Clinical trial NCT00964548: Safety Study of Dantrolene to Treat Cerebral Vasospasm After Subarachnoid Hemorrhage
Official title: Dantrolene in the Treatment of Cerebral Vasospasm After Subarachnoid Hemorrhage - a Phase 1 Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Cerebral Vasospasm After Subarachnoid Hemorrhage
Keywords: vasospasm
subarachnoid hemorrhage
neurocritical care
dantrolene
vasorelaxation
Lead sponsor: University of Massachusetts, Worcester
Sponsor class: OTHER
Collaborators: name: Massachusetts General Hospital
First posted: 2009-08-25
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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 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

Primary outcomes:
measure: Hemodynamic Parameters (Change From Baseline Systolic Blood Pressure (Pre-infusion) Over Time Until 135 Minutes Post-infusion)
timeFrame: baseline until 135 minutes post-infusion
Secondary outcomes:
measure: Transcranial Doppler Peak Systolic Velocity (Change From Baseline Peak Systolic Velocity (Pre-infusion) Over Time Until 135 Minutes Post-infusion)
timeFrame: baseline until 135 minutes post-infusion
measure: Transcranial Doppler Mean Flow Velocity (Change From Baseline Mean Flow Velocity (Pre-infusion) Over Time Until 135 Minutes Post-infusion)
timeFrame: baseline until 135 minutes post-infusion
Other outcomes:
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Worcester
country: United States
facility: UMASS Memorial Medical Center/UMASS Medical School
state: Massachusetts
Study officials:
affiliation: UMASS Medical School
name: Susanne Muehlschlegel, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Massachusetts General Hospital
name: John R Sims, MD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.