Safety Study of Dantrolene in Subarachnoid Hemorrhage

• ClinicalTrials.gov Identifier: NCT01024972
• Recruitment Status: Completed
• First Posted: December 3, 2009
• Results First Posted: March 5, 2015
• Last Update Posted: March 5, 2015
• Sponsor: University of Massachusetts, Worcester
• Collaborator: American Heart Association
• Information provided by (Responsible Party): University of Massachusetts, Worcester

Tracking Information

• First Submitted Date: December 1, 2009
• First Posted Date: 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: October 2009
• Actual Primary Completion Date: July 2013 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 18, 2015)

Hyponatremia [ Time Frame: Seven days ]

Number of subjects who developed hyponatremia (sNa ≤132mmol/L)

• Original Primary Outcome Measures (submitted: December 1, 2009): - Tolerability - Hyponatremia [ Time Frame: Seven days ]

Current Secondary Outcome Measures (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 (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 Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Safety Study of Dantrolene in Subarachnoid Hemorrhage
• Official Title: 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: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Subarachnoid Hemorrhage
• Cerebral Vasospasm

Intervention

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 18, 2015): 31
• Original Estimated Enrollment (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

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: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01024972
• Other Study ID Numbers: 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: University of Massachusetts, Worcester
• Collaborators: American Heart Association

Investigators

• Principal Investigator: Susanne Muehlschlegel, MD; University of Massachusetts, Worcester

• PRS Account: University of Massachusetts, Worcester
• Verification Date: February 2015