Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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 (DeltaSSS), adjusted for baseline SSS, aiming for a 3-point additional mean recovery above placebo. 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 DeltaSSS 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 DeltaSSS 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. 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.

Original publication

DOI

10.1161/01.STR.0000092527.33910.89

Type

Journal article

Journal

Stroke

Publication Date

11/2003

Volume

34

Pages

2543 - 2548

Keywords

Acute Disease, Adult, Aged, Aged, 80 and over, Bayes Theorem, Brain Ischemia, CD11b Antigen, Dose-Response Relationship, Drug, Double-Blind Method, Female, Glycoproteins, Humans, Male, Medical Futility, Middle Aged, Neutrophils, Recombinant Proteins, Severity of Illness Index, Stroke, Time Factors, Tissue Plasminogen Activator, Treatment Outcome