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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2010 |
|---|---|
| Erschienen: |
2010 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:41 |
|---|---|
| Enthalten in: |
Stroke - 41(2010), 4 vom: 01. Apr., Seite 707-11 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Haley, E Clarke [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 03.05.2010 Date Revised 31.03.2022 published: Print-Electronic ClinicalTrials.gov: NCT00252239 Citation Status MEDLINE |
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| doi: |
10.1161/STROKEAHA.109.572040 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM195378784 |
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| 100 | 1 | |a Haley, E Clarke |c Jr |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Phase IIB/III trial of tenecteplase in acute ischemic stroke |b results of a prematurely terminated randomized clinical trial |
| 264 | 1 | |c 2010 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
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| 500 | |a Date Completed 03.05.2010 | ||
| 500 | |a Date Revised 31.03.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a ClinicalTrials.gov: NCT00252239 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Clinical Trial, Phase II | |
| 650 | 4 | |a Clinical Trial, Phase III | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Multicenter Study | |
| 650 | 4 | |a Randomized Controlled Trial | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 7 | |a Fibrinolytic Agents |2 NLM | |
| 650 | 7 | |a Tissue Plasminogen Activator |2 NLM | |
| 650 | 7 | |a EC 3.4.21.68 |2 NLM | |
| 650 | 7 | |a Tenecteplase |2 NLM | |
| 650 | 7 | |a WGD229O42W |2 NLM | |
| 700 | 1 | |a Thompson, John L P |e verfasserin |4 aut | |
| 700 | 1 | |a Grotta, James C |e verfasserin |4 aut | |
| 700 | 1 | |a Lyden, Patrick D |e verfasserin |4 aut | |
| 700 | 1 | |a Hemmen, Thomas G |e verfasserin |4 aut | |
| 700 | 1 | |a Brown, Devin L |e verfasserin |4 aut | |
| 700 | 1 | |a Fanale, Christopher |e verfasserin |4 aut | |
| 700 | 1 | |a Libman, Richard |e verfasserin |4 aut | |
| 700 | 1 | |a Kwiatkowski, Thomas G |e verfasserin |4 aut | |
| 700 | 1 | |a Llinas, Rafael H |e verfasserin |4 aut | |
| 700 | 1 | |a Levine, Steven R |e verfasserin |4 aut | |
| 700 | 1 | |a Johnston, Karen C |e verfasserin |4 aut | |
| 700 | 1 | |a Buchsbaum, Richard |e verfasserin |4 aut | |
| 700 | 1 | |a Levy, Gilberto |e verfasserin |4 aut | |
| 700 | 1 | |a Levin, Bruce |e verfasserin |4 aut | |
| 700 | 0 | |a Tenecteplase in Stroke Investigators |e verfasserin |4 aut | |
| 700 | 1 | |a Lyden, P |e investigator |4 oth | |
| 700 | 1 | |a Hemmen, T |e investigator |4 oth | |
| 700 | 1 | |a Meyer, B |e investigator |4 oth | |
| 700 | 1 | |a Chacon, M |e investigator |4 oth | |
| 700 | 1 | |a Jenson, M |e investigator |4 oth | |
| 700 | 1 | |a Yip, S |e investigator |4 oth | |
| 700 | 1 | |a Brown, W |e investigator |4 oth | |
| 700 | 1 | |a Tafreshi, G |e investigator |4 oth | |
| 700 | 1 | |a Delaney, P |e investigator |4 oth | |
| 700 | 1 | |a Sattin, J |e investigator |4 oth | |
| 700 | 1 | |a Fanale, C |e investigator |4 oth | |
| 700 | 1 | |a Olson, S |e investigator |4 oth | |
| 700 | 1 | |a Rapp, K |e investigator |4 oth | |
| 700 | 1 | |a Werner, J |e investigator |4 oth | |
| 700 | 1 | |a Bell, J |e investigator |4 oth | |
| 700 | 1 | |a Rzesiewicz, T |e investigator |4 oth | |
| 700 | 1 | |a Buda, M |e investigator |4 oth | |
| 700 | 1 | |a Vu, T |e investigator |4 oth | |
| 700 | 1 | |a Kwiatkowski, T |e investigator |4 oth | |
| 700 | 1 | |a Libman, R |e investigator |4 oth | |
| 700 | 1 | |a Schoenberg, L |e investigator |4 oth | |
| 700 | 1 | |a Katz, J |e investigator |4 oth | |
| 700 | 1 | |a Patil, A |e investigator |4 oth | |
| 700 | 1 | |a Gonzaga-Camfield, R |e investigator |4 oth | |
| 700 | 1 | |a Schaefer, M |e investigator |4 oth | |
| 700 | 1 | |a Manlulu, M |e investigator |4 oth | |
| 700 | 1 | |a Faynblat, Z |e investigator |4 oth | |
| 700 | 1 | |a Johnson, A |e investigator |4 oth | |
| 700 | 1 | |a Diamond, A |e investigator |4 oth | |
| 700 | 1 | |a Fanale, C |e investigator |4 oth | |
| 700 | 1 | |a Pratt, R |e investigator |4 oth | |
| 700 | 1 | |a Chang, I |e investigator |4 oth | |
| 700 | 1 | |a Monatt, H |e investigator |4 oth | |
| 700 | 1 | |a Greenwald, C |e investigator |4 oth | |
| 700 | 1 | |a Malleck, K |e investigator |4 oth | |
| 700 | 1 | |a Grotta, J |e investigator |4 oth | |
| 700 | 1 | |a Yatsu, F |e investigator |4 oth | |
| 700 | 1 | |a Alexandrov, A |e investigator |4 oth | |
| 700 | 1 | |a Ribo, M |e investigator |4 oth | |
| 700 | 1 | |a Choi, J |e investigator |4 oth | |
| 700 | 1 | |a Illoh, K |e investigator |4 oth | |
| 700 | 1 | |a Noser, E |e investigator |4 oth | |
| 700 | 1 | |a Gonzales, N |e investigator |4 oth | |
| 700 | 1 | |a Sugg, R |e investigator |4 oth | |
| 700 | 1 | |a Shaltoni, H |e investigator |4 oth | |
| 700 | 1 | |a Khaja, A |e investigator |4 oth | |
| 700 | 1 | |a Albright, K |e investigator |4 oth | |
| 700 | 1 | |a Martin, R |e investigator |4 oth | |
| 700 | 1 | |a Hallevi, H |e investigator |4 oth | |
| 700 | 1 | |a Barreto, A |e investigator |4 oth | |
| 700 | 1 | |a Martin-Schild, S |e investigator |4 oth | |
| 700 | 1 | |a Abraham, A |e investigator |4 oth | |
| 700 | 1 | |a Savitz, S |e investigator |4 oth | |
| 700 | 1 | |a Acosta, I |e investigator |4 oth | |
| 700 | 1 | |a Misra, V |e investigator |4 oth | |
| 700 | 1 | |a Chernyshev, O |e investigator |4 oth | |
| 700 | 1 | |a Matherne, D |e investigator |4 oth | |
| 700 | 1 | |a Wegner, D |e investigator |4 oth | |
| 700 | 1 | |a Casey, R |e investigator |4 oth | |
| 700 | 1 | |a Peck, M |e investigator |4 oth | |
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| 700 | 1 | |a Nguyen, L |e investigator |4 oth | |
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| 700 | 1 | |a Yeung, T |e investigator |4 oth | |
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| 700 | 1 | |a Turtzo, C |e investigator |4 oth | |
| 700 | 1 | |a Jordan, J |e investigator |4 oth | |
| 700 | 1 | |a Alt, J |e investigator |4 oth | |
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