randomization to it discontinued. Randomization continued to 0.1 mg/kg tenecteplase, 0.25 mg/kg tenecteplase, or 0.9 mg/kg rtPA. When the trial was terminated after 112 patients had been randomized, the cumulative difference between the 2 remaining tenecteplase doses had, at times, reached as many as 4 points, but not the 6 needed to reach the dose selection criterion.
Data were collected for 5 additional patients on 0.4 mg/kg tenecteplase beyond the 14 used to eliminate that dose. Four were patients who had already been randomized to triplets that remained open, and therefore unanalyzed, when the 0.4-mg/kg dose was eliminated. The fifth was the only patient randomized at a site that was subsequently closed. The data from these patients did not contribute to the decision to eliminate the 0.4-mg/kg dose but are included in all subsequent analyses.
Table 2 shows the 3-month outcomes and 24-hour MNI rates for the patients by treatment group. Four patients were either lost to follow-up or voluntarily withdrew from the trial. Their 3-month Rankin categories were imputed using the last observation carried forward or the last recorded National Institutes of Health Stroke Scale score using a prespecified algorithm. The 0.1-mg/kg tenecteplase group had the lowest proportion of poor outcomes (7 of 31 [22.6%]), whereas the rtPA group had 10 of 31 (32.3%) poor outcomes. In terms of good outcome, the 0.25-mg/kg tenecteplase group had the highest proportion (15 of 31 [48.4%]), but the 0.1-mg/kg tenecteplase group was similar (14 of 31 [45.2%]). By comparison, the rtPA group had 13 of 31 (41.9%) good outcomes. All probability values were >0.3.
Table 3 shows selected safety measures. There were a total of 6 symptomatic ICHs: 3 of 19 (15.8%) in the 0.4-mg/kg group, 2 of 31 (6.5%) in the 0.25-mg/kg tenecteplase group, and none (0 of 31) in the 0.1-mg/kg tenecteplase group. By comparison, there was 1 of 31 (3.2%) symptomatic ICH in the rtPA group. Additionally, there were 11 asymptomatic ICHs among the 4 treatment groups. There was 1 serious systemic hemorrhage in the 0.25-mg/kg group (a retroperitoneal hemorrhage) that resulted in life-threatening hypotension and neurological worsening.
This randomized, controlled, Phase IIB trial used a number of novel design features in an attempt to answer efficiently several important clinical questions before escalating to a major Phase III efficacy trial. The first issue was to select an optimal dose of tenecteplase to carry forward into Phase III from among 3 doses that had appeared safe in a previous study in patients with acute stroke. We chose an adaptive, sequential dose selection procedure that used MNI at 24 hours balanced by risk, as measured by the incidence of symptomatic ICH, to choose among 3 different doses of tenecteplase. The selection procedure efficiently eliminated 0.4 mg/kg tenecteplase as “inferior” after only 73 patients had been randomized into the study (including patients concurrently randomized to rtPA). The trial was stopped before a propitious dose of tenecteplase could be selected. Based on the prespecified criteria, we could not distinguish between the 0.1-mg/kg and 0.25-mg/kg doses after 28 pairs had been compared. Because there may be as much as an absolute 10% true difference in 24-hour MNI rates between these 2 doses, further study would be required to make this distinction.
The second major purpose of the trial was to develop evidence for either promise or futility of further study of an optimal dose of tenecteplase compared with standard-dose intravenous rtPA. We planned to enroll at least 100 patients to either rtPA or the optimal dose of tenecteplase and then to compare their 3-month outcomes in an interim analysis. Unfortunately, the premature termination of the trial preempted the planned assessment. With only 31 patients in each of the remaining treatment groups, there were major imbalances in several important baseline prognostic factors for outcome, and the uncertainty associated with the outcome proportions was so broad as to make our prespecified decision rules for stopping or continuation substantially less reliable. The promising safety experience observed in the previous pilot dose-escalation study of tenecteplase was not duplicated in this trial. The observed symptomatic ICH rate in the 0.4-mg/kg tenecteplase dose group was 15.8% and contributed to its early relegation as an “inferior” tenecteplase dose. Only 1 of 31 (3.2%) symptomatic ICH was observed in the rtPA group, but the CIs include the widely reported 6% rate. The safest regimen appears to be the 0.1-mg/kg tenecteplase group in which no symptomatic intracranial hemorrhages were observed, and the point estimates suggest an absolute 9.7% reduction in poor outcomes and 3.2% increase in good outcomes in this group compared with rtPA. None of these differences is statistically persuasive, and as noted previously, the rtPA group was older and had more severe stroke deficits at baseline.
Finally, had the Phase IIB trial been completed, the plan was to continue seamlessly into a much larger Phase III efficacy trial comparing the 3-month outcomes between the selected dose of tenecteplase and standard rtPA. The inclusion of the Phase IIB patients in the larger Phase III study has traditionally raised questions among statisticians and clinical trialists of potential bias and lack of control for Type I statistical error. However, simulations demonstrated beyond any reasonable doubt that given the conservatism of the tests for promise or futility, and other features, the Phase III trial as designed maintained excellent control of the Type 1 error rate below 5% overall (results to be reported separately). Despite this, as of this writing, the US Food and Drug Administration has not approved this plan, and had the Phase IIB trial been allowed to continue to completion, a separate, independent Phase III trial might have been required.
Recently, Parsons and colleagues reported the results of a prospective pilot study of 15 patients selected by CT or MRI diffusion/perfusion mismatch and treated with intravenous tenecteplase at a dose of 0.1 mg/kg between 3 and 6 hours from onset of acute ischemic stroke.9 Compared with a nonrandomized control group of 35 patients treated with standard rtPA within the 3-hour time window, more tenecteplase-treated patients had major neurological improvement at 24 hours (66.7% versus 20.0%) as well as improved reperfusion and large vessel recanalization compared with the rtPA-treated group. These observations, along with the results of our trial, suggest that further study of tenecteplase as an alternative treatment for acute ischemic stroke may be warranted.
We thank the patients and families who participated in this clinical trial.
Sources of Funding
Supported by grants (R01-NS37666 and R01-NS45170) from the National Institute of Neurological Disorders and Stroke–National Institutes of Health. Genentech, Inc. supplied study drug (both tenecteplase and alteplase) for this clinical trial but no other financial or other support.
E.C.H. serves as a consultant to GlaxoSmithKline. J.C.G. holds a patent on the experimental compound, caffeinol, and served as a consultant for Lundbeck. P.D.L. received research support from Photothera; consultancies with Photothera, Mitsubishi Pharma, and Benechill; serves on an advisory board for CoAxia; and received honoraria from Mitsubishi Pharma. D.L.B. receives research support from CVR Global, Inc. C.F. serves on a Speaker’s Bureau for Genentech. R.H.L. receives research support from Diogenix. S.R.L. served on an advisory board for Astra Zeneca. K.C.J. serves as a consultant to Diffusion Pharmaceuticals Inc, Remedy Pharmaceutical, and OnoPharma USA; and serves on advisory boards for Astra Zeneca.
- Received November 3, 2009.
- Revision received December 23, 2009.
- Accepted December 24, 2009.
Haley EC, Lyden PD, Johnston KC, Hemmen TM; the TNK in Stroke Investigators. A pilot dose-escalation safety study of tenecteplase in acute ischemic stroke. Stroke. 2005; 36: 607–612.
Brown DL, Johnston KC, Wagner DP, Haley EC. Predicting major neurological improvement with intravenous tissue plasminogen activator treatment of stroke. Stroke. 2004; 35: 147–150.
Lyden P, Raman R, Liu L, Grotta J, Broderick J, Olson S, Shaw S, Spilker J, Meyer B, Emr M, Warren M, Marler J. NIHSS training and certification using a new digital video disk is reliable. Stroke. 2005; 36: 2446–2449.
van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJA, van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke. 1988; 19: 604–607.
Adams HP, del Zoppo G, Alberts MJ, Bhatt D, Brass L, Furlan A, Grubb RL, Hiagshida RT, Jauch EC, Kidwell C, Lyden PD, Morgenstern LB, Qureshi AI, Rosenwasser RH, Scott PA, Wijdiks EFM. Guidelines for the early management of adults with ischemic stroke. A guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups. Stroke. 2007; 38: 1655–1711.
Adams HP, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DS, Marsh EE. Classification subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. Stroke. 1993; 24: 35–41.
Parsons MW, Miteff F, Spratt N, Loisell A, Attia J, Levi CR. Acute ischemic stroke. Imaging guided tenecteplase treatment in an extended time window. Neurology. 2009; 72: 915–921.
Supplemental Appendix: The Tenecteplase in Stroke Investigators
University of California–San Diego (Sharp Memorial Hospital, Alvarado Hospital): P. Lyden, Principal Investigator, T. Hemmen, B. Meyer, M. Chacon, M. Jenson, S. Yip, W. Brown, G. Tafreshi, P. Delaney, J. Sattin, C. Fanale, S. Olson, K. Rapp, J. Werner, J. Bell, T. Rzesiewicz, M. Buda, and T. Vu. Long Island Jewish Medical Center: T. Kwiatkowski, Principal Investigator, R. Libman, L. Schoenberg, J. Katz, A. Patil, R. Gonzaga-Camfield, M. Schaefer, M. Manlulu, Z. Faynblat, A. Johnson, and A. Diamond. Colorado Neurological Instititute (Swedish Medical Center): C. Fanale, Principal Investigator, R. Pratt, I. Chang, H. Monatt, C. Greenwald, and K. Malleck. University of Texas–Houston (Memorial Hermann Hospital, Memorial Southwest Hospital): J. Grotta (Principal Investigator), F. Yatsu, A. Alexandrov, M. Ribo, J. Choi, K. Illoh, E. Noser, N. Gonzales, R. Sugg, H. Shaltoni, A. Khaja, K. Albright, R. Martin, H. Hallevi, A. Barreto, S. Martin-Schild, A. Abraham, S. Savitz, I. Acosta, V. Misra, O. Chernyshev, D. Matherne, D. Wegner, R. Casey, M. Peck, N. Porche-Taylor, S. Shaw, D. Smith, M. Hess, L. Shen, A. Alderman, L. Nguyen, M. Olivares, and T. Yeung. Johns Hopkins–Bayview Medical Center: R. Llinas (Principal Investigator), H. Chang, M. Frohler, C. Cronin, J. Berekely, X. Xiong, S. Zeiler, K. Thomas, R. Hoesch, C. Turtzo, J. Jordan and J. Alt. Mount Sinai Medical Center: S. Levine (Principal Investigator), S. Augustine, I. Cohen, S. Tuhrim, K. Sheinart, D. Horowitz, C. Amory, D. Patterson, J. Weinberger, J. Bruns, Y. Chan, and L. Blas. University of Michigan Health Center: D. Brown (Prinicipal Investigator): W. Barsan, T. Jacobs, J. Majersik, W. Meurer, L. Morgenstern, V. Rajajee, P. Scott, R. Silbergleit, L. Skolarus, M. Wang, D. Zahuranec, K. Maddox, A. Skyles, and S. Weadock. University of Virginia Health Sciences Center: C. Haley (Principal Investigator), M. Davis, K. McCarthy, A. Adams, K. Johnston, B. Nathan, N. Solenski, B. Worrall, K. Barrett, R. Erwin, C. Domangue, and M. Mauermann. Clinical Coordinating Center (University of Virginia): C. Haley (Prinicipal Investigator), M. Davis, C. Beebe, K. McCarthy, C. Hicks, and D. Phillips. Statistical Analysis Center (Columbia University): J. Thompson (Prinicipal Investigator), B. Levin, G. Levy, R. Buchsbaum, R. Arbing, A. Tierney, R. MacArthur, and R. Prodhan. Medical Monitor: T. Bleck. Intracranial Hemorrhage Clinical Adjudicator: G. Albers. Data and Safety Monitoring Board: M. Walker (Chair), J. Hallenbeck, D. Stump, and T. Cook. National Institute of Neurological Disorders and Stroke: S. Janis and P. Gilbert.
This trial was registered with ClinicalTrials.gov (NCT00252239).