Magnesium in Aneurysmal Subarachnoid Hemorrhage (MASH II) Phase III Clinical Trial MASH-II Study Group

Abstract

Rationale Delayed cerebral ischemia (DCI) is an important cause of poor outcome after aneurysmal subarachnoid hemorrhage (SAH). Magnesium is a neuroprotective agent that acts as an NMDA-receptor antagonist and a calcium channel blocker. In a phase II randomized clinical trial of 283 patients, magnesium treatment reduced the risk of DCI by 34% and of poor outcome by 23%. Aims To determine whether magnesium improves clinical outcome in patients with aneurysmal SAH. Design The MASH-II study is a phase III randomized, clinical international multicenter trial. Magnesium sulfate 64 mmol/ day (equals 16 g/day) or placebo is started intravenously within 4 days after the SAH and is continued until 20 days after the hemorrhage. The primary outcome measure is poor outcome, defined as death or dependence (Rankin score > 3) after 3 months. We aim to include 1200 patients in 5 years. Study outcomes Primary outcome will be poor clinical outcome as measured by the modified Rankin scale at 3 months. Sponsor MASH-II is sponsored by the Netherlands Heart Foundation (grant number: 2005BO16). It is registered with IRCTN number: 68742385, EudraCT: 2006-003523-36. Introduction Subarachnoid hemorrhage (SAH) from a ruptured aneurysm is a subset of stroke. The young age (median 55 years) and poor outcome (50% of patients die; 30% of those who survive the initial weeks after the hemorrhage remain dependent) explain why in the population the loss of productive life years from SAH is as large as that from brain infarcts, the most common type of stroke ( 1 ). Summary The MASH-II study is a phase III randomized, clinical international multicenter trial to study the effect of magnesium sulfate after aneurysmal SAH. Magnesium is a neuroprotective agent that acts as a blocker of both the NMDA-glutamate receptor and voltage dependent calcium channels. Patients who are admitted within 4 days after aneurysmal SAH are asked to participate. Study medication (magnesium sulfate 64 mmol/ day or placebo) is given via continuous infusion until 20 days after the hemorrhage. Outcome is determined with the modified Rankin scale 3 months after the hemorrhage. Analysis will be according to the intention-to-treat principle. So far, in May 2007 over 425 patients have been included in five Dutch and one Chilean hospital. Based on the results of the phase II study sample size calculations indicate that 1200 patients are needed to give a statistically significant result (with α = 5% and a power of 80%). We aim to include these patients before 2010. New centers are still very welcome to join the study.