Safety Study of Dantrolene in Subarachnoid Hemorrhage

Phase 1

Completed

Brief Summary: Subarachnoid hemorrhage (SAH) is a devastating acute brain injury due to bleeding onto the brain surface from a ruptured aneurysm. Cerebral vasospasm (cVSP; critical narrowing of brain arteries) is a known complication after SAH and significantly increases disability and death after SAH. Vasospasm is difficult to treat and can lead to stroke. Animal studies have shown that the muscles in the artery wall play a role in cVSP.

Dantrolene has been FDA approved and extensively used in clinical practice as a muscle relaxant for more than 30 years. It has been shown to provide some benefit in animal studies of cVSP, as well as in a small number of humans. However, the first human studies have only been observational and over a short period of time.

This study will evaluate the safety and tolerability of intravenous dantrolene given every 6 hours over seven days to patients with or at risk for cVSP after SAH. The goal is to determine if future efficacy studies should be done to determine if treatment with Dantrolene may improve the outcome of patients with cVSP after SAH.

Detailed Description: Once eligibility criteria are met, patients will be randomized to either dantrolene-IV or placebo (equiosmolar, volume-equivalent sterile water with 5% mannitol as dantrolene-IV also contains 5% mannitol). Study subjects will be visited daily by a study nurse to determine side effects, tolerability, record hemodynamic measures and laboratory values. Patients will have daily serum Na, osmolality, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALK) measured. In addition, daily bedside transcranial doppler will be performed by a blinded examiner. Patients will undergo cerebral angiograms per clinical routine. Angiographic measurements of arterial narrowing will be performed by a blinded radiologist. Specific stop criteria are pre-defined.

Recruitment & Eligibility

Inclusion Criteria

Documented aneurysmal SAH by computed tomography angiography (CTA), magnetic resonance angiography (MRA) or angiography
Secured aneurysm (coiled or clipped)
Enrollment achievable within 14 days after SAH

Exclusion Criteria

Pregnancy
Prior history of cirrhosis or hepatitis B/C, or any two of the following three liver enzymes elevated to greater than: ALT >120 Units/L, AST >120 Units/L, alkaline phosphatase >345 Units/L (three times upper limit of normal)
Patients on verapamil
Patients with brain edema and/or elevated intracranial pressure (>25mm Hg)
Patients treated with hypertonic saline or mannitol prior to enrollment
Patients with too severe SAH with low likelihood of survival (Hunt & Hess 5)

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Equiosmolar volume (5% Mannitol)
Dantrolene	Dantrolene	Dantrolene 1.25mg/kg IV every 6 hours x 7 days

Primary Outcome Measures

Name	Time	Method
Hyponatremia	Seven days	Number of subjects who developed hyponatremia (sNa ≤132mmol/L)

Secondary Outcome Measures

Name	Time	Method
In-hospital Mortality	up to 90 days	Number of subjects who expired during hospitalization.
Liver Toxicity	7 days	Number of subjects who developed liver toxicity as evidenced by Liver Function Test elevation greater than 5 times the upper limit of normal.