Safety Study of Dantrolene in Subarachnoid Hemorrhage

Completed

Phase 1/2 Results

Trial Description

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.

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, 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.

Conditions

Interventions

  • Placebo Drug
    Intervention Desc: equiosmolar volume (5% mannitol) every 6 hours x 7 days
    ARM 1: Kind: Experimental
    Label: Placebo
    Description: Equiosmolar volume (5% Mannitol)
  • Dantrolene (Dantrium (in North America) and Dantrolen (Europe))Drug
    Other Names: Dantrium
    Intervention Desc: Dantrolene 1.25mg/kg IV (includes 5% mannitol) every 6 hours x 7 days
    ARM 1: Kind: Experimental
    Label: Dantrolene
    Description: Dantrolene 1.25mg/kg IV every 6 hours x 7 days
  • Dantrolene vs. Placebo Drug
    Other Names: Dantrium
    Intervention Desc: Dantrolene 1.25mg/kg IV (includes 5% mannitol) or equiosmolar placebo (5% mannitol) every 6 hours x 7 days
    ARM 1: Kind: Experimental
    Label: Dantrolene
    Description: Dantrolene 1.25mg/kg IV every 6 hours x 7 days
    ARM 2: Kind: Experimental
    Label: Placebo
    Description: Equiosmolar volume (5% Mannitol)

Trial Design

  • Allocation: Randomized
  • Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
  • Purpose: Treatment
  • Endpoint: Safety Study
  • Intervention: Parallel Assignment

Patient Involvement

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, and LFTs 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.

Outcomes

Type Measure Time Frame Safety Issue
Primary Tolerability - Hyponatremia
Secondary 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.
Primary - Tolerability - Hyponatremia Seven days Yes
Primary Hyponatremia Seven days Yes
Secondary Liver Toxicity 7 days Yes
Secondary In-hospital Mortality up to 90 days No

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