Clinical trial NCT01024972: Safety Study of Dantrolene in Subarachnoid Hemorrhage
Official title: Dantrolene in the Prevention and Treatment of Cerebral Vasospasm in Subarachnoid Hemorrhage
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Subarachnoid Hemorrhage
Cerebral Vasospasm
Lead sponsor: University of Massachusetts, Worcester
Sponsor class: OTHER
Collaborators: name: American Heart Association
First posted: 2009-12-03
Enrollment: 31
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Hyponatremia
timeFrame: Seven days
Secondary outcomes:
measure: Liver Toxicity
timeFrame: 7 days
measure: In-hospital Mortality
timeFrame: up to 90 days
Other outcomes:
Locations:
city: Worcester
country: United States
facility: UMASS Medical School / UMass Memorial Medical Center
state: Massachusetts
Study officials:
affiliation: University of Massachusetts, Worcester
name: Susanne Muehlschlegel, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Salomone S, Soydan G, Moskowitz MA, Sims JR. Inhibition of cerebral vasoconstriction by dantrolene and nimodipine. Neurocrit Care. 2009;10(1):93-102. doi: 10.1007/s12028-008-9153-0. Epub 2008 Oct 16.
citation: Muehlschlegel S, Rordorf G, Bodock M, Sims JR. Dantrolene mediates vasorelaxation in cerebral vasoconstriction: a case series. Neurocrit Care. 2009;10(1):116-21. doi: 10.1007/s12028-008-9132-5. Epub 2008 Aug 12.
citation: Muehlschlegel S, Sims JR. Dantrolene: mechanisms of neuroprotection and possible clinical applications in the neurointensive care unit. Neurocrit Care. 2009;10(1):103-15. doi: 10.1007/s12028-008-9133-4. Epub 2008 Aug 12.
citation: Muehlschlegel S, Rordorf G, Sims J. Effects of a single dose of dantrolene in patients with cerebral vasospasm after subarachnoid hemorrhage: a prospective pilot study. Stroke. 2011 May;42(5):1301-6. doi: 10.1161/STROKEAHA.110.603159. Epub 2011 Mar 31.
citation: Muehlschlegel S, Carandang R, Hall W, Kini N, Izzy S, Garland B, Ouillette C, van der Bom IM, Flood TF, Gounis MJ, Weaver JP, Barton B, Wakhloo AK. Dantrolene for cerebral vasospasm after subarachnoid haemorrhage: a randomised double blind placebo-controlled safety trial. J Neurol Neurosurg Psychiatry. 2015 Sep;86(9):1029-35. doi: 10.1136/jnnp-2014-308778. Epub 2014 Oct 24.