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)
Phase: PHASE2
Conditions: Heat Stroke
Sponsor: Eagle Pharmaceuticals, Inc.

NCT02513095 
Protocol EGL-4104-C-1502: 
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) 
Document Date: November 2, 2016 
 

 
2.0 SYNOPSIS 
Name of Sponsor/Company: 
Eagle Pharmaceuticals, Inc. 
Individual 
Study Table 
 
(For 
National 
Authority 
Use only) 
Name of Finished Product: 
Ryanodex® (dantrolene sodium) for injectable suspension 
Name of Active Ingredient: 
Dantrolene sodium 
Title of Study: 
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) 
Investigators: 
 
 
Study Centers: 
The study was conducted at a single site with 3 additional satellite site locations in the region of 
Mekkah, Saudi Arabia, during the 2015 Hajj pilgrimage. 
Publication (Reference): 
None 
Study Period: 
22 September 2015 (First Subject Enrolled) - 27 September 2015 (Last 
Subject Completed Treatment) 
Phase of Development: 
2 
Objectives: 
Primary: To evaluate the efficacy of Ryanodex for the treatment of EHS, administered as adjunctive 
treatment to current standard of care (SOC). 
Secondary: To evaluate the safety and tolerability of Ryanodex for the treatment of EHS by comparing 
the treatment groups for the incidence of treatment-emergent adverse events (TEAEs), physical and 
neurological examination findings, clinical laboratory test results, and vital signs. 
Methodology: 
 
 
 
 
 
 
 
 
 
 
 
Eagle Pharmaceuticals, Inc.
Protocol No. EGL-4104-C-1502
02 November 2016 Final
1

 
Name of Sponsor/Company: 
Eagle Pharmaceuticals, Inc. 
Individual 
Study Table 
 
(For 
National 
Authority 
Use only) 
Name of Finished Product: 
Ryanodex® (dantrolene sodium) for injectable suspension 
Name of Active Ingredient: 
Dantrolene sodium 
  
Treatment Groups: 
Upon admission to the emergency medical facility and following assessment of study inclusion and 
exclusion criteria, eligible subjects with probable or definitive EHS were randomized in a 1:1 ratio to one 
of the following treatment groups: 
• Group A: Ryanodex, in addition to immediate implementation of SOC (body cooling and 
supportive measures) 
• Group B: SOC only (body cooling and supportive measures) implemented immediately 
Subjects randomized to Group A received an initial dose of Ryanodex (study drug) of 2 mg/kg 
administered as an IV bolus, in addition to SOC. If the subject did not show adequate clinical response 
between 30 and 90 minutes after the initial dose, a single repeat dosing of 2 mg/kg of study drug could 
be administered between 30 and 90 minutes following the initial dose.
 
 
 
 
  
Subjects who had received up to two 2-mg/kg (up to 4 mg/kg) IV doses of Ryanodex (Group A) during 
the Treatment Phase of the study could receive additional treatment with Ryanodex at a dose of 
1 mg/kg as an IV bolus starting at 90 minutes following the initial dose and continuing every 6 hours for 
up to 24 hours under the following conditions:  
1. If the subject had not achieved an adequate response (defined as rectal temperature ≤ 38.0°C 
and Glasgow Coma Scale (GCS) score ≥ 13); or, 
2. If the subject had achieved an adequate response (defined as rectal temperature ≤ 38.0°C and 
GCS ≥ 13) but the symptoms began to reappear 
 
 
Clinical assessments and symptoms leading to additional doses of study drug were to be clearly 
recorded. The total administered dose of Ryanodex in a 
period was not to exceed 
  
Stopping the study drug: 
If
 
  
 
 
  
 
 
 
 
 
The study protocol included three phases (Screening/Randomization, Treatment Phase, and Follow-up 
Eagle Pharmaceuticals, Inc.
Protocol No. EGL-4104-C-1502
02 November 2016 Final
2

 
Name of Sponsor/Company: 
Eagle Pharmaceuticals, Inc. 
Individual 
Study Table 
 
(For 
National 
Authority 
Use only) 
Name of Finished Product: 
Ryanodex® (dantrolene sodium) for injectable suspension 
Name of Active Ingredient: 
Dantrolene sodium 
Phase), plus a follow-up contact by telephone at approximately 
days after the subject’s discharge 
from the study. 
 
Number of Subjects (Planned and Analyzed): 
A total of 100 subjects (50 per arm) were initially planned to be randomized in the study. Due to 
unforeseen tragic events impacting the location of the study and enrollment plans, 40 subjects were 
screened to participate, and 34 subjects were randomized (6 subjects were screen failures). A total of 
34 subjects were analyzed for efficacy and safety. 
Diagnosis and Main Criteria for Inclusion: 
Male or non-pregnant female subjects were entered into this study if they were diagnosed with probable 
or definitive EHS as evidenced by all of the following:  
• A core body temperature obtained rectally of ≥ 40.0°C (104.0°F) 
• In the judgment of the Investigator, the subject was likely 18 years of age or older, and not older 
than 45 years of age 
• 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 beats per minute [bpm]). 
Test Product, Dose and Mode of Administration, Batch Number: 
Ryanodex (dantrolene sodium) for injectable suspension; 250 mg/vial to be reconstituted with 5 mL of 
sterile water for injection (without a bacteriostatic agent) to yield a 50 mg/mL suspension; administered 
as a rapid IV push of 2.0 mg/kg or 1.0 mg/kg. Batch numbers of Ryanodex and sterile water for injection 
were 
and 
, respectively. 
Duration of Treatment: 
Up to 72 hours, from Screening to medical discharge from the study. 
Reference Therapy: 
Standard of Care (SOC): All subjects in both treatment groups received SOC (efficient cooling and 
supportive measures). 
Criteria for Evaluation: 
Efficacy: 
The primary efficacy endpoint was cumulative incidence of subjects who had achieved a GCS score ≥ 
13 at or prior to 90 minutes post-randomization.  
Secondary efficacy endpoints consisted of the following: 
• 
Cumulative incidence of subjects who had achieved a GCS score ≥ 13 at planned time points 
• 
Changes from Baseline, and percent changes from Baseline in GCS scores over time 
• 
 
 
 
Eagle Pharmaceuticals, Inc.
Protocol No. EGL-4104-C-1502
02 November 2016 Final
3

 
Name of Sponsor/Company: 
Eagle Pharmaceuticals, Inc. 
Individual 
Study Table 
 
(For 
National 
Authority 
Use only) 
Name of Finished Product: 
Ryanodex® (dantrolene sodium) for injectable suspension 
Name of Active Ingredient: 
Dantrolene sodium 
• 
 
 
 
 
 
 
 
 
 
  
Safety: 
Safety was evaluated by the following parameters: 
• 
Adverse events 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
Dantrolene Plasma Concentration Data: 
A single blood sample was collected at 2 hours (± 15 minutes) post-Baseline for the purpose of 
establishing the plasma concentration of dantrolene. The plasma concentration results were used to 
demonstrate that treatment was administered as assigned. 
 
 
 
 
 
Eagle Pharmaceuticals, Inc.
Protocol No. EGL-4104-C-1502
02 November 2016 Final
4

 
Name of Sponsor/Company: 
Eagle Pharmaceuticals, Inc. 
Individual 
Study Table 
 
(For 
National 
Authority 
Use only) 
Name of Finished Product: 
Ryanodex® (dantrolene sodium) for injectable suspension 
Name of Active Ingredient: 
Dantrolene sodium 
Statistical Methods: 
Sample Size: The planned sample size of 100 subjects (50 per group) was based on the predicted 
number of subjects who may be diagnosed with probable EHS during the 2015 Hajj. This sample size 
was planned to provide about 
power to detect a difference between treatment means that was 
equivalent to 50% of the standard deviation (SD) (i.e., a moderate or medium-sized treatment effect) for 
any measure that had an approximately normal distribution, using a two-tailed Student t-test or F-test 
conducted at a significance level of 5%. Also, assuming that 
 of subjects who received SOC 
therapy with adjuvant Ryanodex treatment achieved a GCS ≥ 13 at 90 minutes post-randomization, 
compared to only 
of subjects who received SOC only, the planned sample size would provide 
about 
 power for a 2-sided chi-square test to detect the difference between treatments at a 
significance level of 
.  
Baseline: Baseline body temperature was the first rectal temperature ≥ 40.0°C taken during the 
screening period. 
 
 
 
Analysis sets: The Safety analysis set included all randomized subjects who received any study 
treatment (SOC only or SOC and Ryanodex). The Safety analysis set was used to analyze all safety 
endpoints using actual treatment received. The Intent-to-Treat (ITT) analysis set included all 
randomized subjects for whom SOC was initiated, and was used as the primary efficacy analysis set. 
 
 
 
 
 
The ITT, 
 analysis sets were 
analyzed using planned treatment assignments. Classification of subjects with respect to the ITT, 
 
, and Safety analysis sets was conducted prior to the final database lock. 
Efficacy Parameters: 
The main focus of all efficacy analyses was to describe the course of subject recovery during the study 
and to obtain estimates of the treatment effect. Any observed significance levels (“p-values”) that were 
reported were to be regarded as exploratory, descriptive statistics. 
The primary null hypothesis was that restoration of level of consciousness (defined as a return to GCS 
scores ≥ 13) in subjects with probable or definitive EHS was not different for subjects treated with 
Ryanodex in addition to immediate implementation of SOC (body cooling and supportive measures), 
compared to subjects treated with SOC only (body cooling and supportive measures) implemented 
immediately.
 
 
 the primary endpoint was the cumulative incidence of subjects who had 
achieved a GCS score ≥ 13 prior to or at 90 minutes post-randomization in the ITT analysis set. The 
number and percentage of subjects who achieved a GCS score ≥ 13 are presented by treatment arm. A 
two-sided 95% Wilson confidence interval (CI) for each treatment group proportion and a two-sided 
95% Newcombe CI for the treatment difference were calculated. The odds ratio and its two-sided 95% 
CI were also calculated and reported. The cumulative incidence of subjects who achieved a GCS score 
Eagle Pharmaceuticals, Inc.
Protocol No. EGL-4104-C-1502
02 November 2016 Final
5

 
Name of Sponsor/Company: 
Eagle Pharmaceuticals, Inc. 
Individual 
Study Table 
 
(For 
National 
Authority 
Use only) 
Name of Finished Product: 
Ryanodex® (dantrolene sodium) for injectable suspension 
Name of Active Ingredient: 
Dantrolene sodium 
≥ 13 at or prior to each planned assessment time point is presented as supportive data. S
 
 
Secondary endpoints were analyzed for the ITT analysis set. Endpoints that consisted of actual values, 
changes from Baseline, or percent changes from Baseline were described by treatment group and 
planned time point, using basic descriptive statistics (N, mean, median, SD, two-sided 95% CI around 
the mean, minimum, maximum). Changes from Baseline in GCS and 
 were submitted 
to a repeated measures analysis employing a restricted maximum likelihood-based (REML), repeated-
measure mixed model to obtain more precise estimates of treatment effect. SAS® Proc Mixed was used 
to perform the analysis. Each model included fixed terms for treatment group, time point, and treatment-
by-time point interaction, with the Baseline value as covariate (as applicable), and subject as a random 
factor. An unstructured covariance matrix failed to converge when applied to pre-lock data, so a first-
order autoregressive [AR (1)] covariance structure was used. An empirical (“sandwich”) estimator for 
the variance-covariance matrix and the denominator degrees of freedon (DDFM) = BETWITHIN option 
for calculation of DDFM were used to take account of possible misspecification of the true covariance 
matrix. Predicted least square means, treatment differences between least square means, and two-
sided 95% CI for the treatment differences are reported, overall and by planned time point, for all 
subjects in the analysis set.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Parameters: 
Incidence of TEAEs, serious adverse events (SAEs), related AEs, and related SAEs reported during the 
study was tabulated by treatment arm, overall and by maximum intensity. Deaths due to any cause 
during the study were tabulated by treatment arm. AEs were recorded from start of 
screening/randomization. 
 
Eagle Pharmaceuticals, Inc.
Protocol No. EGL-4104-C-1502
02 November 2016 Final
6

 
Name of Sponsor/Company: 
Eagle Pharmaceuticals, Inc. 
Individual 
Study Table 
 
(For 
National 
Authority 
Use only) 
Name of Finished Product: 
Ryanodex® (dantrolene sodium) for injectable suspension 
Name of Active Ingredient: 
Dantrolene sodium 
 
. 
Other: Demographics, subject disposition, dosing parameters, and 
 
are summarized. 
 
 
 
  

 
Name of Sponsor/Company: 
Eagle Pharmaceuticals, Inc. 
Individual 
Study Table 
 
(For 
National 
Authority 
Use only) 
Name of Finished Product: 
Ryanodex® (dantrolene sodium) for injectable suspension 
Name of Active Ingredient: 
Dantrolene sodium 
Summary – Conclusions: 
Efficacy Results: 
• 
A greater proportion of subjects treated with SOC and Ryanodex exhibited a clinically 
meaningful improvement in their neurological functioning (GCS ≥ 13) within 90 minutes (29.4%) 
and within 24 hours post-randomization (47.1%), compared to SOC only-treated subjects 
(11.8% and 23.5%, respectively) (ITT Analysis Set).  
• 
A greater proportion of subjects treated with SOC and Ryanodex achieved a clinically 
meaningful improvement (GCS score ≥ 13) in their neurological functioning as early as 45 
minutes post-randomization compared to subjects treated with SOC only, and that difference in 
favor of the SOC and Ryanodex group remained unchanged at the end of the Treatment Phase 
(2 hours post-randomization) (ITT and mITT Analysis Sets).   
• 
The odds of achieving a GCS score ≥ 13 within 90 minutes post-randomization was about 3 
times greater for subjects in the SOC and Ryanodex group than for subjects who received SOC 
only, and remained almost unchanged at or prior to 24 hours post-randomization (ITT Analysis 
Set).  
• 
Among fully evaluable subjects at Baseline, the odds of achieving a GCS score ≥ 13 within 90 
minutes post-randomization was about 6 times greater in the SOC and Ryanodex group than for 
subjects who received SOC only (mITT Analysis Set). 
• 
Among fully evaluable subjects at Baseline, the mean change from Baseline in GCS score was 
higher in the SOC and Ryanodex group (3.1; p=0.017) compared with the SOC only group (1.1; 
p=0.179); the mean percent change from Baseline in GCS score was also higher in the SOC 
and Ryanodex group (55.6%; p=0.073) compared with the SOC only group (20.2%; p=0.212). 
In both cases, the within-group p-value clearly favors the SOC and Ryanodex group, compared 
with the SOC only group (mITT Analysis Set). 
• 
The proportion of subjects who achieved complete normalization in their level of consciousness 
(GCS score = 15) was greatest at 24 hours post-randomization and was greatest in the SOC 
and Ryanodex group (41.2%) than in the SOC only group (23.5%) (ITT Analysis Set). 
• 
Duration of SOC was substantially shorter in the SOC and Ryanodex group compared to the 
SOC only group (ITT Analysis Set). 
• 
The time to reach first rectal temperature ≤ 38°C was similar in both treatment groups (ITT 
Analysis Set).  
• 
The median time to reach first rectal temperature ≤ 38°C was shorter in the SOC and Ryanodex 
group (90.0 minutes) than in the SOC only group (103.0 minutes). In addition, the time at which 
at least 75% of the subjects had first rectal temperature ≤ 38°C was also shorter in the SOC and 
Ryanodex group (125.0 minutes) than in the SOC only group (195.0 minutes) (mITT Analysis 
Set). 
• 
Overall mean cooling rates were similar in both treatment groups (ITT and mITT Analysis Sets).  
Subjects treated with Ryanodex in addition to SOC, exhibited greater clinically meaningful improvement 
in their neurological functioning compared to SOC only-treated subjects. The observed incremental 
improvement in neurologic functioning constitutes a clinically relevant benefit, known to be associated 
Eagle Pharmaceuticals, Inc.
Protocol No. EGL-4104-C-1502
02 November 2016 Final
8

 
Name of Sponsor/Company: 
Eagle Pharmaceuticals, Inc. 
Individual 
Study Table 
 
(For 
National 
Authority 
Use only) 
Name of Finished Product: 
Ryanodex® (dantrolene sodium) for injectable suspension 
Name of Active Ingredient: 
Dantrolene sodium 
with lower risk of EHS-related complications, and decreased long-term morbidity and mortality. 
 
Safety Results: 
• 
Ryanodex was safe and well-tolerated by subjects in the SOC and Ryanodex group.  
• 
No new and/or unexpected safety signals were detected.  
• 
The overall incidence of TEAEs was similar in both groups.  
• 
No treatment-related TEAEs were reported.  
• 
No subjects withdrew due to TEAEs.  
• 
There were no clinically meaningful differences in laboratory abnormalities between the two 
treatment groups.  
• 
There were no clinically meaningful differences in vital signs, ECGs, ETCO2, or oxygen 
saturation between the two treatment groups.  
• 
The safety profile of Ryanodex in this study population was consistent with the known and well-
characterized safety profile in the currently approved indications. 
Conclusion: 
Overall, Ryanodex administered to EHS subjects was safe and well tolerated. The safety profile of 
Ryanodex in this severely ill population was consistent with its known and well-characterized safety 
profile in the currently approved indications.  
Subjects treated with Ryanodex, in addition to SOC, exhibited greater clinically meaningful 
improvement in their neurological functioning compared to SOC only-treated subjects. The observed 
incremental improvement in neurologic functioning constitutes a clinically relevant benefit, known to be 
associated with lower risk of EHS-related complications, and decreased long-term morbidity and 
mortality. 
The results of the study provide clinical evidence of the therapeutic benefit that Ryanodex may deliver 
to patients with EHS. 
 
Eagle Pharmaceuticals, Inc.
Protocol No. EGL-4104-C-1502
02 November 2016 Final
9