Albumin in Acute Ischemic Stroke Trial

Study Overview
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Brief Summary
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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.

Detailed Description
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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.]

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

Conditions
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Ischemic Stroke

Intervention / Treatment
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* Biological: Albumin
* Drug: Saline


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 83 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stroke