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Safety Study of Dantrolene to Treat Cerebral Vasospasm After Subarachnoid Hemorrhage

This study has been completed.
Sponsor:
Collaborator:
Massachusetts General Hospital
Information provided by (Responsible Party):
Susanne Muehlschlegel, University of Massachusetts, Worcester
ClinicalTrials.gov Identifier:
NCT00964548
First received: August 23, 2009
Last updated: April 25, 2012
Last verified: April 2012
History of Changes
  Purpose

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.


Condition Intervention Phase
Cerebral Vasospasm After Subarachnoid Hemorrhage
 Drug: Dantrolene
 Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Dantrolene in the Treatment of Cerebral Vasospasm After Subarachnoid Hemorrhage - a Phase 1 Study

Resource links provided by NLM:

U.S. FDA Resources

Further study details as provided by University of Massachusetts, Worcester:

Primary Outcome Measures:
  • Hemodynamic Parameters (Change From Baseline Systolic Blood Pressure (Pre-infusion) Over Time Until 135 Minutes Post-infusion) [ Time Frame: baseline until 135 minutes post-infusion ] [ Designated as safety issue: Yes ]
    Systolic Blood Pressure (Change from baseline systolic blood pressure (pre-infusion) over time until 135 minutes post-infusion).


Secondary Outcome Measures:
  • Transcranial Doppler Peak Systolic Velocity (Change From Baseline Peak Systolic Velocity (Pre-infusion) Over Time Until 135 Minutes Post-infusion) [ Time Frame: baseline until 135 minutes post-infusion ] [ Designated as safety issue: No ]
    Peak Systolic Velocity of vessel in vasospasm (Change from baseline peak systolic velocity (pre-infusion) over time 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) [ Time Frame: baseline until 135 minutes post-infusion ] [ Designated as safety issue: No ]
    Mean flow velocities of vessel in vasospasm (Change from baseline mean flow velocity (pre-infusion) over time until 135 minutes post-infusion).


Enrollment: 10
Study Start Date: July 2007
Study Completion Date: October 2009
Primary Completion Date: October 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Dantrolene (low dose) Drug: Dantrolene
1.25 mg/kg IV once over 60 min
Experimental: Dantrolene (high dose) Drug: Dantrolene
2.5 mg/kg IV once over 60 min

Detailed Description:

Our main objectives are: 1) to evaluate the safety and tolerability of varying doses of dantrolene, by determining the treatment related adverse events, in participants with cVSP after SAH; and 2) to determine the maximal tolerated dose to be adopted in subsequent studies and 3) to determine efficacy trends of dantrolene on brain vessels as assessed by ultrasound of brain vessels (transcranial Doppler).

We hypothesize that dantrolene is well-tolerated and has minimal serious adverse effects in patients with cVSP after SAH. The results can potentially bring a new treatment to patients with SAH. cVPS after SAH is a frequent cause of disability and death. A successful study demonstrating the safety of dantrolene in would be of considerable public health significance.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00964548

Locations
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
UMASS Memorial Medical Center/UMASS Medical School
Worcester, Massachusetts, United States, 01655
Sponsors and Collaborators
University of Massachusetts, Worcester
Massachusetts General Hospital
Investigators
Principal Investigator: Susanne Muehlschlegel, MD UMASS Medical School
Study Director: John R Sims, MD Massachusetts General Hospital
  More Information

Publications:

Responsible Party: Susanne Muehlschlegel, Study Principle Investigator, University of Massachusetts, Worcester
ClinicalTrials.gov Identifier: NCT00964548     History of Changes
Other Study ID Numbers: H-13076
Study First Received: August 23, 2009
Results First Received: November 18, 2011
Last Updated: April 25, 2012
Health Authority: United States: Institutional Review Board

Keywords provided by University of Massachusetts, Worcester:
vasospasm
subarachnoid hemorrhage
neurocritical care
dantrolene
vasorelaxation

Additional relevant MeSH terms:
Hemorrhage
Subarachnoid Hemorrhage
Vasospasm, Intracranial
Pathologic Processes
Intracranial Hemorrhages
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
 Cardiovascular Diseases
Dantrolene
Muscle Relaxants, Central
Physiological Effects of Drugs
Pharmacologic Actions
Neuromuscular Agents
Peripheral Nervous System Agents
Central Nervous System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on May 22, 2013