Overview

The FAST-MAG Phase 3 Trial is a multicenter, randomized, placebo-controlled, double-blind, parallel group trial of intravenous magnesium sulfate initiated by paramedics in the field within 2 hours of symptom onset in 1298 patients with acute stroke. The primary objective of the study is to evaluate the efficacy and safety of field-initiated magnesium sulfate in improving the long-term functional outcome of patients with acute stroke. The study is being conducted within the service area of the Los Angeles County Emergency Medical Services Agency, whose component systems provide prehospital care to a population of 9.8 million. Patients with acute stroke are identified in the field by licensed paramedics who have received training in basic and advanced cardiac life support, stroke recognition, and specific procedures relevant to the proposed study. Physician-investigators approve each patient for study entry after cellular phone contact with paramedics. Physician-investigators also by phone elicit explicit informed consent to participate in the study, from patients when the subject is competent and from on scene legally authorized persons when the subject is not competent.

Paramedics initiate a loading dose of 4 grams magnesium sulfate iv over 15 minutes or matched placebo, followed after hospital arrival by a maintenance infusion of 16 grams magnesium sulfate iv over 24 hours or matched placebo. Follow-up assessments are performed at ED arrival, 24 hours, 48 hours, day 4, day 30, and day 90. The enrollment period will last 3.5 years and the follow-up period an additional 3 months. The sites involved in the study will be up to all (~330) rescue engines of the Los Angeles County EMS system and up to all (~80) hospitals with a licensed adult patient Emergency Department in the County of Los Angeles.

Study Hypotheses

The central aim of this study 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 study design 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, with study agent initiated in all individuals within two hours of stroke 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.

Primary Hypothesis:
Treatment with magnesium sulfate improves the long-term functional outcome of hyperacute stroke patients.

The primary study endpoint analyzed to test this hypothesis 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 Hypotheses:
Treatment with magnesium sulfate improves the long-term outcome of hyperacute stroke patients on measures of activities of daily living, neurologic deficit, quality of life, and mortality.

The secondary study endpoints analyzed to test these hypotheses will be the difference in distribution of scores between magnesium sulfate and placebo groups on the Barthel Activities of Daily Living Scale, the National Institute of Health Stroke Scale (neurologic deficit), the Stroke Impact Scale (stroke-specific quality of life), and in mortality, assessed 3 months poststroke.

Treatment with magnesium sulfate improves the long-term functional outcome of each of the following subgroups of hyperacute stroke patients:

1. Patients with ischemic stroke

2. Patients with intracerebral hemorrhage

3. Patients with ischemic stroke treated with conventional intravenous tissue plasminogen activator

4. Patients with ischemic stroke not treated with conventional intravenous tissue plasminogen activator

5. Patients with ischemic stroke treated within 60 minutes of onset

6. Patients with ischemic stroke treated within 61-120 minutes of onset

To test these hypotheses, the primary study endpoint, differences in the distribution of scores between magnesium sulfate and placebo groups on the modified Rankin Scale measure of global handicap, will be separately analyzed in each of these subgroups.