Safety Study of Dantrolene in Subarachnoid Hemorrhage

NCT01024972 | Completed Phase 1 Results DMC

• 1 other identifier: H-13441
• Study Type: interventional
• Target: 31
• Locations: 1 country
• Sites: 1

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.

Conditions

Subarachnoid Hemorrhage; Cerebral Vasospasm

Outcome Measures

Primary Outcomes (1)

• Hyponatremia

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

  Seven days

Secondary Outcomes (2)

• Liver Toxicity

  7 days

• In-hospital Mortality

  up to 90 days

Study Arms (2)

Dantrolene

EXPERIMENTAL

Dantrolene 1.25mg/kg IV every 6 hours x 7 days

Drug: Dantrolene

Placebo

PLACEBO COMPARATOR

Equiosmolar volume (5% Mannitol)

Drug: Placebo

Interventions

Dantrolene DRUG

Dantrolene 1.25mg/kg IV (includes 5% mannitol) every 6 hours x 7 days

Also known as: Dantrium

Dantrolene

Placebo DRUG

equiosmolar volume (5% mannitol) every 6 hours x 7 days

Also known as: Free water/5% mannitol solution

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• University of Massachusetts, Worcester: lead
• American Heart Association: collaborator

Study Sites (1)

UMASS Medical School / UMass Memorial Medical Center

Worcester, Massachusetts, 01655, United States

Location

Related Publications (5)

• 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.

  PMID: 18923817 BACKGROUND

• 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.

  PMID: 18696267 BACKGROUND

• 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.

  PMID: 18696266 BACKGROUND

• 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.

  PMID: 21454813 BACKGROUND

• 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.

  PMID: 25344064 RESULT

MeSH Terms

Conditions

Subarachnoid Hemorrhage; Vasospasm, Intracranial

Interventions

Dantrolene

Condition Hierarchy (Ancestors)

Intracranial Hemorrhages; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Hemorrhage; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Hydantoins; Imidazolidines; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Limitations and Caveats

Placebo group consisted of free water with 5% mannitol to achieve the same equiosmolar solution as IV-D which requires reconstitution in free water. Unable to differentiate whether hyponatremia or brain oedema was due to IV-D or its solution.

Results Point of Contact

• Title: Dr. Susanne Muehlschlegel
• Organization: University of Massachusetts Medical School

susanne.muehlschlegel@umassmemorial.org

508-421-5500

Study Officials

• Susanne Muehlschlegel, MD

  University of Massachusetts, Worcester

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 1, 2009
• First Posted: December 3, 2009
• Study Start: October 1, 2009
• Primary Completion: July 1, 2013
• Study Completion: October 1, 2013
• Last Updated: March 5, 2015
• Results First Posted: March 5, 2015

Record last verified: 2015-02

Locations

US (1)