Abstract 2542: Randomized, Placebo-Controlled Trial of Dantrolene for the Prevention and Treatment of Cerebral Vasospasm After Subarachnoid Hemorrhage - Interim Analysis
Introduction: Cerebral vasospasm (cVSP) after aneurysmal subarachnoid hemorrhage (aSAH) is a major cause of disability and death. Dantrolene blocks ryanodine receptor-mediated intracellular calcium release from the sarco-endoplasmic reticulum. It is neuroprotective in animal models and may attenuate cerebral vasoconstriction. Safety and feasibility of a single dose with aSAH has recently been demonstrated in humans. We present the interim safety analysis of a randomized, placebo-controlled trial using repeated doses.
Methods: In this single-center, randomized, double-blind, placebo-controlled Phase II trial, 30 patients with aSAH are being enrolled comparing intravenous dantrolene 1.25 mg IV every 6 hours x 7 days to placebo. The primary endpoint is incidence and degree of hyponatremia (sNa ≤ 134 mEq/L) and liver toxicity (proportion of patients who develop liver function tests ALT, AST and AlkPhos >5x upper limit of normal). Secondary safety endpoints include tolerability, systemic hypotension, and intracranial hypertension. Efficacy assessments include occurrence of clinical and angiographic cVSP, and three-month clinical outcome. This pre-planned interim safety analysis was conducted after 16 patients. Statistical analysis was performed using non-parametric tests due to the small n. Longitudinal data were analyzed using Generalized Estimating Equation.
Results: Randomization resulted in equal n=8 per group. No group imbalances were noted except that three patients in the placebo had dropped out: two due to nausea/vomiting, one due to headache. Hyponatremia occurred in n=7/8 (87.5%) in the placebo, and n=5/8 (62.5%) in the dantrolene group (χ2; p=0.285). Mean sNa decreased in both groups, with a maximal Δ -5±4.8 mEq/L in the placebo and -3.9±2.3 mEq/L in the dantrolene group (GEE; p=0.8333). To treat hyponatremia, 444±430 mEq of Na was used in the placebo vs. 303±380 mEq in the dantrolene group (Wilcoxon; p=0.47). No patient developed liver toxicity. Systemic hypotension occurred never in the placebo vs. once in the dantrolene group. No intracranial hypertension occurred. There were 3 adverse events reported in the placebo, vs. 9 in the dantrolene group (of which only vein irritation/infiltration were attributed to drug). There was one death in each group, both unrelated to the study.
Conclusions: This interim analysis shows that there are no major safety concerns thus far. The DSMB has recommended the continuation of the study. Due to the small n, an efficacy analysis will be performed with the final study analysis.
- © 2012 by American Heart Association, Inc.