Albumin Administration in Acute Ischemic Stroke: Safety Analysis of the ALIAS Part 2 Multicenter Trial

BACKGROUND: Albumin treatment of ischemic stroke was associated with cardiopulmonary adverse events in previous studies and a low incidence of intracranial hemorrhage. We sought to describe the neurological and cardiopulmonary adverse events in the ALIAS Part 2 Multicenter Trial. METHODS: Ischemic stroke patients, aged 18-83 and a baseline NIHSS ≥ 6, were randomized to treatment with ALB or saline control within 5 hours of stroke onset. Neurological adverse events included symptomatic intracranial hemorrhage, hemicraniectomy, neurological deterioration and neurological death. Cardiopulmonary adverse events included pulmonary edema/congestive heart failure, acute coronary syndromes, atrial fibrillation, pneumonia and pulmonary thromboembolism. RESULTS: Among 830 patients, neurological and cardiopulmonary adverse events were not differentially associated with poor outcome between ALB and saline control subjects. The rate of symptomatic intracranial hemorrhage in the first 24h was low overall (2.9%, 24/830) but more common in the ALB treated subjects (RR = 2.4, CI95 1.01-5.8). The rate of pulmonary edema/CHF in the first 48h was 7.9% (59/830) and was more common among ALB treated subjects (RR = 10.7, CI95 4.3-26.6); this complication was expected and was satisfactorily managed with mandated diuretic administration and intravenous fluid guidelines. Troponin elevations in the first 48h were common, occurring without ECG change or cardiac symptoms in 52 subjects (12.5%). CONCLUSIONS: ALB therapy was associated with an increase in symptomatic ICH and pulmonary edema/congestive heart failure but this did not affect final outcomes. Troponin elevation occurs routinely in the first 48 hours after acute ischemic stroke. TRIAL REGISTRATION: ClincalTrials.gov NCT00235495

A Dose-Escalation and Safety Study of Albumin Therapy for Acute Ischemic Stroke—I: Physiological Responses and Safety Results

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Abstract T P49: Improving Outcome of Placebo- but not Albumin-Treated Subjects Over the Course of the ALIAS Part 2 Multicenter Trial: Differential Influence of Thrombolytic Therapy

In the ALIAS2 Trial, 841 subjects were randomized 1:1 to treatment with either 25% albumin (ALB, 2 g/kg) or normal saline within 5 hours of stroke onset, and the primary outcome (NIHSS 0-1 and/or modified Rankin scale 0-1) was assessed at 90 days. While overall outcomes did not differ by treatment (44% for both groups), we observed a steadily improving favorable rate in the saline-placebo arm but not in the ALB arm over the trial’s 3.5 year course. This was further analyzed here. Methods and Findings: Logistic regression confirmed a significant randomization-order x treatment interaction (p<0.001). Thus, at the first pre-specified interim analysis of N=275 subjects, favorable outcome was seen in 44.8% with ALB but only 30.3% with saline (relative benefit 1.48, p=0.0028), while at the second interim analysis of N=550 subjects, the saline rate had risen to 37.5% while the ALB rate remained steady at 44.6% (relative benefit 1.21, p=0.0176). This trend-over-time in saline subjects was highly significant (Jonckheere-Terpstra (J-T) test, p=0.001; Pearson coefficient r=0.792), but there was no such trend in ALB subjects (J-T p=1.000). Simulation analysis confirmed that the saline trend could not have arisen by chance (p=0.0007). Importantly, intravenous tPA use also increased significantly during the trial in both ALB and saline subjects (initial rate 74%, final rate 95%, p<0.0001). Separate logistic regression analyses revealed a highly significant effect of IV tPA use on outcome in saline subjects (odds ratio 2.8, 95% CI 1.5-5.3, p=0.001) but only a marginal effect in ALB subjects (odds ratio 1.7, p=0.06). Conclusion: ALB treatment appears to have conferred a stable (and desirable) therapeutic “ceiling effect” throughout the trial (in the absence of significant toxicity), while saline subjects (who were unable to benefit from ALB) were susceptible to improved outcome from increasing tPA use as the trial progressed

The beta-hCG+erythropoietin in acute stroke (BETAS) study: a 3-center, single-dose, open-label, noncontrolled, phase IIa safety trial.

Background and purposeAnimal data suggest the use of beta-human chorionic gonadotropin followed by erythropoietin to promote brain repair after stroke. The current study directly translated these results by evaluating safety of this sequential growth factor therapy through a 3-center, single-dose, open-label, noncontrolled, Phase IIa trial.MethodsPatients with ischemic stroke 24 to 48 hours old and National Institutes of Health Stroke Scale score of 6 to 24 started a 9-day course of beta-human chorionic gonadotropin (once daily on Days 1, 3, and 5 of study participation) followed by erythropoietin (once daily on Days 7, 8, and 9 of study participation). This study also evaluated performance of serially measured domain-specific end points.ResultsA total of 15 patients were enrolled. Two deaths occurred, neither related to study medications. No safety concerns were noted among clinical or laboratory measures, including screening for deep vein thrombosis and serial measures of serum hemoglobin. In several instances, domain-specific end points provided greater insight into impairments as compared with global outcome measures.ConclusionsResults support the safety of this sequential, 2-growth factor therapy initiated 24 to 48 hours after stroke onset

The beta-hCG+erythropoietin in acute stroke (BETAS) study: a 3-center, single-dose, open-label, noncontrolled, phase IIa safety trial.

Background and purposeAnimal data suggest the use of beta-human chorionic gonadotropin followed by erythropoietin to promote brain repair after stroke. The current study directly translated these results by evaluating safety of this sequential growth factor therapy through a 3-center, single-dose, open-label, noncontrolled, Phase IIa trial.MethodsPatients with ischemic stroke 24 to 48 hours old and National Institutes of Health Stroke Scale score of 6 to 24 started a 9-day course of beta-human chorionic gonadotropin (once daily on Days 1, 3, and 5 of study participation) followed by erythropoietin (once daily on Days 7, 8, and 9 of study participation). This study also evaluated performance of serially measured domain-specific end points.ResultsA total of 15 patients were enrolled. Two deaths occurred, neither related to study medications. No safety concerns were noted among clinical or laboratory measures, including screening for deep vein thrombosis and serial measures of serum hemoglobin. In several instances, domain-specific end points provided greater insight into impairments as compared with global outcome measures.ConclusionsResults support the safety of this sequential, 2-growth factor therapy initiated 24 to 48 hours after stroke onset