Albumin in Acute Ischemic Stroke Trial (ALIAS)

• Overall clinical outcome (as assessed by global statistical test of NIHSS, mRS, and BI scores) [ Time Frame: at 3 months ] [ Designated as safety issue: Yes ]
• mRS (dichotomized and full-scale) [ Time Frame: at 1, 3, 6, 9, and 12 months ] [ Designated as safety issue: Yes ]
• Symptomatic ICH [ Time Frame: within 24 hours ] [ Designated as safety issue: Yes ]
• Congestive heart failure [ Time Frame: within 48 hours ] [ Designated as safety issue: Yes ]
• Pulmonary edema [ Time Frame: within 48 hours ] [ Designated as safety issue: Yes ]
• Barthel Index [ Time Frame: at 3 and 12 months ] [ Designated as safety issue: Yes ]
• Quality-of-life measures: EuroQol at 3 and 12 months, and SSQO at 3 months [ Time Frame: at 3 and 12 months ] [ Designated as safety issue: Yes ]
• Recurrent ischemic stroke [ Time Frame: at 3, 6, 9, and 12 months ] [ Designated as safety issue: Yes ]
• Death within 3 months and at 12 months after randomization [ Time Frame: within 3 months and at 12 months ] [ Designated as safety issue: Yes ]
• Cognition (Trailmaking A and B) [ Time Frame: at 3 months ] [ Designated as safety issue: Yes ]

• mRS
• NIHSS
• symptomatic ICH
• congestive heart failure
• pulmonary edema

The goal of the trial is to determine whether human albumin, administered within 5 hours of symptom onset, improves the 3-month outcome of subjects with acute ischemic stroke.

Human serum albumin, at 2 g/kg, administered over 2 hours by intravenous infusion, will be compared to placebo (isovolumic normal saline) among patients with acute ischemic stroke. All patients will have a baseline stroke severity measured as NIH Stroke scale score > 5. Patients will treated according to the best standard of care including concurrent treatment with intravenous or intra-arterial thrombolysis where appropriate. The primary outcome will be determined at 3 months. The primary hypothesis is that, using the composite outcome of a modified Rankin score 0-1 or NIH stroke scale score 0-1 at 3 months (or both), the proportion of patients with improved outcomes will be greater by 10% or more in the active treatment group. [The current trial is termed "Part 2" and incorporates revisions to the initial protocol that were instituted after the DSMB suspended subject recruitment because of a safety concern after 434 subjects had been enrolled. The protocol revisions of Part 2 resulted from the study team's thorough review of the Part-1 safety data and were designed to optimize safety going forward.]

• Biological: human serum albumin infusion
  human albumin, 25%, 2.0g/kg intravenously (or equivalent volume of saline control), infused over 2 h, commencing within 5 hours of stroke onset
• Drug: placebo
  equivalent volume of saline control

• Experimental: 1
  Treatment with 25% Albumin, 2.0 g/kg
  Intervention: Biological: human serum albumin infusion
• Placebo Comparator: 2
  Treatment with same volume of normal saline
  Interventions:

  • Biological: human serum albumin infusion
  • Drug: placebo

Inclusion Criteria:

• Acute ischemic stroke
• NIH stroke scale score > 5
• Age >= 18 and <= 83
• ALB or placebo can be administered within 5 hours of symptom onset
• ALB or placebo can be administered within 60 minutes of tPA administration in the thrombolysis group
• Signed informed consent

Exclusion Criteria:

• Episode/exacerbation of congestive heart failure (CHF) from any cause in the last 6 months. An episode of congestive heart failure is any heart failure that required a change in medication, diet or hospitalization.
• Known valvular heart disease with CHF in the last 6 months.
• Severe aortic stenosis or mitral stenosis.
• Cardiac surgery involving thoracotomy (e.g., coronary artery bypass graft (CABG), valve replacement surgery) in the last 6 months.
• Acute myocardial infarction in the last 6 months.
• Signs or symptoms of acute myocardial infarction, including ECG findings, on admission.
• Baseline elevated serum troponin level on admission (>0.1 mcg/L)
• Suspicion of aortic dissection on admission.
• Acute arrhythmia (including any tachycardia - or bradycardia) with hemodynamic instability.
• Findings on physical examination of any of the following: (1) jugular venous distention (JVP > 4 cm above the sternal angle); (2) 3rd heart sound; (3) resting tachycardia (heart rate > 100/min) attributable to congestive heart failure; (4) abnormal hepatojugular reflux; (5) lower extremity pitting edema attributable to congestive heart failure; and/or (6) definite chest x-ray evidence of pulmonary edema.
• Current acute or chronic lung disease requiring supplemental chronic or intermittent oxygen therapy.
• Historical mRS ≥2. Patients who live in a nursing home or who are not fully independent for activities of daily living immediately prior to the stroke are not eligible for the trial.
• In-patient stroke. I.e., patients with a stroke occurring as a complication of hospitalization for another condition, or as a complication of a procedure.
• Planned acute use of intra-arterial (IA) tPA or acute endovascular intervention (e.g., stenting, angioplasty, thrombus retrieval device use) must conform to the following criteria: (1) begin within 5 hours of symptom onset, and (2) finish within 7 hours of symptom-onset.
• Fever, defined as core body temperature > 37.5oC (99.5oF).
• Serum creatinine > 2.0 mg/dL or 180 µmol/L.
• Profound dehydration.
• Evidence of intracranial hemorrhage (intracerebral hematoma (ICH), subarachnoid hemorrhage (SAH), epidural hemorrhage, acute or chronic subdural hematoma (SDH)) on the baseline CT or MRI scan.
• History of allergy to albumin.
• History of latex rubber allergy.
• Severe chronic anemia with Hgb < 7.5 g/dL
• Pregnancy, breastfeeding or positive pregnancy test. (Women of childbearing age must have a negative pregnancy test prior to ALB administration.)
• Concurrent participation in any other therapeutic clinical trial.
• Evidence of any other major life-threatening or serious medical condition that would prevent completion of 3-month follow-up, impair the assessment of outcome, or in which ALB therapy would be contraindicated or might cause harm to the subject.

• National Institute of Neurological Disorders and Stroke (NINDS)
• University of Calgary
• Medical University of South Carolina
• Neurological Emergencies Treatment Trials Network (NETT)