Efficacy and Safety of Ryanodex® (EGL-4104) as Adjuvant Treatment in Subjects With Exertional Heat Stroke (EHS)

Study Overview
=================
Brief Summary
-----------------
Study EGL-4104-C-1502 is a phase 2, single-site, open-label, randomized, 2-arm parallel study of Ryanodex for the adjuvant treatment of exertional heat stroke (EHS) administered intravenously (IV), to current standard of care (SOC). SOC for the treatment of EHS is defined as effective body cooling, which should be implemented as quickly as available after diagnosis of exertional heat stroke.

Detailed Description
-----------------
The study will take place at emergency medical facilities. Due to the life-threatening nature of exertional heat stroke (EHS), rapid assessment for inclusion into the study and subsequent immediate treatment must occur. Following initial triage and primary assessment of a subject, the subject's baseline status should be documented, and once a diagnosis of EHS is obtained, SOC treatment will be initiated immediately, the subject will be randomized to one of two treatment arms (SOC only or SOC plus Ryanodex). Patients will be remain hospitalized for up to 72 hours after administration of the first dose of study drug and implemented SOC and will receive all necessary supportive measures until resolution of symptoms. Study duration: 72 hours

Official Title
-----------------
Phase 2, Single-Site, Open-Label, Randomized, 2-Arm Parallel Study to Assess the Efficacy and Safety of Ryanodex® (EGL-4104) as Adjuvant Treatment in Subjects With Exertional Heat Stroke (EHS)

Conditions
-----------------
Heat Stroke

Intervention / Treatment
-----------------
* Drug: Dantrolene sodium for injectable suspension


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects may be entered in the study if they have a core body temperature obtained rectally of ≥ 40.0°C (104°F) Recent history or suspected recent history (prior 24 hours) of performing intense physical activity (exertional activity) The subject has an impaired consciousness level as evidenced by a GCS score < 13 The subject has tachycardia (heart rate ≥ 100 bpm) Exclusion Criteria: The subject is diagnosed with or is suspected of having an acute clinically severe infection, which in the opinion of the Investigator may increase the subject's risk for participating in the study and/or may impair the ability of performing and/or interpreting study assessments The subject has severe hyperthermia secondary to a condition other than heat stroke (e.g., serotonin syndrome, thyrotoxicosis, pheochromocytoma, or brain hemorrhage) There is likelihood of head trauma in the past 6 months, or other significant cardiovascular, pulmonary, hepatic, endocrine, or renal illness that in the opinion of the Investigator may increase the subject's risk for participating in the study and/or may impair the ability of performing and/or interpreting study assessments A female subject has a positive pregnancy test (urine) or evidence of active lactation Reported known use of potent CYP3A4 inhibitors A known history of allergy or hypersensitivity to dantrolene A history of chronic and ongoing assisted mechanical ventilation prior to the onset of EHS via an established artificial or supported airway (e.g., for severe chronic obstructive pulmonary disease [COPD], upper airway disease, impaired respiratory function). Note: Endotracheal intubation and mechanical ventilation as part of supportive measures for the treatment of EHS are allowed

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ryanodex<br>Ryanodex (dantrolene sodium) for injectable suspension administered as an IV bolus, in addition to standard of care (SOC) treatment. | Drug: Dantrolene sodium for injectable suspension<br>* Ryanodex will be administered as a rapid IV push as a single doses of 2 mg/kg or as 1 mg/kg.<br>* Other names: Ryanodex; EGL-4104;|
| No Intervention: Standard of Care only (SOC)<br>Standard of Care (SOC) treatment only, consisting of body cooling and supportive measures implemented immediately. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Achieving Recovery of Level of Consciousness Defined as a Glasgow Coma Scale (GCS) GCS ≥ 13 | Number of subjects achieving a Glasgow Coma Scale(GCS) ≥ 13 at or prior to 90 minutes post-randomization. The Glasgow Coma Scale (GCS) is a reliable and objective way of recording the initial and subsequent level of consciousness in a person after a brain injury. The range of total GCS score is 3 to15 where a higher GCS score represents a better outcome. The scores of subscales are summed to determine the total score*. A GCS score of 13-15 is considered Mild impairment of consciousness; a GCS score of 9-12 is considered Moderate impairment of consciousness; and a GCS score of 3-8 is considered Severe. *Subscales: Eyes Response -Spontaneous=4; To sound =3; To Pressure=2; None=1; not tested. Verbal Response- Oriented=5; Confused=4; Words=3; Sounds=2; None-1; Not tested. Motor Response: Obeys Commands=6; Localizes=5; Normal Flexion=4; Abnormal Flexion=3; Extension=2; None=1; Not tested. | 90 minutes post-randomization |