Safety Study of Dantrolene to Treat Cerebral Vasospasm After Subarachnoid Hemorrhage

NCT00964548 | Completed Phase 1 Results

• 1 other identifier: H-13076
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 2

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. Therefore, we plan to undertake this study to evaluate the safety and tolerability of treatment with dantrolene in patients with cVSP after SAH, and to determine the maximal tolerated dose to be used in future studies to determine if treatment with Dantrolene can improve the outcome of patients with cVSP after SAH.

Conditions

Cerebral Vasospasm After Subarachnoid Hemorrhage

Keywords

vasospasm; subarachnoid hemorrhage; neurocritical care; dantrolene; vasorelaxation

Outcome Measures

Primary Outcomes (1)

• Hemodynamic Parameters (Change From Baseline Systolic Blood Pressure (Pre-infusion) Over Time Until 135 Minutes Post-infusion)

  Systolic Blood Pressure (Change from baseline systolic blood pressure (pre-infusion) over time until 135 minutes post-infusion).

  baseline until 135 minutes post-infusion

Secondary Outcomes (2)

• Transcranial Doppler Peak Systolic Velocity (Change From Baseline Peak Systolic Velocity (Pre-infusion) Over Time Until 135 Minutes Post-infusion)

  baseline until 135 minutes post-infusion

• Transcranial Doppler Mean Flow Velocity (Change From Baseline Mean Flow Velocity (Pre-infusion) Over Time Until 135 Minutes Post-infusion)

  baseline until 135 minutes post-infusion

Study Arms (2)

Dantrolene (low dose)

EXPERIMENTAL

Drug: Dantrolene

Dantrolene (high dose)

EXPERIMENTAL

Drug: Dantrolene

Interventions

Dantrolene DRUG

1.25 mg/kg IV once over 60 min

Dantrolene (low dose)

Eligibility Criteria

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

You may qualify if:

• Participants with aneurysmal SAH admitted to the Massachusetts General Hospital NeuroICU (Blake 12) and undergoing standard-of-care daily transcranial doppler (TCD).
• Participants with unilateral or bilateral anterior cerebral artery (ACA), middle cerebral artery (MCA), posterior cerebral artery (PCA), or basilar artery vasospasm as defined by the following TCD criteria
• a \>50% mean velocity increase from the baseline mean TCD velocity (baseline is the first TCD measurement, usually within 24hrs of admission), or
• peak systolic TCD velocities of 200 cm/s or higher in the MCA or ACA (for MCA with a concurrent ipsilateral LR of 3.0 or higher), or peak systolic TCD velocities of 120 cm/s or higher in the PCA or basilar artery, or
• any daily 100 cm/s peak systolic TCD velocity increase from the previous day, or
• any longitudinal mean TCD velocity increase of 80 cm/s or more

You may not qualify if:

• Inability to obtain consent from patient or health care proxy
• Age \< 18 years
• Pregnancy
• Traumatic SAH
• Known allergy to dantrolene
• Prior history of cirrhosis or hepatitis B/C, or any two of the following three liver enzymes elevated to greater than: ALT \>165 Units/L, AST \>120 Units/L, alkaline phosphatase \>345 Units/L (three times upper limit of normal)
• Participants on verapamil

Sponsors & Collaborators

• University of Massachusetts, Worcester: lead
• Massachusetts General Hospital: collaborator

Study Sites (2)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

UMASS Memorial Medical Center/UMASS Medical School

Worcester, Massachusetts, 01655, United States

Location

Related Publications (4)

• 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

• 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, 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 RESULT

MeSH Terms

Conditions

Subarachnoid Hemorrhage; Aneurysm

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

Limitations of this trial include the small n. No power analysis was performed, but rather a convenience sample was chosen as this was a proof-of-concept study. Transcranial Doppler measurements are operator dependent.

Results Point of Contact

• Title: Susanne Muehlschlegel, MD, MPH, Principal Investigator
• Organization: UMASS Medical School

susanne.muehlschlegel@umassmemorial.org

508-856-4667

Study Officials

• Susanne Muehlschlegel, MD

  UMASS Medical School

  PRINCIPAL INVESTIGATOR

• John R Sims, MD

  Massachusetts General Hospital

  STUDY DIRECTOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Study Principle Investigator

Study Record Dates

• First Submitted: August 23, 2009
• First Posted: August 25, 2009
• Study Start: July 1, 2007
• Primary Completion: October 1, 2009
• Study Completion: October 1, 2009
• Last Updated: May 25, 2012
• Results First Posted: May 25, 2012

Record last verified: 2012-04

Locations

US (2)