Significance

Stroke is the third leading cause of death and the leading cause of adult disability in the United States. Each year in the US, over 750,000 Americans suffer a symptomatic stroke. More than 4 out of 5 strokes are due to ischemic infarction. Unfortunately, current therapies for acute ischemic stroke are of extremely limited effectiveness. To date, the only FDA approved treatment for acute ischemic stroke is intravenous tissue plasminogen activator (tPA), a thrombolytic agent which must be administered within 3 hours of symptom onset, and only after neuroimaging has ruled out intracerebral hemorrhage. Current estimates are that only 1-3% of acute ischemic stroke patients in the US receive TPA. The only other agent of proven utility in acute ischemic stroke is aspirin, which confers only minimal benefit, helping only one of every 110 patients treated. New, effective, widely applicable treatments for acute ischemic stroke are desperately needed.

The FAST-MAG Study will address this urgent need in two critical ways: 1) the study will constitute a definitive phase 3 trial of magnesium sulfate, a highly promising neuroprotective agent; and 2) the study will pioneer the prehospital initiation of neuroprotective agents in pivotal clinical trials of neuroprotective agents, permitting more patients to be treated in the first critical minutes after onset, and solving a major design defect of prior trials of neuroprotective stroke therapy.


The Neuroprotective Strategy for Treatment of Acute Stroke

When focal occlusions disrupt blood flow to the brain, a cascade of molecular events producing cell injury ensues. Cell death proceeds rapidly in the infarct core, where blood flow is most drastically curtailed, but more slowly in the ischemic penumbra, where blood flow is variably reduced and molecular elaboration of neuronal injury may proceed over hours. Central molecular events in the ischemic cascade include accumulation of intracellular calcium, release of excitatory amino acid neurotransmitters, generation of oxygen-free radicals, nitric oxide formation, and the release of cytokines by infiltrating polymorphonuclear leukocytes. These and additional events afford numerous targets for pharmacologic blockade. A multitude of neuroprotective drugs interfering with various pathways of ischemic injury reduce infarct volume substantially in focal stroke animal models when administered 10-120 minutes after ischemia onset, including excitatory amino acid antagonists, oxygen free radical scavengers, and voltage sensitive calcium channel blockers.

The ideal neuroprotective agent for stroke would be inexpensive, readily available, easy to administer and have no significant adverse side effects. An agent demonstrated to be safe and potentially beneficial in both ischemic and hemorrhagic stroke would have the added benefit of potentially earlier administration prior to obtaining a head CT scan. Intravenous magnesium sulfate offers promise as just such an agent.


Magnesium Sulfate

Magnesium ions cross the intact blood-brain barrier efficaciously so that intravenous magnesium sulfate significantly raises cerebrospinal fluid and brain extracellular fluid magnesium to supraphysiologic levels.[5,6] Magnesium sulfate is neuroprotective in preclinical models of cerebral and spinal cord ischemia, excitotoxic injury, and head trauma. Magnesium (Mg) is economical, widely available, simple to administer and has a long established safety and tolerability profile in myocardial infarction and eclampsia, as well as in pilot human focal stroke studies. Unlike most synthetic neuroprotective compounds, parenteral magnesium has no major adverse effects in doses that achieve serum levels in the range of preclinical neuroprotective concentrations.

Laboratory studies have identified multiple neuronal and vascular effects of magnesium that likely contribute to the potent neuroprotective effects observed in stroke models, as delineated in a recent comprehensive review. In a wide variety of in vitro systems and animal models, magnesium has been shown to inhibit presynaptic release of excitatory neurotransmitters, noncompetitively block the N-methyl-D-aspartate (NMDA) receptor, presynaptically potentiate adenosine, block voltage-gated calcium channels, suppress cortical spreading depression and anoxic depolarizations, relax vascular smooth muscle resulting in vasodilation of large and small vascular beds and increased cerebral blood flow, antagonize endothelin-1 and other vasoconstrictors, and replete an underlying and/or ischemia-induced Mg deficient state.

Magnesium is neuroprotective in rodent models of reversible and permanent focal cerebral ischemia and in animal models of global ischemia. At least nine preclinical studies have examined the effect of systemic magnesium sulfate upon final infarct size in animal focal ischemic stroke models. Eight of the nine demonstrated substantial decreases in infarct size in treated animals, with reductions ranging from 26-61% in unconfounded studies.

Eight phase 2 trials of magnesium in focal human stroke have been performed. All suggested good tolerability and potential efficacy.

An international phase III trial of late, in-hospital administration of magnesium in focal human stroke was reported in 2004, the Intravenous Magnesium Efficacy in Stroke Trial (IMAGES) study, funded by the British Medical Research Council. The IMAGES trial was designed at a time when the crucial need to treat patients within the first few hours after stroke onset was not fully appreciated. Accordingly, the IMAGES trial permitted enrollment of stroke patients up until 12 hours after stroke onset. Final worldwide enrollment was 2589 patients.

Overall, IMAGES was a neutral trial, with no statistically significant effect of magnesium sulfate on the primary endpoint of reduced death or disability, nor on any secondary efficacy or safety endpoint. Most relevant to FAST-MAG are the results observed in IMAGES for patients enrolled in early time epochs. Among the 79 patients enrolled within 3 hours of onset, on the IMAGES primary endpoint, the global odds ratio comparing magnesium vs placebo for a favorable death or disability outcome was 0.66 (95%CI 0.25-1.70). Considering the modified Rankin component of the IMAGES primary endpoint, a non-disabled outcome (mRS 0-1) was achieved in 45.9% of magnesium patients vs 33.3% of placebo patients, a 12.6% absolute difference. The IMAGES data thus provide a signal of potential efficacy of magnesium sulfate in acute stroke when administered within the first 3 hours after stroke onset. FAST-MAG will constitute a definitive, phase 3 trial test to validate this signal of potential benefit.


Prior Neuroprotective Agent Trials, the Key Variable of Time, and the Prehospital Strategy

In the past several decades, more than 50 neuroprotective agents have been tested in randomized controlled clinical trials in acute ischemic stroke, but none has been shown unequivocally to be beneficial in definitive phase III trials. Leading basic and clinial neuroscientists have identified 4 key design defects of past human clinical trials of neuroprotective clinical trials: 1) failure to administer study agents at neuroprotective doses in humans because of limiting side effects, 2) failure to select patients for trials who will respond to the known mechanisms of action of study drug, 3) failure to employ sample sizes large enough to detect modest benefits of study agent, and 4) failure to treat patients early enough after stroke onset.

The FAST-MAG trial is designed to remedy each of these past difficulties. The trial will employ magnesium sulfate at doses known to be both well tolerated and to yield serum levels neuroprotective in animal models. The trial will employ an agent likely to be beneficial for both gray and white matter ischemic injury, based on vasodilating effects in both superficial and deep circulations and cytoprotective effects in both gray and white matter. The trial is adequately powered to detect even a modest treatment effect, and will be larger than 95% of all previous phase 3 neuroprotective trials.

Most importantly, the FAST-MAG trial is designed to address the crucial factor of delayed time to treatment which has hindered all past human clinical trials of neuroprotective drugs. Rodent and nonhuman primate experimental studies suggest the duration of the therapeutic window within which neuroprotective intervention can ameliorate bioenergetic failure in the ischemic penumbra is very brief, generally less than 2-3 hours. Most animal studies of neuroprotective agents initiate therapy within 1-60 minutes after ischemia onset. However, although it is in the first 2 hours of onset that neuroprotective agents in general are beneficial in focal animal stroke models, no prior human clinical neuroprotective agent trial has enrolled any substantial cohort of patients in this time window. Devising methods to safely initiate experimental neuroprotective therapies more quickly is critical if the dramatic benefits of neuroprotective agents evident in the laboratory are to be achieved in human stroke victims.

Enrolling patients in the field in acute neuroprotective trials is a highly promising approach to the challenge of testing neuroprotective agents in hyperacute time epochs. Panels of emergency physicians and neurologists active in stroke research have suggested the desirability of paramedic treatment of acute stroke in the field. A vision of future stroke care widely shared in the stroke research community is: 1) paramedic administration of a group of complementary neuroprotective agents in the field to protect the brain during transfer and extend the time window for recanalization therapy, 2) definitive thrombolysis or other revascularization procedure on hospital arrival, and 3) in-hospital administration of a second group of neuroprotective agents specifically active against reperfusion injury.


Feasibility of Prehospital Neuroprotection in Focal Stroke - The FAST-MAG Pilot Trial

Prehospital trials for focal stroke pose several unique study design challenges, including stroke identification, stroke characterization, deficit evolution in the field, and consent elicitation. To address these issues, a pilot trial was performed and demonstrated the practicality for a pivotal trial of several prehospital trial instruments, including the Los Angeles Prehospital Stroke Screen (LAPSS) to identify patients for trial entry, the Los Angeles Motor Scale (LAMS) for pretreatment characterization of stroke severity, the Paramedic Global Impression of Change score to delineate prehospital deficit evolution, and physician cell phone elicitation of consent for trial participation in the field (Saver JL, Kidwell C, Eckstein M, Starkman S, for the FAST-MAG Pilot Trial Investigators. Prehospital neuroprotective therapy for acute stroke: results of the Field Administration of Stroke Therapy Magnesium (FAST-MAG) Pilot Trial. Stroke 2004;35:e106-e108. (DOI: 10.1161/01.STR.0000124458.98123.52). Prehospital enrollment in the FAST-MAG Pilot Trial succeeded in accelerating start of neuroprotective therapy, decreasing the interval from paramedic arrival on scene to start of study infusion by nearly 2 hours. Clinical outcomes in the open-label pilot trial must be interpreted cautiously, but were encouraging. Dramatic early recovery occurred in 42% of <2h infarct patients. Good 90 day global functional outcome (Rankin < 2) was achieved by 69% of all patients and 75% of <2h infarct patients. No serious adverse events specifically related to field initiation of study agent were noted.

The FAST-MAG Pilot Trial demonstrated that field initiation of magnesium sulfate in acute stroke is feasible, safe, and potentially efficacious. Based on these results, the large-scale, pivotal FAST-MAG Phase 3 trial of magnesium sulfate was planned with field initiation of study agent within 1-2h of onset, a time window not previously explored in neuroprotective studies, when the benefits of neuroprotective acute stroke therapies are likely to be greatest. By utilizing field delivery, the FAST-MAG trial will be the first neuroprotective study ever performed in the 0-2 hour window, when patients are most likely to benefit from neuroprotective interventions

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