Safety Study of Dantrolene in Subarachnoid Hemorrhage
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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. However, the first human studies have only been observational and over a short period of time.
This study will evaluate the safety and tolerability of intravenous dantrolene given every 6 hours over seven days to patients with or at risk for cVSP after SAH. The goal is to determine if future efficacy studies should be done to determine if treatment with Dantrolene may improve the outcome of patients with cVSP after SAH.
| Condition | Intervention | Phase |
|---|---|---|
|
Subarachnoid Hemorrhage Cerebral Vasospasm |
Drug: Dantrolene vs. Placebo |
Phase 1 Phase 2 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Safety Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Investigator, Outcomes Assessor) Primary Purpose: Treatment |
| Official Title: | Dantrolene in the Prevention and Treatment of Cerebral Vasospasm in Subarachnoid Hemorrhage |
- - Tolerability - Hyponatremia [ Time Frame: Seven days ] [ Designated as safety issue: Yes ]
- Liver toxicity; hemodynamic measures; intracranial pressure; change in daily TCD velocities from baseline; number of required intraarterial vasospasm treatments; degree of angiographic vasospasm; outcome trends at 90 days assessed by GOS, mRS and BI. [ Time Frame: 90 days ] [ Designated as safety issue: Yes ]
| Estimated Enrollment: | 30 |
| Study Start Date: | October 2009 |
| Estimated Study Completion Date: | April 2013 |
| Estimated Primary Completion Date: | January 2013 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Dantrolene
Dantrolene 1.25mg/kg IV every 6 hours x 7 days
|
Drug: Dantrolene vs. Placebo
Dantrolene 1.25mg/kg IV (includes 5% mannitol) or equiosmolar placebo (5% mannitol) every 6 hours x 7 days
Other Name: Dantrium
|
|
Placebo Comparator: Placebo
Equiosmolar volume (5% Mannitol)
|
Drug: Dantrolene vs. Placebo
Dantrolene 1.25mg/kg IV (includes 5% mannitol) or equiosmolar placebo (5% mannitol) every 6 hours x 7 days
Other Name: Dantrium
|
Detailed Description:
Once eligibility criteria are met, patients will be randomized to either dantrolene-IV or placebo (equiosmolar, volume-equivalent sterile water with 5% mannitol as dantrolene-IV also contains 5% mannitol). Study subjects will be visited daily by a study nurse to determine side effects, tolerability, record hemodynamic measures and laboratory values. Patients will have daily serum Na, osmolality, AST, ALT and ALK measured. In addition, daily bedside transcranial doppler will be performed by a blinded examiner. Patients will undergo cerebral angiograms per clinical routine. Angiographic measurements of arterial narrowing will be performed by a blinded radiologist. Specific stop criteria are pre-defined.
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Documented aneurysmal SAH by CTA, MRA or angiography
- Secured aneurysm (coiled or clipped)
- Enrollment achievable within 14 days after SAH
Exclusion Criteria:
- Pregnancy
- Prior history of cirrhosis or hepatitis B/C, or any two of the following three liver enzymes elevated to greater than: ALT >120 Units/L, AST >120 Units/L, alkaline phosphatase >345 Units/L (three times upper limit of normal)
- Patients on verapamil
- Patients with brain edema and/or elevated intracranial pressure (>25mm Hg)
- Patients treated with hypertonic saline or mannitol prior to enrollment
- Patients with too severe SAH with low likelihood of survival (Hunt & Hess 5)
Contacts and Locations| United States, Massachusetts | |
| UMASS Medical School / UMass Memorial Medical Center | |
| Worcester, Massachusetts, United States, 01655 | |
| Principal Investigator: | Susanne Muehlschlegel, MD | University of Massachusetts, Worcester |
More Information
Publications:
| Responsible Party: | Susanne Muehlschlegel, Study Principal Investigator, University of Massachusetts, Worcester |
| ClinicalTrials.gov Identifier: | NCT01024972 History of Changes |
| Other Study ID Numbers: | H-13441 |
| Study First Received: | December 1, 2009 |
| Last Updated: | November 30, 2012 |
| Health Authority: | United States: Institutional Review Board |
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 23, 2013