Stroke is the third leading cause of death and the leading cause of adult disability in the United States. Each year in the US, 795,000 Americans suffer a symptomatic stroke. The central aim of this proposal is to demonstrate that paramedic initiation of the neuroprotective agent magnesium sulfate in the field is an efficacious and safe treatment for acute stroke. The proposal is a multicenter, randomized, double-blind, phase 3 clinical trial, using intention to treat analysis, of magnesium sulfate versus placebo among ambulance-transported patients with acute stroke. Study agent will be initiated within two hours of stroke onset in all enrolled individuals, and within one hour of onset in approximately one- half of enrolled individuals. A total of 1700 patients will be enrolled, 850 in each treatment arm. The dose of magnesium sulfate employed will be 4 gram IV loading dose over 15 minutes followed by 16 gram IV maintenance dose over 24 hours. The primary study hypothesis is that treatment with magnesium sulfate improves the long-term functional outcome of hyperacute stroke patients. The primary study endpoint will be the difference in distribution of scores between magnesium sulfate and placebo groups on the modified Rankin Scale measure of global handicap, assessed 3 months poststroke. Secondary analyses will analyze treatment efficacy on endpoints indexing neurologic deficit, activities of daily living, global outcome, and quality of life, and in prespecified patient subgroups, including patients with ischemic stroke, ischemic stroke co-treated with tissue plasminogen activator, ischemic stroke not co-treated with tissue plasminogen activator, intracerebral hemorrhage, patients treated within 15-60 minutes of symptom onset, and within 61-120 minutes of symptom onset. Successful conduct of the trial will serve as a pivotal test of the promising neuroprotective agent magnesium sulfate in acute stroke, and will also demonstrate for the first time that field enrollment and treatment of acute stroke patients is a practical and feasible strategy for phase 3 stroke trials, permitting enrollment of greater numbers of patients in hyperacute time windows.

Public Health Relevance

Stroke is the third leading cause of death and the leading cause of adult disability in the United States. The central aim of this clinical trial enrolling 1700 patients is to demonstrate that paramedic start of the brain protective agent magnesium sulfate in the field improves stroke outcomes. Successful conduct of the trial will serve as a pivotal test of the promising neuroprotective agent magnesium sulfate in acute stroke, and will also demonstrate for the first time that field treatment of acute stroke patients is a practical strategy for stroke trials, permitting enrollment of greater numbers of patients in the critical first two hours early after onset.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01NS044364-10
Application #
8442766
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Janis, Scott
Project Start
2002-07-01
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
10
Fiscal Year
2013
Total Cost
$2,133,125
Indirect Cost
$613,316
Name
University of California Los Angeles
Department
Neurology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Kim, Seo Hyun; Saver, Jeffrey L (2015) Initial body temperature in ischemic stroke: nonpotentiation of tissue-type plasminogen activator benefit and inverse association with severity. Stroke 46:132-6
Saver, Jeffrey L; Starkman, Sidney; Eckstein, Marc et al. (2014) Methodology of the Field Administration of Stroke Therapy - Magnesium (FAST-MAG) phase 3 trial: Part 1 - rationale and general methods. Int J Stroke 9:215-9
Brandler, Ethan S; Sharma, Mohit; Sinert, Richard H et al. (2014) Prehospital stroke scales in urban environments: a systematic review. Neurology 82:2241-9
Patel, Richa D; Saver, Jeffrey L (2013) Evolution of reperfusion therapies for acute brain and acute myocardial ischemia: a systematic, comparative analysis. Stroke 44:94-8
Froehler, Michael T; Tateshima, Satoshi; Duckwiler, Gary et al. (2013) The hyperdense vessel sign on CT predicts successful recanalization with the Merci device in acute ischemic stroke. J Neurointerv Surg 5:289-93
Saver, Jeffrey L; Altman, Hernan (2012) Relationship between neurologic deficit severity and final functional outcome shifts and strengthens during first hours after onset. Stroke 43:1537-41
Saver, Jeffrey L (2011) Optimal end points for acute stroke therapy trials: best ways to measure treatment effects of drugs and devices. Stroke 42:2356-62
Lee, Meng; Saver, Jeffrey L; Towfighi, Amytis et al. (2011) Efficacy of fibrates for cardiovascular risk reduction in persons with atherogenic dyslipidemia: a meta-analysis. Atherosclerosis 217:492-8
Nogueira, Raul G; Smith, Wade S; Sung, Gene et al. (2011) Effect of time to reperfusion on clinical outcome of anterior circulation strokes treated with thrombectomy: pooled analysis of the MERCI and Multi MERCI trials. Stroke 42:3144-9
Saver, J L (2011) Improving reperfusion therapy for acute ischaemic stroke. J Thromb Haemost 9 Suppl 1:333-43

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