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| Name | Class |
|---|---|
| American Heart Association | OTHER |
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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.
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, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Dantrolene | Experimental | Dantrolene 1.25mg/kg IV every 6 hours x 7 days |
|
| Placebo | Placebo Comparator | Equiosmolar volume (5% Mannitol) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Dantrolene | Drug | Dantrolene 1.25mg/kg IV (includes 5% mannitol) every 6 hours x 7 days |
|
| Measure | Description | Time Frame |
|---|---|---|
| Hyponatremia | Number of subjects who developed hyponatremia (sNa ≤132mmol/L) | Seven days |
| Measure | Description | Time Frame |
|---|---|---|
| Liver Toxicity | Number of subjects who developed liver toxicity as evidenced by Liver Function Test elevation greater than 5 times the upper limit of normal. | 7 days |
| In-hospital Mortality | Number of subjects who expired during hospitalization. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Susanne Muehlschlegel, MD | University of Massachusetts, Worcester | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| UMASS Medical School / UMass Memorial Medical Center | Worcester | Massachusetts | 01655 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 18923817 | Background | 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. | |
| 18696267 | Background | 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. |
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Routine patient management: All aSAH patients were treated according to our institutional protocol following published aSAH critical care guidelines, including admission to our closed neuroscience intensive care unit (neuroICU) with board-certified neurointensivist as the primary attending.
All patients with aSAH were screened for eligibility between 10/2009 and 10/2012. Inclusion criteria were aSAH ≥18 years, aneurysm fully secured by coiling or clipping, Hunt&Hess grade <5, modified Fisher Scale >1, ALT, AST, AlkPhos <3x upper limit of normal, serum Na (sNa) ≥135mmol/L and no mannitol or hypertonic saline prior to drug infusion.
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| ID | Title | Description |
|---|---|---|
| FG000 | Dantrolene | Dantrolene 1.25mg/kg IV every 6 hours x 7 days Dantrolene vs. Placebo: Dantrolene 1.25mg/kg IV (includes 5% mannitol) or equiosmolar placebo (5% mannitol) every 6 hours x 7 days |
| FG001 | Placebo | Equiosmolar volume (5% Mannitol) Dantrolene vs. Placebo: Dantrolene 1.25mg/kg IV (includes 5% mannitol) or equiosmolar placebo (5% mannitol) every 6 hours x 7 days |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Dantrolene | Intravenous Datrolene 1.25 mg/kg (includes 5% mannitol) every 6 hours for seven days. |
| BG001 | Placebo | Equiosmolar volume (5% mannitol) every 6 hours for seven days. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Hyponatremia | Number of subjects who developed hyponatremia (sNa ≤132mmol/L) | Posted | Number | participants | Seven days |
|
|
90 days
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Dantrolene | Dantrolene 1.25mg/kg IV (includes 5% mannitol) every 6 hours x 7 days |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Neurological deterioration | Nervous system disorders | Non-systematic Assessment | Neurological deterioration requiring osmotherapy |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Venous infiltration | Vascular disorders | Non-systematic Assessment |
Placebo group consisted of free water with 5% mannitol to achieve the same equiosmolar solution as IV-D which requires reconstitution in free water. Unable to differentiate whether hyponatremia or brain oedema was due to IV-D or its solution.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Susanne Muehlschlegel | University of Massachusetts Medical School | 508-421-5500 | susanne.muehlschlegel@umassmemorial.org |
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| ID | Term |
|---|---|
| D013345 | Subarachnoid Hemorrhage |
| D020301 | Vasospasm, Intracranial |
| ID | Term |
|---|---|
| D020300 | Intracranial Hemorrhages |
| D002561 | Cerebrovascular Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
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| ID | Term |
|---|---|
| D003620 | Dantrolene |
| ID | Term |
|---|---|
| D006827 | Hydantoins |
| D048289 | Imidazolidines |
| D007093 | Imidazoles |
| D001393 | Azoles |
| D006573 |
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| Placebo | Drug | equiosmolar volume (5% mannitol) every 6 hours x 7 days |
|
|
| up to 90 days |
| 18696266 | Background | 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. |
| 21454813 | Background | 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. |
| 25344064 | Result | Muehlschlegel S, Carandang R, Hall W, Kini N, Izzy S, Garland B, Ouillette C, van der Bom IM, Flood TF, Gounis MJ, Weaver JP, Barton B, Wakhloo AK. Dantrolene for cerebral vasospasm after subarachnoid haemorrhage: a randomised double blind placebo-controlled safety trial. J Neurol Neurosurg Psychiatry. 2015 Sep;86(9):1029-35. doi: 10.1136/jnnp-2014-308778. Epub 2014 Oct 24. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Number | participants |
|
|
|
| Secondary | Liver Toxicity | Number of subjects who developed liver toxicity as evidenced by Liver Function Test elevation greater than 5 times the upper limit of normal. | Posted | Number | participants | 7 days |
|
|
|
| Secondary | In-hospital Mortality | Number of subjects who expired during hospitalization. | Posted | Number | participants | up to 90 days |
|
|
|
| 4 |
| 16 |
| 12 |
| 16 |
| EG001 | Placebo | equiosmolar, volume-equivalent sterile water with 5% mannitol every 6 hours x 7 days | 2 | 15 | 1 | 15 |
|
| Liver toxicity | Hepatobiliary disorders | Non-systematic Assessment | Liver function test elevation greater than 5 times upper limit of normal |
|
| Acute respiratory failure | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Headache | Nervous system disorders | Non-systematic Assessment |
|
| Drug administration error | General disorders | Non-systematic Assessment |
|
| Nausea/vomiting | Gastrointestinal disorders | Non-systematic Assessment |
|
| Headache | Nervous system disorders | Non-systematic Assessment |
|
| Urinary tract infection | Renal and urinary disorders | Non-systematic Assessment |
|
| Myocardial Infarction | Cardiac disorders | Systematic Assessment | Non-(ST wave)-elevation myocardial infarction |
|
| Constipation | Gastrointestinal disorders | Non-systematic Assessment |
|
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| D009422 | Nervous System Diseases |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D006470 | Hemorrhage |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |