on October 16, 2003
Published online before print October 16, 2003, doi: 10.1161/01.STR.0000092527.33910.89
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on May 9, 2003
From Pfizer Global Research and Development, Sandwich, UK (M.K., A.P.G.); University Department of Medicine and Therapeutics, Gardiner Institute, Western Infirmary, Glasgow, UK (K.R.L.); Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany (W.H.); CHU Pellegrin, Bordeaux, France (J-M.O.); and Wolfson Unit of Clinical Pharmacology, Newcastle University, Newcastle, UK (G.A.F.). * To whom correspondence should be addressed. E-mail: Michael_krams{at}groton.pfizer.com.
Background and Purpose--UK-279,276 (neutrophil inhibitory factor) reduced infarct volume in a rat middle cerebral artery occlusion reperfusion model. ASTIN (Acute Stroke Therapy by Inhibition of Neutrophils) was an adaptive phase 2 dose-response-finding, proof-of-concept study to establish whether UK-279,276 improves recovery in acute ischemic stroke. The prime objective was to determine the dose that gave a clinically relevant effect in patients. Methods--A Bayesian sequential design with real-time efficacy data capture and continuous reassessment of the dose response allowed double-blind, randomized, adaptive allocation to 1 of 15 doses (dose range, 10 to 120 mg) or placebo and early termination for efficacy or futility. The primary end point was change from baseline to day 90 on the Scandinavian Stroke Scale ( Results--Nine hundred sixty-six acute stroke patients (887 ischemic, 204 cotreated with intravenous tissue plasminogen activator; mean baseline SSS score, 28; range, 10 to 40) were treated within 6 hours of symptom onset. Mean Conclusions--UK-279,276 did not improve recovery in acute ischemic stroke patients but was devoid of serious side effects. The adaptive design facilitated early termination for futility.
Accepted on June 24, 2003
Acute Stroke Therapy by Inhibition of Neutrophils (ASTIN). An Adaptive Dose-Response Study of UK-279,276 in Acute Ischemic Stroke
Michael Krams MD*;
SSS), adjusted for baseline SSS, aiming for a 3-point additional mean recovery above placebo.SSS was approximately +17 points of improvement on SSS for the overall evaluable population. There was no treatment effect for UK-279,276 (posterior probability of futility, 0.89). The trial was stopped early for futility. Post hoc analysis indicated a mean 1.6-point additional improvement on SSS in the tissue plasminogen activator-treated subset (credible interval=0.5, 2.6). UK-279,276 was generally well tolerated, with no increased incidence of infections.
Key words: dose-response relationship, drug • neuroprotection • neutrophils • research design
This article has been cited by other articles:
 |
|
 |
|
  B. R. Luce, J. M. Kramer, S. N. Goodman, J. T. Connor, S. Tunis, D. Whicher, and J. S. Schwartz Rethinking Randomized Clinical Trials for Comparative Effectiveness Research: The Need for Transformational Change Ann Intern Med, August 4, 2009; 151(3): 206 - 209. [Full Text] [PDF]
|
|
|
|
 |
|
 M. D. Ginsberg Current Status of Neuroprotection for Cerebral Ischemia: Synoptic Overview Stroke, March 1, 2009; 40(3_suppl_1): S111 - S114. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. R. Konig, A. Ziegler, E. Bluhmki, W. Hacke, P. M.W. Bath, R. L. Sacco, H. C. Diener, C. Weimar, and on behalf of the Virtual International Stroke Tria Predicting Long-Term Outcome After Acute Ischemic Stroke: A Simple Index Works in Patients From Controlled Clinical Trials Stroke, June 1, 2008; 39(6): 1821 - 1826. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. H. Buck, D. S. Liebeskind, J. L. Saver, O. Y. Bang, S. W. Yun, S. Starkman, L. K. Ali, D. Kim, J. P. Villablanca, N. Salamon, et al. Early Neutrophilia Is Associated With Volume of Ischemic Tissue in Acute Stroke Stroke, February 1, 2008; 39(2): 355 - 360. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Rother Neuroprotection Does Not Work! Stroke, February 1, 2008; 39(2): 523 - 524. [Full Text] [PDF]
|
|
|
|
|
|
G. A. Donnan The 2007 Feinberg Lecture: A New Road Map for Neuroprotection Stroke, January 1, 2008; 39(1): 242 - 242. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Maloney, M. O. Karlsson, and U. S. H. Simonsson Optimal Adaptive Design in Clinical Drug Development: A Simulation Example J. Clin. Pharmacol., October 1, 2007; 47(10): 1231 - 1243. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. G. Maki, J. K. Wathen, S. R. Patel, D. A. Priebat, S. H. Okuno, B. Samuels, M. Fanucchi, D. C. Harmon, S. M. Schuetze, D. Reinke, et al. Randomized Phase II Study of Gemcitabine and Docetaxel Compared With Gemcitabine Alone in Patients With Metastatic Soft Tissue Sarcomas: Results of Sarcoma Alliance for Research Through Collaboration Study 002 J. Clin. Oncol., July 1, 2007; 25(19): 2755 - 2763. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. P. Adams Jr, G. del Zoppo, M. J. Alberts, D. L. Bhatt, L. Brass, A. Furlan, R. L. Grubb, R. T. Higashida, E. C. Jauch, C. Kidwell, et al. 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: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Circulation, May 22, 2007; 115(20): e478 - e534. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. P. Adams Jr, G. del Zoppo, M. J. Alberts, D. L. Bhatt, L. Brass, A. Furlan, R. L. Grubb, R. T. Higashida, E. C. Jauch, C. Kidwell, et al. 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: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists Stroke, May 1, 2007; 38(5): 1655 - 1711. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Gee, A. Kalil, C. Shea, and K. J. Becker Lymphocytes: Potential Mediators of Postischemic Injury and Neuroprotection Stroke, February 1, 2007; 38(2): 783 - 788. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Muller, D. A. Berry, A. P. Grieve, and M. Krams A Bayesian Decision-Theoretic Dose-Finding Trial Decision Analysis, December 1, 2006; 3(4): 197 - 207. [Abstract] [PDF]
|
|
|
|
|
|
A. E. Baird The Forgotten Lymphocyte: Immunity and Stroke Circulation, May 2, 2006; 113(17): 2035 - 2036. [Full Text] [PDF]
|
|
|
|
 |
|
 H F McFarland and S C Reingold The future of multiple sclerosis therapies: redesigning multiple sclerosis clinical trials in a new therapeutic eraa Multiple Sclerosis, December 1, 2005; 11(6): 669 - 676. [Abstract] [PDF]
|
|
|
|
|
|
P. W. Ho, D. C. Reutens, T. G. Phan, P. M. Wright, R. Markus, I. Indra, D. Young, and G. A. Donnan Is White Matter Involved in Patients Entered into Typical Trials of Neuroprotection? Stroke, December 1, 2005; 36(12): 2742 - 2744. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. A. Donnan and S. M. Davis Stroke Drug Development: Usually, But Not Always, Animal Models Stroke, October 1, 2005; 36(10): 2326 - 2326. [Full Text] [PDF]
|
|
|
|
 |
|
 A. P Grieve and M. Krams ASTIN: a Bayesian adaptive dose-response trial in acute stroke Clinical Trials, August 1, 2005; 2(4): 340 - 351. [Abstract] [PDF]
|
|
|
|
|
|
M. Fisher and for the Stroke Therapy Academic Industry Roundtabl Enhancing the Development and Approval of Acute Stroke Therapies: Stroke Therapy Academic Industry Roundtable Stroke, August 1, 2005; 36(8): 1808 - 1813. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. A. Donnan, S. M. Davis, and D. A. Berry Clinical Trials: Is the Bayesian Approach Ready for Prime Time? Yes! Stroke, July 1, 2005; 36(7): 1621 - 1622. [Full Text] [PDF]
|
|
|
|
|
|
G. A. Donnan, S. M. Davis, and J. Ludbrook The Bayesian Principle: Can We Adapt? Stroke, July 1, 2005; 36(7): 1623 - 1624. [Full Text] [PDF]
|
|
|
|
|
|
M. Krams, K. R. Lees, and D. A. Berry The Past Is the Future: Innovative Designs in Acute Stroke Therapy Trials Stroke, June 1, 2005; 36(6): 1341 - 1347. [Full Text] [PDF]
|
|
|
|
 |
|
 K. Yonekawa and J. M. Harlan Targeting leukocyte integrins in human diseases J. Leukoc. Biol., February 1, 2005; 77(2): 129 - 140. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Sughrue, E. S. Connolly Jr, M. Krams, K. R. Lees, W. Hacke, A. P. Grieve, J.-M. Orgogozo, and G. A. Ford Effectively Bridging the Preclinical/Clinical Gap: The Results of the ASTIN Trial * Response Stroke, April 1, 2004; 35(4): e81 - e82. [Full Text] [PDF]
|
|