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Safety Study of Dantrolene to Treat Cerebral Vasospasm After Subarachnoid Hemorrhage

Primary Purpose

Cerebral Vasospasm After Subarachnoid Hemorrhage

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Dantrolene

About this trial

This is an interventional treatment trial for Cerebral Vasospasm After Subarachnoid Hemorrhage focused on measuring vasospasm, subarachnoid hemorrhage, neurocritical care, dantrolene, vasorelaxation

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Massachusetts General Hospital
UMASS Memorial Medical Center/UMASS Medical School

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Dantrolene (low dose)

Dantrolene (high dose)

Arm Description

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

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

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)

Mean flow velocities of vessel in vasospasm (Change from baseline mean flow velocity (pre-infusion) over time until 135 minutes post-infusion).

Full Information

NCT ID

NCT00964548

First Posted

August 23, 2009

Last Updated

April 25, 2012

Sponsor

University of Massachusetts, Worcester

Collaborators

Massachusetts General Hospital

1. Study Identification

Unique Protocol Identification Number

NCT00964548

Brief Title

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

2. Study Status

Record Verification Date

April 2012

Overall Recruitment Status

Completed

Study Start Date

July 2007 (undefined)

Primary Completion Date

October 2009 (Actual)

Study Completion Date

October 2009 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of Massachusetts, Worcester

Collaborators

Massachusetts General Hospital

4. Oversight

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Cerebral Vasospasm After Subarachnoid Hemorrhage

Keywords

vasospasm, subarachnoid hemorrhage, neurocritical care, dantrolene, vasorelaxation

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

10 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Dantrolene (low dose)

Arm Type

Experimental

Arm Title

Dantrolene (high dose)

Arm Type

Experimental

Intervention Type

Drug

Intervention Name(s)

Dantrolene

Intervention Description

1.25 mg/kg IV once over 60 min

Intervention Type

Drug

Intervention Name(s)

Dantrolene

Intervention Description

2.5 mg/kg IV once over 60 min

Primary Outcome Measure Information:

Title

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

Description

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

Time Frame

baseline until 135 minutes post-infusion

Secondary Outcome Measure Information:

Title

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

Description

Peak Systolic Velocity of vessel in vasospasm (Change from baseline peak systolic velocity (pre-infusion) over time until 135 minutes post-infusion).

Time Frame

baseline until 135 minutes post-infusion

Title

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

Description

Mean flow velocities of vessel in vasospasm (Change from baseline mean flow velocity (pre-infusion) over time until 135 minutes post-infusion).

Time Frame

baseline until 135 minutes post-infusion

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Susanne Muehlschlegel, MD

Organizational Affiliation

UMASS Medical School

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

John R Sims, MD

Organizational Affiliation

Massachusetts General Hospital

Official's Role

Study Director

Facility Information:

Facility Name

Massachusetts General Hospital

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02114

Country

United States

Facility Name

UMASS Memorial Medical Center/UMASS Medical School

City

Worcester

State/Province

Massachusetts

ZIP/Postal Code

01655

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

18696267

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.

Results Reference

background

PubMed Identifier

18923817

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.

Results Reference

background

PubMed Identifier

18696266

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.

Results Reference

background

PubMed Identifier

21454813

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.

Results Reference

result

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Safety Study of Dantrolene to Treat Cerebral Vasospasm After Subarachnoid Hemorrhage

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