London, United Kingdom 2013 4 Large clinical trials (RCTs) B 11:00 - 11:10 THE ALBUMIN IN ACUTE STROKE (ALIAS) PART 2 CLINICAL TRIAL – A RAN-DOMIZED MULTICENTER INVESTIGATION OF ALBUMIN- NEUROPROTEC-TION FOR ACUTE ISCHEMIC STROKE. 2: PRIMARY AND SECONDARY EFFICACY OUTCOMES M.D. Ginsberg1, Y.Y. Palesch2, M.D. Hill3, R.H. Martin4, C.S. Moy5, W.G. Barsan6, K.J. Ry-ckborst7, D. Tamariz8, B.D. Waldman9 ALIAS Trial Investigators University of Miami Miller School of Medicine, Miami, USA1,Medical University of South Carolina, Charleston, USA2, University of Calgary, Calgary, CANADA3, Medical University of South Carolina, Charleston, USA4, National Institute of Neurological Disorders and Stroke, Rockville, USA5, University of Michigan, Ann Arbor, USA6, University of Calgary, Calgary, CANADA7, University of Miami Miller School of Medicine, Miami, USA8, Medical University of South Carolina, Charleston, USA9 Background: The ALIAS Part 2 Trial began in Feb. 2009, as a definitive phase III efficacy trial of albu-min- neuroprotection. Its design incorporated numerous protocol modifications arising from our safety analysis of the Part 1 Trial (see previous abstract). Methods: The trial’s objective was to assess whether a weight-adjusted dose 2 g/kg of 25% albumin would confer neurological and functional benefit. A favorable primary outcome was defined as NIHSS and/or mRS scores of 0-1 at 90 days. Secondary outcomes were followed out to 1 year. Subjects were randomized 1:1 to ALB or saline control. Inclusion criteria were acute ischemic stroke, age 18-83, baseline NIHSS >/=6, treatment initiated within 5 h of onset, and informed consent. Major exclusion criteria included recent congestive heart failure (CHF) or myocardial infarction, arrhythmia with hemodynamic instability, significant pulmonary disease, elevated baseline troponin, historical mRS >1, and in-hospital stroke. Standard-of-care IV and/or in-tra- arterial thrombolytic and clot-removal strategies were permitted, and the two-cohort design of Part 1 (with and without thrombolysis) was eliminated. Strict fluid guidelines and diuretic therapy were mandated, as were rigorous personnel training and certification. Total intended sample size was set at 1,100, to detect a 10% minimum effect size in the primary outcome with ~85% power and to allow for 3 interim analyses. Results: In Sept. 2012, upon interim analysis of 732 subjects, the DSMB recommended that enrollment be halted because the trial’s pre-specified primary endpoint was unlikely to differ significant-ly between groups. A total of 843 subjects (i.e., 76.6% of target) had been enrolled as of then at 69 sites in the U.S., 13 in Canada, 5 in Israel, and 2 in Finland. All subjects were followed through 90 days. Data-cleaning is in progress, and unblinded analysis will begin in the spring, 2013. Conclusions: At the ESC, we shall present efficacy outcomes in detail. Cerebrovasc Dis 2013; 35 (suppl 3)1-854 107 3 Large clinical trials (RCTs) B 10:50 - 11:00 THE ALBUMIN IN ACUTE STROKE (ALIAS) PART 2 CLINICAL TRIAL – A RAN-DOMIZED MULTICENTER INVESTIGATION OF ALBUMIN- NEUROPROTEC-TION FOR ACUTE ISCHEMIC STROKE. 1: RATIONALE, TRIAL DESIGN AND SAFETY OUTCOMES M.D. Ginsberg1, M.D. Hill2, Y.Y. Palesch3, R.H. Martin4, C.S. Moy5, W.G. Barsan6, K.J. Ry-ckborst7, D. Tamariz8, B.D. Waldman9 ALIAS Trial Investigators University of Miami Miller School of Medicine, Miami, USA1,University of Calgary, Cal-gary, CANADA2, Medical University of South Carolina, Charleston, USA3, Medical University of South Carolina, Charleston, USA4, National Institute of Neurological Disorders and Stroke, Rockville, USA5, University of Michigan, Ann Arbor, USA6, University of Calgary, Calgary, CANADA7, University of Miami Miller School of Medicine, Miami, USA8, Medical Universi-ty of South Carolina, Charleston, USA9 Background: In pre-clinical studies, high-dose human albumin (ALB) consistently reduced infarct size and improved behavior in acute focal ischemia, with a therapeutic window of 4-5h. ALB enhanced penumbral perfusion, reduced swelling, reversed microvascular changes, improved collateral flow, and led to hemodilution. In 2001-2006, the NIH funded a 2-center dose-escalation pilot trial in 82 subjects with acute ischemic stroke, which established safety. The sole ALB-related adverse event was mild or moderate pulmonary edema in 13.4% of subjects, which was readily managed. NIH then funded a definitive phase III trial. Methods: ALIAS was a randomized efficacy trial to assess whether ALB therapy would confer benefit in acute ischemic stroke. Inclusion criteria included age >/=18 years, baseline NIHSS >/=6, treatment within 5h of onset, and informed consent. Exclusion criteria included recent con-gestive heart failure or myocardial infarction. In the original (Part 1) design, thrombolytic and non-thrombolytic cohorts were separately randomized. A sample size of 1,800 was planned. In Dec. 2007, the DSMB halted Part 1 enrollment after 434 subjects because of a safety con-cern. Results: Unblinded safety analysis of Part 1 revealed an imbalance in early deaths (5-30d) by treatment (13% ALB vs. 5.5% saline). In subjects >83 years, deaths within 90d were 2.3x higher with ALB than saline. Thus, an upper-age limit was set in the Part 2 trial. In addition, 90-d death rates differed by treatment in subjects who had received excessive IV fluids. Pulmonary edema within 48h occurred in 12.1% of ALB- and 4.1% of saline-treated subjects. In Part 2, we re-stricted 48-h IV fluids to </=4200 ml and mandated diuretic therapy. Conclusions: The ALIAS Part 2 Trial began in Feb., 2009. Adverse event rates as of 820 subjects were: pulmonary edema within 48h, 6.9%; symptomatic ICH within 24h, 2.9%; death within 30d, 10.0%. At the ESC, we shall present detailed safety outcomes.
Karger_ESC London_2013
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