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Safety Study of Dantrolene to Treat Cerebral Vasospasm After Subarachnoid Hemorrhage

Information source: University of Massachusetts, Worcester
ClinicalTrials.gov processed this data on August 20, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Cerebral Vasospasm After Subarachnoid Hemorrhage

Intervention: Dantrolene (Drug); Dantrolene (Drug)

Phase: Phase 1/Phase 2

Status: Completed

Sponsored by: University of Massachusetts, Worcester

Official(s) and/or principal investigator(s):
Susanne Muehlschlegel, MD, Principal Investigator, Affiliation: UMASS Medical School
John R Sims, MD, Study Director, Affiliation: Massachusetts General Hospital

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.

Clinical Details

Official title: Dantrolene in the Treatment of Cerebral Vasospasm After Subarachnoid Hemorrhage - a Phase 1 Study

Study design: Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

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

Secondary outcome:

Transcranial Doppler Peak Systolic Velocity (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)

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

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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

Locations and Contacts

Massachusetts General Hospital, Boston, Massachusetts 02114, United States

UMASS Memorial Medical Center/UMASS Medical School, Worcester, Massachusetts 01655, United States

Additional Information

Related publications:

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.

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, 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.

Starting date: July 2007
Last updated: April 25, 2012

Page last updated: August 20, 2015

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