Phase IIB/III trial of tenecteplase in acute ischemic stroke: Results of a prematurely terminated randomized clinical trial

E. Clarke Haley, John L P Thompson, James C. Grotta, Patrick D. Lyden, Thomas G. Hemmen, Devin L. Brown, Christopher Fanale, Richard Libman, Thomas G. Kwiatkowski, Rafael H Llinas, Steven R. Levine, Karen C. Johnston, Richard Buchsbaum, Gilberto Levy, Bruce Levin

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)707-711
Number of pages5
JournalStroke
Volume41
Issue number4
DOIs
StatePublished - Apr 2010

Fingerprint

Randomized Controlled Trials
Stroke
Medical Futility
Intracranial Hemorrhages
tenecteplase
Fibrinolytic Agents
Controlled Clinical Trials
Tissue Plasminogen Activator
Clinical Trials

Keywords

  • Acute ischemic stroke
  • Tenecteplase
  • Thrombolysis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Clinical Neurology
  • Advanced and Specialized Nursing

Cite this

Haley, E. C., Thompson, J. L. P., Grotta, J. C., Lyden, P. D., Hemmen, T. G., Brown, D. L., ... Levin, B. (2010). Phase IIB/III trial of tenecteplase in acute ischemic stroke: Results of a prematurely terminated randomized clinical trial. Stroke, 41(4), 707-711. https://doi.org/10.1161/STROKEAHA.109.572040

Phase IIB/III trial of tenecteplase in acute ischemic stroke : Results of a prematurely terminated randomized clinical trial. / Haley, E. Clarke; Thompson, John L P; Grotta, James C.; Lyden, Patrick D.; Hemmen, Thomas G.; Brown, Devin L.; Fanale, Christopher; Libman, Richard; Kwiatkowski, Thomas G.; Llinas, Rafael H; Levine, Steven R.; Johnston, Karen C.; Buchsbaum, Richard; Levy, Gilberto; Levin, Bruce.

In: Stroke, Vol. 41, No. 4, 04.2010, p. 707-711.

Research output: Contribution to journalArticle

Haley, EC, Thompson, JLP, Grotta, JC, Lyden, PD, Hemmen, TG, Brown, DL, Fanale, C, Libman, R, Kwiatkowski, TG, Llinas, RH, Levine, SR, Johnston, KC, Buchsbaum, R, Levy, G & Levin, B 2010, 'Phase IIB/III trial of tenecteplase in acute ischemic stroke: Results of a prematurely terminated randomized clinical trial', Stroke, vol. 41, no. 4, pp. 707-711. https://doi.org/10.1161/STROKEAHA.109.572040
Haley, E. Clarke ; Thompson, John L P ; Grotta, James C. ; Lyden, Patrick D. ; Hemmen, Thomas G. ; Brown, Devin L. ; Fanale, Christopher ; Libman, Richard ; Kwiatkowski, Thomas G. ; Llinas, Rafael H ; Levine, Steven R. ; Johnston, Karen C. ; Buchsbaum, Richard ; Levy, Gilberto ; Levin, Bruce. / Phase IIB/III trial of tenecteplase in acute ischemic stroke : Results of a prematurely terminated randomized clinical trial. In: Stroke. 2010 ; Vol. 41, No. 4. pp. 707-711.
@article{c93a45526c2f4b678d153bb3fa1d5fd6,
title = "Phase IIB/III trial of tenecteplase in acute ischemic stroke: Results of a prematurely terminated randomized clinical trial",
abstract = "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.",
keywords = "Acute ischemic stroke, Tenecteplase, Thrombolysis",
author = "Haley, {E. Clarke} and Thompson, {John L P} and Grotta, {James C.} and Lyden, {Patrick D.} and Hemmen, {Thomas G.} and Brown, {Devin L.} and Christopher Fanale and Richard Libman and Kwiatkowski, {Thomas G.} and Llinas, {Rafael H} and Levine, {Steven R.} and Johnston, {Karen C.} and Richard Buchsbaum and Gilberto Levy and Bruce Levin",
year = "2010",
month = "4",
doi = "10.1161/STROKEAHA.109.572040",
language = "English (US)",
volume = "41",
pages = "707--711",
journal = "Stroke",
issn = "0039-2499",
publisher = "Lippincott Williams and Wilkins",
number = "4",

}

TY - JOUR

T1 - Phase IIB/III trial of tenecteplase in acute ischemic stroke

T2 - Results of a prematurely terminated randomized clinical trial

AU - Haley, E. Clarke

AU - Thompson, John L P

AU - Grotta, James C.

AU - Lyden, Patrick D.

AU - Hemmen, Thomas G.

AU - Brown, Devin L.

AU - Fanale, Christopher

AU - Libman, Richard

AU - Kwiatkowski, Thomas G.

AU - Llinas, Rafael H

AU - Levine, Steven R.

AU - Johnston, Karen C.

AU - Buchsbaum, Richard

AU - Levy, Gilberto

AU - Levin, Bruce

PY - 2010/4

Y1 - 2010/4

N2 - 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.

AB - 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.

KW - Acute ischemic stroke

KW - Tenecteplase

KW - Thrombolysis

UR - http://www.scopus.com/inward/record.url?scp=77950251479&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77950251479&partnerID=8YFLogxK

U2 - 10.1161/STROKEAHA.109.572040

DO - 10.1161/STROKEAHA.109.572040

M3 - Article

C2 - 20185783

AN - SCOPUS:77950251479

VL - 41

SP - 707

EP - 711

JO - Stroke

JF - Stroke

SN - 0039-2499

IS - 4

ER -