Acute Stroke Therapy by Inhibition of Neutrophils (ASTIN): an adaptive dose-response study of UK-279,276 in acute ischemic stroke.
OBJECTIVE
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.
Krams
Michael
M
Pfizer Global Research and Development, Sandwich, UK. Michael_krams@groton.pfizer.com
Lees
Kennedy R
KR
Hacke
Werner
W
Grieve
Andrew P
AP
Orgogozo
Jean-Marc
JM
Ford
Gary A
GA
D000208:Acute Disease; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001499:Bayes Theorem; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy*; D039481:CD11b Antigen / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006023:Glycoproteins / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D018447:Medical Futility; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects*; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use; D012720:Severity of Illness Index; D020521:Stroke / Q000150:complications / Q000188:drug therapy*; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use; D016896:Treatment Outcome
D039481:CD11b Antigen; D006023:Glycoproteins; D011994:Recombinant Proteins; C476006:UK279276; D010959:Tissue Plasminogen Activator