Albumin in Acute Ischemic Stroke Trial (ALIAS)

A Phase III Randomized Multicenter Clinical Trial Of High-Dose Human Albumin Therapy For Neuroprotection In Acute Ischemic Stroke

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.

Study Overview

• Status: Terminated
• Conditions: Ischemic Stroke
• Intervention / Treatment: Biological: Albumin; Drug: Saline

Detailed Description

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 Data Safety Monitoring Board (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.]

• Study Type: Interventional
• Enrollment (Actual): 841
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 2T9
      • Foothills Hospital, University of Calgary
    • Edmonton, Alberta, Canada, T6G 1Z1
      • University of Alberta
    • Edmonton, Alberta, Canada, T6L 5X8
      • Grey Nuns Community Hospital
  • British Columbia
    • Kamloops, British Columbia, Canada, V2C 2T1
      • Royal Island Hospital
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • Vancouver General Hospital
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H-3A7
      • Queen Elizabeth II Health Science Centre
  • Ontario
    • London, Ontario, Canada, N6A 5A5
      • London Health Sciences Centre-University Hospital
    • Mississauga, Ontario, Canada, L5B 1B8
      • Trillium Health Centre
    • Ottawa, Ontario, Canada, K1Y 4E9
      • The Ottawa Hospital
    • Thunder Bay, Ontario, Canada, P7B 7C7
      • Thunder Bay Regional Health Sciences Centre
    • Toronto, Ontario, Canada, M5C 1R6
      • University of Toronto, St. Michael's Hospital
  • Quebec
    • Greenfield Park, Quebec, Canada, J4V 2H1
      • Hopital Charles LeMoyne, Centre de Recherche
    • Saguenay, Quebec, Canada, G7H 5H6
      • Centre de Sante et de Service Sociaux de Chicoutimi
• Finland
  • Helsinki, Finland, FI-00290
    • Helsinki University Central Hospital
  • Tampere, Finland, Fi-33521
    • Tampere University Hospital
• Israel
  • Beer Sheva, Israel, 84101
    • Soroka Medical Center
  • Haifa, Israel, 31096
    • Rambam Health Care Campus
  • Tel Aviv, Israel, 64239
    • Tel-Aviv Sourasky Medical Center
  • Jerusalem
    • Ein Kerem, Jerusalem, Israel
      • Hadassah Medical Organization, Hadassah University Hospital
  • Ramat Gan
    • Tel Hashomer, Ramat Gan, Israel, 52621
      • Chaim Sheba Medical Center at Tel-Hashomer
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Hospital
    • Tucson, Arizona, United States, 85724
      • University of Arizona Medical Center
    • Tucson, Arizona, United States, 85724-5030
      • University of Arizona Medical Center-South Campus
  • California
    • Concord, California, United States, 94520
      • John Muir Medical Ctr-Concord
    • Mountain View, California, United States, 94040-4378
      • El Camino Hospital
    • San Francisco, California, United States, 94110
      • UCSF Medical Center
    • San Francisco, California, United States, 94110
      • UCSF-San Francisco General Hospital
    • San Francisco, California, United States, 94114
      • California Pacific Medical Center, Davies Campus
    • San Francisco, California, United States, 94115
      • California Pacific Medical Center, Pacific Campus
    • San Jose, California, United States, 95128
      • O'Connor Hospital
    • Santa Monica, California, United States, 90024
      • UCLA Medical Center, Santa Monica
    • Stanford, California, United States, 94305
      • Stanford University Medical Center
    • Walnut Creek, California, United States, 94598
      • John Muir Medical Ctr-Walnut Creek
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale University School of Medicine
  • Delaware
    • Newark, Delaware, United States, 19718
      • Christiana Hospital
  • Florida
    • Jacksonville, Florida, United States, 32209
      • University of Florida/Shands
    • Miami, Florida, United States, 33136-1096
      • Jackson Memorial Hospital, University of Miami
    • Ocala, Florida, United States, 34474
      • The Villages Research Group
    • Orlando, Florida, United States, 32804
      • Neuroscience Research Institute at Florida Hospital Orlando
    • Sarasota, Florida, United States, 34239
      • Intercoastal Neurology/Medical Research Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Hospital
    • Atlanta, Georgia, United States, 30303
      • Grady Memorial Hospital
  • Illinois
    • Maywood, Illinois, United States, 60153
      • Loyola University Medical Center
  • Kentucky
    • Edgewood, Kentucky, United States, 41017
      • St. Elizabeth Medical Center South
    • Florence, Kentucky, United States, 41042
      • St. Elizabeth Hospital
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky Hospital
  • Maryland
    • Baltimore, Maryland, United States, 21201-1595
      • University of Maryland Medical Center
    • Bel Air, Maryland, United States, 21014
      • Upper Chesapeake Medical Center
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
    • Detroit, Michigan, United States, 48201
      • Detroit Receiving Hospital
    • Detroit, Michigan, United States, 48235
      • Sinai-Grace Hospital
    • Royal Oak, Michigan, United States, 48073
      • William Beaumont Hospital
  • Minnesota
    • Edina, Minnesota, United States, 55435
      • Fairview Southdale Hospital
    • Minneapolis, Minnesota, United States, 55415
      • Hennepin County Medical Center
    • Minneapolis, Minnesota, United States, 55454
      • University of Minnesota Medical Center Fairview
    • Saint Paul, Minnesota, United States, 55102
      • HealthEast Care System/St. Joseph's Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Saint Louis University
  • New Jersey
    • Summit, New Jersey, United States, 07902
      • Atlantic Neuroscience Institute, Overlook Hospital
  • New York
    • Brooklyn, New York, United States, 11215
      • New York Methodist Hospital
    • Buffalo, New York, United States, 14203
      • Buffalo General Medical Center
    • Buffalo, New York, United States, 14220
      • Mercy Hospital of Buffalo
    • Mineola, New York, United States, 11501
      • Winthrop University Hospital
    • New York, New York, United States, 10032
      • Columbia University Medical Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-7025
      • University Of North Carolina At Chapel Hill
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
    • Raleigh, North Carolina, United States, 27610
      • Wake Med Health and Hospitals
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • University of Cincinnati Medical Center
    • Cincinnati, Ohio, United States, 45220
      • Good Samaritan Hospital
    • Cincinnati, Ohio, United States, 45219
      • Christ Hospital
    • Cincinnati, Ohio, United States, 45242-4402
      • Bethesda North Hospital
    • Cleveland, Ohio, United States, 44109-1998
      • MetroHealth Medical Center
    • Columbus, Ohio, United States, 43210
      • Ohio State University Medical Center
    • Fairfield, Ohio, United States, 45014
      • Mercy Health Fairfield Hospital
  • Oregon
    • Portland, Oregon, United States, 97213
      • Providence Portland Medical Center
    • Portland, Oregon, United States, 97239-3098
      • Oregon Health & Science University
    • Portland, Oregon, United States, 97225
      • Providence St. Vincent Medical Center
    • Portland, Oregon, United States, 97227
      • OHSU Legacy Emmanuel Hospital
    • Springfield, Oregon, United States, 97477
      • Sacred Heart Medical Center
  • Pennsylvania
    • Abington, Pennsylvania, United States, 19001
      • Abington Memorial Hospital
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania Medical Center
    • Philadelphia, Pennsylvania, United States, 19130
      • Temple University Hospital
    • Philadelphia, Pennsylvania, United States, 19140
      • Hahnemann University Hospital
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center
  • Texas
    • Austin, Texas, United States, 78701
      • Seton Medical Center
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
    • Houston, Texas, United States, 77030
      • Memorial Hermann Texas Medical Center
  • Virginia
    • Richmond, Virginia, United States, 23219
      • Virginia Commonwealth University Medical Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Froedtert Memorial Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 83 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Tissue Plasminogen Activator (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 Modified Rankin Score (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 > 37.5° C (99.5°F).
• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Albumin (ALB); Albumin (human albumin, 25% solution, 2.0 g/kg), infused intravenously over a period of 2 hours	Biological: Albumin; human albumin, 25%, 2.0g/kg intravenously (or equivalent volume of saline control), infused over 2 h, commencing within 5 hours of stroke onset
Placebo Comparator: Saline; Saline (isotonic solution), 8 ml/kg, infused intravenously over a 2-hour period	Drug: Saline; equivalent volume of isotonic saline control

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Number of Participants With Favorable Outcome Defined as National Institute of Health Stroke Scale (NIHSS) Score of 0-1 and/or Modified Rankin Scale (mRS) of 0-1.	The National Institutes of Health Stroke Scale (NIHSS) is a systematic assessment tool that provides a quantitative measure of stroke-related neurologic deficit. The scores range from 0 to 42 with a score of greater than 20 indicating severe neurologic deficit. The mRS ranges from 0-6 representing perfect health without symptoms to death. A score of 0 is no symptoms at all and a score of 1 is no significant disability. Able to carry out all usual duties and activities.	at 3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With a Composite Outcome of mRS 0-1 and/or NIHSS 0-1 and/or Decrease in NIHSS From Baseline by 10 or More Points		at 3 months
Number of Participants With a NIHSS of 0-1 at 24 Hours	The National Institutes of Health Stroke Scale (NIHSS) is a systematic assessment tool that provides a quantitative measure of stroke-related neurologic deficit. The scores range from 0 to 42 with a score of greater than 20 indicating severe neurologic deficit.	at 24 hours
Number of Participants With a NIHSS 0-1 at 90 Days.	The National Institutes of Health Stroke Scale (NIHSS) is a systematic assessment tool that provides a quantitative measure of stroke-related neurologic deficit. The scores range from 0 to 42 with a score of greater than 20 indicating severe neurologic deficit.	at 90 days
The Number of Participants With a Score on the mRS 0-1 at 90 Days.	The mRS ranges from 0-6 representing perfect health without symptoms to death. 0 = No symptoms at all. 1 = No significant disability. Able to carry out all usual duties and activities. 2 = Slight disability. Unable to carry out all previous activities but able to look after own affairs without assistance. 3 = Moderate disability. Requires some help, but able to walk unassisted. 4 = Moderately severe disability. Unable to walk unassisted and unable to attend to own bodily needs without assistance. 5 = Severe disability. Bedridden, incontinent, and requires constant nursing care and attention. 6 = Dead.	at 90 days
The Number of Participants With a Score on the mRS of 0-2 at 90 Days.	The mRS ranges from 0-6 representing perfect health without symptoms to death. 0 = No symptoms at all. 1 = No significant disability. Able to carry out all usual duties and activities. 2 = Slight disability. Unable to carry out all previous activities but able to look after own affairs without assistance. 3 = Moderate disability. Requires some help, but able to walk unassisted. 4 = Moderately severe disability. Unable to walk unassisted and unable to attend to own bodily needs without assistance. 5 = Severe disability. Bedridden, incontinent, and requires constant nursing care and attention. 6 = Dead.	at 90 days
Number of Participants With a Favorable Outcome Per Modified Rankin Scare (mRS)	Assessed as the final global disability level on the modified Rankin scale (mRS) at 90 days better than expectation (sliding dichotomy analysis) ) assessed in the intention to treat population. mRS Scale: 0 - No symptoms.; - No significant disability. Able to carry out all usual activities, despite some symptoms.; - Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities.; - Moderate disability. Requires some help, but able to walk unassisted.; - Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted.; - Severe disability. Requires constant nursing care and attention, bedridden, incontinent.; - Dead.	90 days
Barthel Index (BI) 95-100	The Barthel Index (BI) is an ordinal scale used to measure a subject's performance in activities of daily living (ADL) in ten variables - feeding, transfer (bed to chair), grooming, toilet use, bathing, mobility on a level surface, stair use, dressing, bowels and bladder. It is an assessment of independence in ADL and is scored in increments of 5 points. the highest total score for fully independent subjects equals 100. A higher number is associated with a greater likelihood of being able to live at home with a degree of independence.	at 90 days
Number of Participants With an EuroQol (EQ-5D) Favorable Score < 0.78	The EQ-5D measures the subject's overall health state in a descriptive system of health-related quality of life (QoL) states consisting of five dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) each of which can take one of three responses. The responses record three levels of severity ('no problems', 'some problems', and 'extreme problems) within a particular EQ-5D dimension. The EQ-5D results can be converted to health utility scores.	at 90 days
Number of Participants With a Stroke Specific Quality of Life Scale (SSQOL) Score of >=3	Stroke, specific, health-related quality of life (SSQoL) is a self-reported survey that includes 12 domains and 49 items which are scored on a 5pt Likert response format with a lower score indicating worse function/lower ability on that item or domain. Domain scores were calculated as an unweighted average of item scores in that domain. Overall Total Score was calculated as an unweighted average of domain scores. Each Domain Score and the Overall Total Score all range from 1-5 with 1 being worst and 5 being the best. We have presented data here for the number of participants that have an unweighted average of domain scores of 3 or greater.	at 90 days
Trailmaking A	The Trail Making Test is a neuropsychological test of visual attention and task switching that is thought to be sensitive to the presence of cerebral dysfunction. It is a timed test consisting of two parts where the subject is asked to draw a "trail" made by connecting numbers in sequential order (part A) and then in part B the combination of numbers and letters. Scoring is calculated separately for Parts A and B but both scores are provided as the minutes and seconds it takes for the subject to complete ach part. Normally, the entire test (A and B) can be completed in 5-10 minutes.	at 90 days
Trailmaking B	The Trail Making Test is a neuropsychological test of visual attention and task switching that is thought to be sensitive to the presence of cerebral dysfunction. It is a timed test consisting of two parts where the subject is asked to draw a "trail" made by connecting numbers in sequential order (part A) and then in part B the combination of numbers and letters. Scoring is calculated separately for Parts A and B but both scores are provided as the minutes and seconds it takes for the subject to complete ach part. Normally, the entire test (A and B) can be completed in 5-10 minutes.	at 90 days
Number of Participants With Neurological Deterioration Within 48 Hours	This is assessed as the number of participants with a neurological adverse event.	within 48 hours
Neurological Death Within 7 Days		within 7 days
Recurrent Ischemic Stroke Within 30 Days		within 30 days
Atrial Fibrillation Within 48 Hours		within 48 hours
Pulmonary Edema Within 48 Hours		within 48 hours
Shortness of Breath Within 48 Hours		within 48 hours
Symptomatic Intracerebral Hemorrhage (ICH) Within 24 Hours		within 24 hours
Asymptomatic ICH Within 24 Hours		within 24 hours
Death Within 30 Days		within 30 days
Death Within 90 Days		within 90 days

Collaborators and Investigators

• Sponsor: University of Miami
• Collaborators: Medical University of South Carolina; National Institute of Neurological Disorders and Stroke (NINDS); University of Calgary; Neurological Emergencies Treatment Trials Network (NETT)
• Investigators: Study Chair: Myron D. Ginsberg, MD, University of Miami; Principal Investigator: Michael D. Hill, MD MSc, University of Calgary

Publications and helpful links

General Publications

• Martin RH, Yeatts SD, Hill MD, Moy CS, Ginsberg MD, Palesch YY; ALIAS Parts 1 and 2 and NETT Investigators. ALIAS (Albumin in Acute Ischemic Stroke) Trials: Analysis of the Combined Data From Parts 1 and 2. Stroke. 2016 Sep;47(9):2355-9. doi: 10.1161/STROKEAHA.116.012825. Epub 2016 Jul 26.
• Hill MD, Martin RH, Palesch YY, Moy CS, Tamariz D, Ryckborst KJ, Jones EB, Weisman D, Pettigrew C, Ginsberg MD. Albumin Administration in Acute Ischemic Stroke: Safety Analysis of the ALIAS Part 2 Multicenter Trial. PLoS One. 2015 Sep 1;10(9):e0131390. doi: 10.1371/journal.pone.0131390. eCollection 2015.
• Ginsberg MD, Palesch YY, Hill MD, Martin RH, Moy CS, Barsan WG, Waldman BD, Tamariz D, Ryckborst KJ; ALIAS and Neurological Emergencies Treatment Trials (NETT) Investigators. High-dose albumin treatment for acute ischaemic stroke (ALIAS) Part 2: a randomised, double-blind, phase 3, placebo-controlled trial. Lancet Neurol. 2013 Nov;12(11):1049-58. doi: 10.1016/S1474-4422(13)70223-0. Epub 2013 Sep 27.
• Hill MD, Martin RH, Palesch YY, Tamariz D, Waldman BD, Ryckborst KJ, Moy CS, Barsan WG, Ginsberg MD; ALIAS Investigators; Neurological Emergencies Treatment Trials Network. The Albumin in Acute Stroke Part 1 Trial: an exploratory efficacy analysis. Stroke. 2011 Jun;42(6):1621-5. doi: 10.1161/STROKEAHA.110.610980. Epub 2011 May 5.

Study record dates

Study Major Dates

• Study Start: June 1, 2006
• Primary Completion (Actual): February 1, 2013
• Study Completion (Actual): February 1, 2013

Study Registration Dates

• First Submitted: September 14, 2005
• First Submitted That Met QC Criteria: October 5, 2005
• First Posted (Estimate): October 10, 2005

Study Record Updates

• Last Update Posted (Actual): December 17, 2019
• Last Update Submitted That Met QC Criteria: December 3, 2019
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Keywords: stroke
• Additional Relevant MeSH Terms: Pathologic Processes; Necrosis; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Brain Ischemia; Infarction; Brain Infarction; Stroke; Ischemic Stroke; Ischemia; Cerebral Infarction
• Other Study ID Numbers: 20060083; U01NS054630 (U.S. NIH Grant/Contract); NIH NINDS 5U01 NS040406-08 (Other Identifier: Internal tracking number); 20060233 (Other Identifier: Western IRB)