Phase 3, Multi-Center, Double-Blind, 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)
Phase: PHASE3
Conditions: Exertional Heat Stroke
Sponsor: Eagle Pharmaceuticals, Inc.

NCT03600376 
Protocol EGL-4104-C-1801: 
Phase 3, Multi-Center, Double-Blind, 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) 
Document Date: January 3, 2020 
 

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2.
SYNOPSIS
Name of Sponsor/Company: 
Eagle Pharmaceuticals, Inc. 
Name of Finished Product: 
Ryanodex® (EGL-4104) (dantrolene sodium) for injectable suspension) 
Name of Active Ingredient: 
Dantrolene sodium 
Protocol: EGL-4104-C-1801 
Title of the Study: Phase 3, Multi-Center, Double-Blind, 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) 
Investigator: Nawfal Aljerian, MD, MHPE 
Study Center: Four (4) Emergency Departments in the Makkah region of Kingdom of Saudi 
Arabia  
Publications (reference): None 
Studied Period: 
(first subject enrolled): 21 August 2018 
(last subject completed): 13 August 2019 
Phase of Development: 
Phase 3 
Objectives: 
Primary Objective: 
To evaluate the efficacy of Ryanodex® for the treatment of exertional heat stroke (EHS), 
administered as adjunctive treatment to current standard of care (SOC), compared to administration 
of SOC only. 
Secondary Objective: 
To evaluate the safety and tolerability of Ryanodex for the treatment of EHS, administered as 
adjunctive treatment to current SOC. 
Methodology: 
Study EGL-4104-C-1801 was a Phase 3, multi-center, double-blind, randomized, 2-arm parallel 
study of Ryanodex for the adjuvant treatment of EHS administered intravenously (IV), to current 

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SOC. 
Standard  of  care  (SOC)  for  the  treatment  of  EHS  is  defined  as  effective  body  cooling  and 
supportive  measures,  which  
is  
to  be  
implemented  as  quickly  as  available  after  diagnosis  of  heat 
stroke. 
Due  to  the  life-threatening  nature  of  EHS,  rapid  assessment  for  inclusion  into  the  study  and 
subsequent immediate treatment was to occur.
 
 
 
 
 
 
 
 
Number of Subjects (Planned and Analyzed): 
Planned: 100                                  Analyzed: 17 
Diagnosis and Main Criteria for Inclusion:   
Male or non-pregnant female subjects were to be entered into this study if they were diagnosed with 
known or suspected EHS as evidenced by meeting all of the following criteria at Screening: 
• Subjects had a core body temperature obtained rectally of ≥ 40.0°C (104.0°F); 
• In the judgment of the Investigator, the subject was likely to be at least 18 years of age  
• Subject  had  recent  history  or  suspected  recent  history  (prior  24  hours)  of  performing 
intense physical activity (exertional activity) 
• The subject had impaired consciousness level as evidenced by a GCS score < 13 
• The subject had tachycardia (heart rate ≥ 100 bpm). 
Diagnosis and Main Criteria for Exclusion:   
Male  or  non-pregnant  
female  subjects  were  
to  be  excluded  
from  entering  
this  study  
if  
they  were 
diagnosed with known or suspected EHS and met any of the following criteria at Screening: 
• The subject  was  diagnosed  with  or  was  suspected  to  have  an  acute  clinically  severe 
infection, which in the opinion of the Investigator may have increased the subject’s risk for 
participating  in  the  study  and/or  may  have  impaired  the  ability  of  performing  and/or 
interpreting study assessments. 
• The subject had severe hyperthermia secondary to a condition other than heat stroke (e.g., 
serotonin syndrome, thyrotoxicosis, pheochromocytoma, or brain hemorrhage). 
• The  subject  required  endotracheal  
intubation  as  a  supportive  measure  prior  
to,  or  at  
the 

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time of entering the study. 
• The  subject  
required  administration  of  sedative  drugs  
(e.g.  midazolam,  ketamine)  
for  
the 
treatment of psychiatric symptoms (e.g. aggressiveness, agitation) prior to, or at the time, 
of entering the study. NOTE: The use of sedative drugs, such as benzodiazepines, for the 
treatment of psychiatric symptoms or seizures appearing after the subject had entered the 
study, was allowed. 
• There  was  likelihood  of  head  trauma  in  the  past  six  (6)  months,  or  other  significant 
cardiovascular,  pulmonary,  hepatic,  endocrine,  or  renal  
illness  
that  
in  
the  opinion  of  
the 
Investigator may have increased the subject’s risk for participating in the study and/or may 
have impaired the ability of performing and/or interpreting study assessments. 
• A  female  subject  had  a  positive  pregnancy  test  (urine)  or  evidence  of  active  lactation. 
NOTE: Pregnancy test may have been waived if female subject was an unmarried Muslim 
and  performing  such  a  test  would  be  in  conflict  with  her  religious  faith  and  cultural 
background, according to the Investigator. 
•  Recent history, suspected recent history (prior 30 days), or current myocardial infarction. 
•  A known history of allergy or hypersensitivity to dantrolene. 
•  A known history of seizure disorders or epilepsy. 
•  Known concomitant or prior use (within the past 2 weeks) of calcium channel blockers. 
Test Product, Dose and Mode of Administration, Batch Number: 
Ryanodex (dantrolene sodium) for injectable suspension; 250 mg/vial to be reconstituted in 5 mL of 
sterile water for injection (without a bacteriostatic agent) to yield a 50 mg/mL suspension; was to 
be administered as a rapid IV push of 2.5 mg/kg or 1 mg/kg, as described in the protocol. 
 
Duration  of  Treatment: Up  
to  six  
(6)  hours  
from  Screening  
to  End  of  Study/Early  Termination 
visit 
Reference Therapy, Dose and Mode of Administration, Batch Number: 
Standard of Care (SOC): All subjects in both treatment groups were to receive SOC. Standard of 
care for the treatment of EHS was defined as effective body cooling and supportive measures.  
Supportive  Measures: All  subjects  were  
to  
receive  adequate  supportive  measures  depending  on 
their clinical status 
Batch Number: Not applicable 
CRITERIA FOR EVALUATION 
 
Efficacy 

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Primary Endpoint: Cumulative incidence of subjects achieving a GCS score ≥ 13 at or prior to 90 
minutes post-randomization. 
Secondary Endpoints: 
• Cumulative incidence of subjects who achieve a GCS score ≥ 13 at planned time points; 
• Actual values, changes from baseline, and percent changes from baseline in GCS scores over 
time; 
• 
 
 
 
Dantrolene Plasma Concentration Data 
Blood  sample  was  to  be  collected  for  the  purpose  of  determining  the  plasma  concentration  of 
dantrolene  sodium  and  was  only  to  be  used to  demonstrate  that  treatment  was  administrated  as 
assigned. This assessment was considered as not needed (Protocol Amendment 1; 11 July 2019) for 
subjects  randomized  in  2019  because  well-established  roles  and  processes  exist  to  accurately 
document administration of study drug (Ryanodex).  
Safety 
Safety was assessed using the following parameters: 
• Adverse Events; 
• Vital Signs (heart rate, blood pressure, respiratory rate, core body temperature); 
• Clinical safety laboratory tests (hematology, coagulation parameters, and blood chemistry); 
• ECG monitoring; 
• Oxygen saturation (measured with pulse oximeter); 
• End-tidal CO
2 (ETCO
2) 
• Physical exam 
• Brief neurological exam 
• Use of concomitant medications 
Statistical Methods:  
A  Statistical  Analysis  Plan  
(SAP) was  
finalized  prior  
to  database  
lock. Statistical  methods  
in  
the 
SAP were to take precedence over those described in this protocol. All collected study data was to 
be  presented  in  subject  data  listings.  Statistical  analyses  was  to  be  performed  using  SAS®  for 
Windows, version 9.4 or later. 
Sample Size: 
A  
total  of  100  
(50  per  
treatment  group)  eligible  subjects  were  planned  
to  be  
randomized  
in  
this 
study.  The  nQuery  Advisor  6.01  software  was  to  be  used  for  this  sample  size  calculation.  The 
sample size calculation was based on the assumption that 50% of subjects who receive SOC therapy 
and  Ryanodex  was  to  achieve  a  GCS  score  ≥  13  at  or  prior  to  90  minutes  post-randomization, 
compared  with  only  14.3%  of  subjects  who  receive  SOC  therapy  alone.  Under  the  above 

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assumptions, 50 subjects per treatment group were to be required to meet the Type I error rate of 
0.05, 2-sided and over 95% statistical power to detect the difference between treatments; for a total 
of 100 subjects for the study. 
Baseline:  
Baseline  body  temperature  was  to  be  the  first  rectal  temperature  ≥  40.0°C  taken  during  the 
Screening Phase. Baseline results for other study assessments were to be the value closest in time to 
the  baseline  
rectal  
temperature  and  prior  
to  
randomization.  The  SAP  may  specify  additional  data 
handling rules. 
Analysis Populations:  
The  safety  population  was  
to  
include  all  randomized  subjects  who  received  any  study  
treatment 
(SOC  only  or  SOC  plus  Ryanodex).  The  safety  population  was  
to  be  used  
to  analyze  all  safety 
endpoints using actual treatment received.  
The  Intent-to-Treat  (ITT)  population  was  to  include  all  randomized  subjects  who  received  any 
study  
treatment  and  was  
to  be  used  as  
the  primary  efficacy  population.  Subjects  who  achieved  a 
GCS total score of ≥ 13 prior to receiving any study treatment were to be excluded from the ITT 
population.  
The Per Protocol population (PP) was to include all ITT subjects who met all inclusion/exclusion 
criteria,  had  a  baseline  and  at  
least  1  post-baseline  GCS  
total  score,  and  had  no  major  protocol 
deviations that could affect the efficacy assessments.  
The  
ITT  and Per Protocol populations were  
to  be  analyzed  using  planned  
treatment  assignments. 
Classification of subjects with respect to the ITT, PP, and Safety populations was to be conducted 
prior to the database lock. 
 
Efficacy Analysis: 
The primary analyses of the primary and secondary efficacy endpoints were to be conducted on the 
ITT  population.  The  PP  population  analyses  of  primary  and  secondary  endpoints were  to  be 
considered supportive. For the primary endpoint, Logit model was to be used to compare proportion 
of  subjects  achieving  a  GCS  score  ≥  13  at  or  prior  to  90  minutes  post-randomization  between 
treatment groups. 
For  the  secondary  endpoints,  the  data  was  to  be  summarized  and  compared  according  to  the 
variable type: 
• Continuous data summaries was to include: 
• Descriptive  summary  of  number  of  observations,  mean,  standard  deviation,  median,  and 
minimum and maximum values. 
• Mixed  Model  Repeated Measures  (MMRM)  for  inferential  statistics  was  to  be  used  if  the 
Normality assumption is met. 
• Non-parametric methods were to be used for inferential statistics if the Normality assumption 
was not met. 
• Categorical data summaries was to include: 
• Frequency counts and percentages. 

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• Logit model for inferential statistics 
• Time-to-event data summaries was to use: 
• Kaplan-Meier  (K-M)  methods  to  depict  the  data  and  Cox  proportional  hazards  model  for 
inferential statistics. 
Safety Analysis: 
The Safety Population was to be used for the safety analysis. No modeling or inferential statistics 
was to be conducted on the safety assessments. 
Other: 
Demographics, subject disposition, dosing parameters, and prior/ concomitant medications were to 
be summarized. Other concomitant therapies and medical history were to be listed. 
SUMMARY OF RESULTS  
Efficacy: 
The  primary  objective  of  this  Phase  3  study  was  to  evaluate  the  efficacy  of  Ryanodex  for  the 
treatment  of  EHS  when  administered  as  an  adjunctive  treatment  to  the  current  standard  of  care 
(SOC), compared to the administration of SOC only. Standard of care, comprised by body cooling 
and  
supportive  measures,  
should  be  considered  as  an  active  control.  Evaluations  of efficacy  were 
made using the Glasgow Coma Scale (GCS) 
  
The primary endpoint for the study was the cumulative proportion of subjects achieving a GCS ≥ 
13 at or prior to 90 minutes post randomization. At baseline, subjects in the SOC + Ryanodex group 
were reported with a median GCS score of 5.0. Subjects in the SOC only group were reported with 
a median score of 4.5.  
At  or  prior  to  90  minutes  post  randomization,  a  greater  proportion  of  subjects  in  the  SOC  + 
Ryanodex group were reported with GCS scores ≥ 13 than in the SOC only group.  
 
 
 
 
 
 
 
 
 
 
 
Safety: 
This study was designed to assess the safety of Ryanodex in the adjuvant setting with standard of 
care  (SOC)  therapy  on  subjects  diagnosed  with  Exertional  Heat  Stroke  (EHS).    Subjects  were 

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randomized to receive Ryanodex plus SOC or SOC treatment alone. Safety evaluations were based 
on the assessment of treatment emergent adverse events (TEAEs),
 
 
 
  
A total of 17 subjects were enrolled, nine of which were randomized to the SOC + Ryanodex 
treatment group. Subjects were to receive an initial dose of Ryanodex of 2.5 mg/kg administered as 
an IV bolus within 
 after randomization, in addition to SOC which was initiated 
 after diagnosis of hyperthermia.. 
 
 
  
A total of four subjects (44.4%, 4/9) received 
 Ryanodex doses. 
 
 
 
 
A total of 14 AEs were reported for 12 subjects (70.6%, 12/17) in groups SOC + Ryanodex or SOC 
only groups.  By treatment group, nine AEs were reported for seven subjects (77.8%, 7/9) in the 
SOC + Ryanodex group and five AEs for five subjects (62.5%, 5/8) in the SOC only group. Based 
on severity, two severe AEs were reported, one in each treatment group. No AEs were reported that 
led to death or study treatment interruption or discontinuation.   
 
Based on the MedDRA version 21.0 classification, the most commonly reported system organ 
classes were metabolism and nutrition disorders (17.6%, 3/17) and nervous system disorders 
(17.6%, 3/17), followed by gastrointestinal disorders, investigations, and vascular disorders, each 
reported at an incidence of 11.8% (2/17). The remaining categories were reported in < 10% of 
subjects. Of the three subjects with AEs in the system organ class of metabolism and nutrition 
disorders, two subjects (22.2%, 2/9) were in the SOC + Ryanodex treatment group with the 
remaining subject (12.5%, 1/8) in the SOC only group.  All subjects with AEs reported in the 
category of nervous system disorders were randomized to the SOC only treatment group with three 
events of seizure (by PT) reported for three subjects (37.5%, 3/8). 
Of the two severe AEs, one subject in the SOC + Ryanodex treatment group was reported with the 
AE of coma scale abnormal (by PT) in the system organ class of investigations. In the SOC only 
group, one subject was reported with dyspnoea (by PT) in the system organ class of respiratory, 
thoracic, and mediastinal disorders.  
There were three SAEs reported for three subjects (17.6%, 3/17). One subject (11.1%, 1/9) was 
randomized to the SOC + Ryanodex and two subjects (25.0%, 2/8) to the SOC only group.  
In the SOC + Ryanodex, the SAE reported was presented by PT as coma scale abnormal.  In the 
SOC group, the SAEs were reported in each subject by PT as seizure and dyspnoea, respectively. 

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CONCLUSIONS 
Study EGL-4104-1801 was a Phase 3, multicenter, double blind, randomized, 2-arm, parallel, 
active controlled trial to evaluate the safety and efficacy of Ryanodex as adjuvant treatment to 
standard of care (SOC), compared to SOC only, in subjects with Exertional Heat Stroke (EHS). 
 
 
 
  
Ryanodex (dantrolene sodium) for injectable suspension was administered as a rapid IV push. 
Glasgow Coma Scale (GCS) was used to assess subjects’ neurologic condition in the study. The 
primary efficacy endpoint was the cumulative incidence of subjects achieving a GCS score ≥ 13 at 
or prior to 90 minutes post-randomization. 
 
 
. A greater proportion of subjects in 
the SOC + Ryanodex treatment group achieved a GCS score ≥ 13 at or prior to 90 minutes post 
randomization, compared to the SOC only group. In addition, the cumulative incidence of GCS 
score ≥ 13 over time was higher in the SOC + Ryanodex group at all planned time points 
throughout the study.  
 
 
 
  
 
 
  
 
 
Date of Report: 6 January 2020