Safety Study of Dantrolene in Subarachnoid Hemorrhage

Study Overview
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Brief Summary
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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
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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.

Official Title
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Dantrolene in the Prevention and Treatment of Cerebral Vasospasm in Subarachnoid Hemorrhage

Conditions
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Subarachnoid Hemorrhage, Cerebral Vasospasm

Intervention / Treatment
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* Drug: Dantrolene
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dantrolene<br>Dantrolene 1.25mg/kg IV every 6 hours x 7 days | Drug: Dantrolene<br>* Dantrolene 1.25mg/kg IV (includes 5% mannitol) every 6 hours x 7 days<br>* Other names: Dantrium;|
| Placebo Comparator: Placebo<br>Equiosmolar volume (5% Mannitol) | Drug: Placebo<br>* equiosmolar volume (5% mannitol) every 6 hours x 7 days<br>* Other names: Free water/5% mannitol solution;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hyponatremia | Number of subjects who developed hyponatremia (sNa ≤132mmol/L) | Seven days | 

Secondary Outcome Measures

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