IVIG in Acute Ischemic Stroke: A Pilot Study

Study Overview
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Brief Summary
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The purpose of the study is to evaluate the ability of IVIG to affect the rate of progression of brain ischemia, as evidenced by neuroimaging. The results of an ongoing epidemiological study indicate that patients with primary immunodeficiency (PID) on IVIG replacement therapy have an overall prevalence of stroke that is 5 times less than in the general population. Even more striking is the absence of stroke in IVIG-treated PID patients over 65, while in the same general population age group the stroke prevalence goes up to 8.1%. This suggests that the degree of stroke protection correlates with the length of IVIG treatment, since older PID patients have been treated with IVIG significantly longer than younger ones.

Detailed Description
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Two pre-clinical studies demonstrated the effectiveness of IVIG preparations in improving the clinical outcome of stroke and at the same time provided evidence of the role of complement fragments in the pathogenesis of ischemia-induced brain damage. Scavenging of these active fragments by IVIG is the likely mechanism of beneficial effect. In one of these studies CSL's own Privigen preparation was used. Considering that it exhibited in-vitro scavenging abilities more pronounced than several other IVIG preparations, and that its in-vivo scavenging capacity was also proven in a relevant animal model, a need to test this preparation in stroke patients is warranted. In addition, activation of complement and the level of activated fragments in humans seem to correlate with the severity of the disease, making them an ideal therapeutic target.

Official Title
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IVIG in Acute Ischemic Stroke: A Pilot Study

Conditions
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Ischemic Stroke

Intervention / Treatment
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* Biological: Privigen
* Other: Normal Saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Onset of neurological symptoms between 4.5 and 8 hours Male or Female age 45 -75 years old Score of 10-15 points on the National Institutes of Health Stroke Scale (NIHSS) with clinical signs suggestive of ischemic stroke Acute brain ischemia with a distinct penumbra (at least 20%), measured by magnetic resonance perfusion imaging (PI) and diffusion-weighted imaging (DWI), in the territory of the middle cerebral artery, anterior cerebral artery, or posterior cerebral artery with a hemispheric distribution Ability and willingness to provide informed consent and comply with study requirements and procedures Exclusion Criteria: Eligibility for acute thrombolytic (rtPA) treatment Normal brain MRI Transient ischemic attack or rapidly improving neurological symptoms Previous disability Hemorrhagic stroke on brain MRI (T2*/SWI) Ongoing infection defined by clinical and laboratory signs: an evidence-based guideline will be followed to detect infectious complications (in short, physical and laboratory measures including WBC, ESR, hsCRP, PCT, fever, abnormal urine, chest X-ray or positive cultures) Diagnosis of malignancy Known sensitivity to any ingredients in the study drug or radiological contrast material Participation in another clinical trial within the past 30 days Stroke in the previous 3 months Chronic liver, kidney or hematological disease Contraindications to MRI -Brain aneurysm clip, implanted neural stimulator, implanted cardiac pacemaker or defibrillator, cochlear implant, ocular foreign body e.g. metal shavings, other implanted medical devices: (e.g. Swan Ganz catheter) insulin pump, metal shrapnel or bullet. Diabetes Hypertension Females who are pregnant or breastfeeding

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 75 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Privigen<br>The IVIG preparation to be used is 10% liquid (Privigen). IVIG will be applied at a dose of 1.0g/kg, which is approximately 1/2 of the optimal dose used for other immuno/inflammatory indications. The infusion will start at 0.5 ml/kg/hr for the first 30 minutes, to watch for the signs of hypersensitivity to immunoglobulins, and then increased to 2.5 ml/kg/hr, two times slower than the recommended rate indicated in the product package insert (5 ml/kg/hr). Such a low, single dose has not been associated with hyperviscosity and together with a slow infusion will safeguard against occurrence of adverse events related to IVIG infusions. They will receive a total of 1g/kg and depending on patient's weight, it will take between 3.5 to 4+ hours to infuse that amount. | Biological: Privigen<br>* 10% liquid intravenous immunoglobulin at a single dose of 1.0g/kg, run at 0.5ml/kg/hr for the first 30 minutes, then increased to 2.5ml/kg/hr until complete ( 3-4 hours depending on weight).<br>* Other names: Immune Globulin Intravenous (Human), 10% Liquid;|
| Placebo Comparator: Normal Saline<br>The placebo is the normal saline. Since saline solution will be infused at the volume equivalent to that in which the intended dose of immunoglobulin molecules will be delivered, the placebo (comparator) arm will also serve as a control for the volume of fluid infused to the treatment arm participants. | Other: Normal Saline<br>* Normal Saline is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment. It contains no antimicrobial agents. The pH is 5.0 (4.5 to 7.0). It contains 9 g/L Sodium Chloride with an osmolarity of 308 mOsmol/L and 154 mEq/L Sodium and Chloride. The infusion will start at 0.5 ml/kg/hr for the first 30 minutes and then increased to 2.5 ml/kg/hr for 3-4 hours.<br>* Other names: 0.9% Sodium Chloride Solution;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Post-IVIG DWI/PI mismatch measurement | Decrease in the size of post IVIG necrotic area relative to baseline values and percent of penumbra saved, defined by neuroimaging as DWI/PI mismatch. | 3 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Favorable clinical outcome | Favorable clinical outcome at Day 90, which requires fulfillment of all three of the following criteria: improvement in NIHSS of 8 points or more from baseline; modified Rankin scale (mRS) score of 0-2 points; and Barthel index (BI) of 75-100 | 90 days | 
| Clinical outcome measure by NIHSS | Clinical outcome measured by change in NIHSS scores will be also examined on Day 3 | 3 days | 
| Active complement fragment levels | Levels of active complement fragments, C3a, C5a, C5b-9 and C4d at Day 0 and post-IVIG and Day 90. | 90 days | 
| Adverse Events | Incidence in adverse events. | 90 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IVIg, Acute Ischemic Stroke, Stroke, CVA, Cerebrovascular Accident