117 Update: Dantrolene Sodium Suspension (250 Mg/5mL) in Patients with Exertional Heat Stroke

Abstract

Exertional heat stroke (EHS) is a rare, sudden and unpredictable hyperthermic, hypermetabolic crisis that may affect anyone performing intense physical activity. EHS is one of the most severe forms of heat illness and a leading cause of death and disability in athletes, outdoor workers and military personnel. EHS is marked by severe hyperthermia (core body temp. ≥40°C) and CNS dysfunction (eg, seizures, coma, abnormal behavior). The sporadic, unpredictable and life-threatening nature of EHS limits the ability to conduct prospective controlled clinical trials. Current treatment is limited to efficient body cooling which is infrequently available and inconsistently administered. Up to 1/3 of survivors may have long-term neurologic sequelae despite rapid body cooling. The objective was to evaluate the efficacy and safety of dantrolene sodium for injectable suspension (Ryanodex®) (DSS) for the treatment of EHS, administered as an adjunct to body cooling (BC). We conducted two comparable clinical studies evaluating DSS+BC compared to BC alone in patients with EHS. Study 1 (ITT N=34, mITT N=24) and Study 2 (ITT N=17) were randomized, controlled, 2-arm parallel studies. Patients had a core temp. ≥40°C, impaired level of consciousness (LOC)(GCS score <13) and tachycardia. The primary efficacy endpoint in both studies was the cumulative incidence of recovery of LOC defined as a GCS score ≥13 at or prior to 90 minutes post-randomization. Safety and tolerability were assessed. As reported at the 2017 ACEP Research Forum, the mITT population in Study 1 excluded patients who were intubated at baseline (precluding full assessment of GCS). Study 2 ran from August 2018 to August 2019. These multicenter studies were conducted in a real-world emergency medicine setting in the same hospitals. Due to the limitations enrolling EHS patients and given the comparability of the studies, an integrated analysis of efficacy was warranted. Study 1 and Study 2 demonstrated consistent, clinically meaningful results. Demographics and baseline characteristics in the integrated analysis were balanced between the DSS+BC (n=19) and BC only (n=22) groups regarding age (median 45 vs 43.5 yrs.), baseline GCS (mean 7.1 vs 6.2) and baseline rectal temp. (mean 41.6 vs 41.3°C). 51% were male. A statistically significant number of patients in the DSS+BC group met the primary endpoint vs BC alone (47.4% vs 18.2%, p=0.0452). Safety and tolerability findings were comparable in both groups and consistent with the known safety profile in the approved indication. Conducting clinical studies for EHS is challenging due to its rare, unpredictable and life-threatening nature. We conducted two comparable studies showing consistent and clinically meaningful benefit from the addition of DSS to BC. Approximately twice as many DSS treated subjects in each study achieved the primary endpoint. The integrated analysis of efficacy demonstrates that DSS added to BC results in a clinically meaningful and statistically significant improvement of neurologic impairment in subjects with EHS within 90 minutes of administration.