Safety Study of Dantrolene in Subarachnoid Hemorrhage

Tracking Information
First Submitted Date ICMJE	December 1, 2009
First Posted Date ICMJE	December 3, 2009
Results First Submitted Date	January 2, 2015
Results First Posted Date	March 5, 2015
Last Update Posted Date	March 5, 2015
Study Start Date ICMJE	October 2009
Actual Primary Completion Date	July 2013 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: February 18, 2015)	Hyponatremia [ Time Frame: Seven days ]; Number of subjects who developed hyponatremia (sNa ≤132mmol/L)
Original Primary Outcome Measures ICMJE; (submitted: December 1, 2009)	- Tolerability - Hyponatremia [ Time Frame: Seven days ]
Change History	Complete list of historical versions of study NCT01024972 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: February 18, 2015)	Liver Toxicity [ Time Frame: 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.; In-hospital Mortality [ Time Frame: up to 90 days ]Number of subjects who expired during hospitalization.
Original Secondary Outcome Measures ICMJE; (submitted: December 1, 2009)	Liver toxicity; hemodynamic measures; intracranial pressure; change in daily TCD velocities from baseline; number of required intraarterial vasospasm treatments; degree of angiographic vasospasm; outcome trends at 90 days assessed by GOS, mRS and BI. [ Time Frame: 90 days ]
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Safety Study of Dantrolene in Subarachnoid Hemorrhage
Official Title ICMJE	Dantrolene in the Prevention and Treatment of Cerebral Vasospasm in Subarachnoid Hemorrhage
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.
Study Type ICMJE	Interventional
Study Phase	Phase 1; Phase 2
Study Design ICMJE	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition ICMJE	Subarachnoid Hemorrhage; Cerebral Vasospasm
Intervention ICMJE	Drug: Dantrolene Dantrolene 1.25mg/kg IV (includes 5% mannitol) every 6 hours x 7 days Other Name: Dantrium; Drug: Placebo equiosmolar volume (5% mannitol) every 6 hours x 7 days Other Name: Free water/5% mannitol solution
Study Arms	Experimental: Dantrolene Dantrolene 1.25mg/kg IV every 6 hours x 7 days Intervention: Drug: Dantrolene; Placebo Comparator: Placebo Equiosmolar volume (5% Mannitol) Intervention: Drug: Placebo
Publications *	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.; 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.; 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. Review.; 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.; 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.
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Completed
Actual Enrollment ICMJE; (submitted: February 18, 2015)	31
Original Estimated Enrollment ICMJE; (submitted: December 1, 2009)	30
Actual Study Completion Date	October 2013
Actual Primary Completion Date	July 2013 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	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)
Sex/Gender	Sexes Eligible for Study: All
Ages	18 Years and older (Adult, Older Adult)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT01024972
Other Study ID Numbers ICMJE	H-13441
Has Data Monitoring Committee	Yes
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	University of Massachusetts, Worcester
Study Sponsor ICMJE	University of Massachusetts, Worcester
Collaborators ICMJE	American Heart Association
Investigators ICMJE	Principal Investigator: Susanne Muehlschlegel, MD University of Massachusetts, Worcester
PRS Account	University of Massachusetts, Worcester
Verification Date	February 2015
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP