Clinical trial NCT02513095
Conditions: Heat Stroke
Sponsor: Eagle Pharmaceuticals, Inc.
Start date: 2015-09-01; Completion date: 2015-10-01
Enrollment: 34 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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

Arms: arm 1: Ryanodex (dantrolene sodium) for injectable suspension administered as an IV bolus, in addition to standard of care (SOC) treatment. arm 2: Standard of Care (SOC) treatment only, consisting of body cooling and supportive measures implemented immediately.
Interventions: intervention 1: Dantrolene sodium for injectable suspension
Intervention descriptions: intervention 1: Ryanodex will be administered as a rapid IV push as a single doses of 2 mg/kg or as 1 mg/kg.

Protocol documents:
Prot_SAP_000.pdf: 
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
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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 
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Protocol No. EGL-4104-C-1502
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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 
• 
 
 
 
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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
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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 
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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. 
 
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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 
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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. 
 
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SAP_001.pdf: 
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 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.7 
Statistical Methods Planned in the Protocol and 
Determination of Sample Size 
9.7.1 
Statistical and Analytical Plans 
This section presents statistical methods used in the analyses as described in the final 
statistical analysis plan (SAP) dated 30 November 2015 and an SAP addendum dated 06 
April 2016. Both documents were prepared by 
and approved by the Sponsor before 
final database lock. Changes from analyses planned in the protocol are listed separately in 
Section 9.8.2. 
 
 
Subsequent to the approval of the SAP Addendum, a few items received further clarification 
or adjustment: 
• Subjects who were intubated and/or heavily sedated at Baseline were eligible for the 
study, but were not considered fully evaluable on the GCS.  
• It was stated that the modified Intent-to-Treat (mITT) Analysis Set should contain all 
Intent-to-Treat (ITT) subjects who were fully evaluable on the GCS at Baseline and 
who had at least 1 post-Baseline GCS assessment in the interval from 0 through 90 
minutes post-randomization. Although the description of this analysis set changed 
after database lock, none of the subjects included/excluded in this set changed as a 
result. 
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• The final analyses did not treat GCS scores of 2 as ‘missing’ (as specified in the SAP 
Addendum), but reverted to the original planned handling to ensure that any potential 
post-Baseline deterioration of subjects would be captured. 
9.7.1.1 
General Considerations 
Baseline core body temperature was the first rectal temperature ≥ 40.0°C taken during the 
Screening period. 
 
  
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. In general, all efficacy and safety 
variables were summarized using descriptive statistics. Continuous variables were 
summarized by descriptive statistics (sample size [n], mean, standard deviation [SD], 2-sided 
95% confidence interval [CI] around the mean; median, minimum, and maximum). 
Categorical variables and binomials (such as occurrence of events) were summarized in 
frequency tables which display the number and percentage of subjects reporting a particular 
response or outcome. All observed significance levels (“p-values”) that were reported were 
from 2-sided statistical tests unless otherwise specified, and were regarded as exploratory. 
Individual subject data were presented in listings. 
All analyses, summaries, and listings were generated using SAS® version 9.4 or later.  
9.7.1.2 
Data to be Analyzed 
Data to be analyzed were collected using Inform version 5.5. Data handling was the 
responsibility of 
 The data were inspected for inconsistencies by performing 
validation checks. All data collected during the study were reported.  
9.7.1.3 
Analysis Sets 
The Enrolled Analysis Set included: 
− Subjects who gave informed consent prior to participation. 
− Subjects whose family member or authorized representative gave informed consent 
for the subject prior to participation. 
− Subjects who entered the study under a waiver of informed consent. 
Waiver of a subject’s informed consent occurred in the event the subject was unable to 
consent due to his/her medical status and a family member or authorized representative was 
not available at the time of hospital admission.  
Once the study subject was capable of providing his/her own informed consent, then the 
subject was re-consented. If the subject was unwilling to provide consent at that time, the 
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subject was withdrawn from the study; and no further study procedures or  testing were 
performed. 
The Randomized Analysis Set contained all enrolled subjects who were randomized. For 
analyses and displays based on the Randomized Analysis Set, subjects were classified 
according to randomized treatment. 
• 
The ITT Analysis Set included all randomized subjects for whom SOC was initiated. 
Generally, the ITT population mimics ‘real-world’ clinical practice more closely than 
other analysis populations because no one is excluded. In this study, the ITT population 
was used as the primary efficacy population. All ITT analyses used the randomized 
treatment assignment.  
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
• 
The Safety Analysis Set included all randomized subjects who received any study 
treatment (SOC and Ryanodex or SOC only). The Safety Analysis Set was used for 
analysis of all safety endpoints using actual treatment received.  
All efficacy was analyzed by planned treatment arm. Classification of subjects with respect 
to the ITT, 
 and Safety Analysis Sets was conducted prior to the final database 
lock. 
9.7.1.4 
Missing Data 
Imputation of data in the mixed-model repeat measure (MMRM) analyses was not required, 
as the MMRM method provided appropriate weighting of the sample means based on the 
amount of data that each subject contributes.  
Imputation of data was not required for any time-to-event analysis. Subjects were censored at 
the earlier of the 72 hours or discontinuation from the study. 
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Imputation of missing data was done on cooling rate (based on rectal temperature), using 
straight-line interpolation for non-monotonically missing data points only.  
All other efficacy analyses methods consisted of descriptive statistics for observed cases. 
 
 
9.7.1.5 
Adjustments for Covariates and Factors to be Included in 
Analyses 
Analysis of covariance (ANCOVA) models, including repeated-measure ANCOVA models, 
included the subject’s respective Baseline value as a covariate. 
Study site (location) was originally planned as a stratification factor in various analyses. 
Study sites were 
 
 The specific analysis 
sections of the original SAP described how study site was to be used in the models (where 
applicable). Due to the actual study size, study site was deleted from all models and no tables 
or figures by study site were produced. 
 
 
 
 
 
 
 
9.7.1.6 
Multicenter Studies 
This study was conducted at a single main site 
) and 
satellite site locations 
). 
 
. Randomization to 
treatment arms was stratified by study site. All data were pooled for analyses. A term for 
treatment-by-center (study site) interaction was not included in the primary analysis model, 
but the presence of such an interaction was explored via graphical methods (e.g., Forest 
plots) to assess whether the interaction was quantitative (i.e., the treatment effect was 
consistent in direction but not size of effect) or qualitative (i.e., the treatment was beneficial 
at some but not other treatment locations). 
9.7.1.7 
Subject Disposition 
The disposition summary included all subjects. The summary included the number and 
percentage of subjects who were screened, enrolled, screen-failed (with reasons for failure), 
were randomized, were treated, completed the study, or discontinued prematurely, along with 
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the primary reason for discontinuation. The informed consent status and (where applicable) 
the reasons why informed consent was not obtained were also presented. The summary was 
presented by treatment arm. 
9.7.1.8 
Subject Characteristics 
Subject characteristics included, but were not limited to: age, sex, race, country of origin, 
height, approximate and actual body weight, 
 GCS score at Baseline, 
.  
Subject characteristics were obtained at screening or prior to discharge from the study and 
were summarized for all randomized subjects. If it was not possible to obtain all of the 
planned information at screening due to a subject’s poor medical condition at enrollment, an 
attempt was made to obtain it prior to subject discharge. All recorded data were included in 
subject data listings. 
Summaries included descriptive statistics for continuous variables (sample size, mean, and 
SD, median, minimum, and maximum) and for categorical variables (sample size, frequency, 
and percent). 
Subject characteristics were summarized using the Randomized Analysis Set. No inferential 
statistics were planned. 
9.7.1.9 
Efficacy Analyses 
9.7.1.9.1 
Primary Analyses 
The primary null hypothesis was that restoration of level of consciousness (defined as a 
return to GCS scores ≥ 13) of subjects with probable or definitive EHS was not different for 
subjects treated with SOC plus adjuvant Ryanodex therapy compared to subjects treated with 
SOC only. 
 
 
, the primary endpoint was the cumulative incidence of subjects 
achieving a GCS score ≥ 13 at or prior to 90 minutes post-randomization in the ITT Analysis 
Set. 
The number and percentage of subjects who achieved a GCS score ≥ 13 at or prior to 
90 minutes post-randomization were presented by treatment arm. A 2-sided 95% Wilson CI 
for each treatment group proportion and a 2-sided 95% Newcombe CI for the treatment 
difference were calculated. 
 
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9.7.1.9.2 
Sensitivity Analyses of the Primary Efficacy Variable 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.7.1.9.3 
Secondary Analyses 
The secondary endpoints were the following: 
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• 
Cumulative percentage of subjects who achieved a GCS score ≥ 13 at planned time points 
in the ITT and 
Analysis Sets 
• 
Actual values, changes from Baseline, and percent changes from Baseline GCS scores 
over time (at planned time points) in the ITT and 
 Analysis Sets 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
The cumulative incidence of subjects who achieved a GCS score ≥ 13 at each planned time 
point was presented as supportive data to the primary analysis. The analysis included the 
number and percentage of subjects achieving the endpoint at or prior to each time point.  
GCS actual values, changes from Baseline, and percent changes from Baseline were 
described by treatment group and planned time point using basic descriptive statistics (N, 
mean, median, SD, 2-sided 95% CI around the mean, minimum, maximum).  
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.7.1.9.4 
Exploratory Analyses 
 
 
 
. 
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9.7.1.9.5 
Subgroup Analyses 
 
9.7.1.10  Safety 
All safety variables were summarized using the Safety Analysis Set. All post-Baseline data 
were included. 
9.7.1.10.1 
Adverse Events 
Adverse events were coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 17.1. For each study treatment, numbers of events and incidence rates 
were tabulated by preferred term and system organ class. For each subject, an event that 
occurred one or more times after randomization contributed one observation to the numerator 
of the incidence rate. The denominator of the rate comprised all randomized subjects who 
received any treatment (i.e., the Safety Analysis Set). If the severity or seriousness of the AE 
changed, the overall severity or seriousness were the maximum severity or seriousness of the 
multiple occurrences. 
Adverse events were listed for each subject and summarized by MedDRA system organ class 
and preferred term. 
For this study, “treatment-emergent” AEs (TEAEs) were defined as AEs that started or 
worsened in severity on or after the initiation of first administered study treatment (SOC and 
Ryanodex, or SOC only). The incidence of all TEAEs, SAEs, related AEs, and related SAEs, 
was tabulated by treatment arm, overall and by maximum intensity. AEs leading to death, 
and AEs leading to withdrawal of subjects also were tabulated for each treatment group. 
Deaths due to any cause during the study were tabulated by treatment arm. Cases of 
rhabdomyolysis and ARF were identified at Baseline; any new cases that were identified 
post-Baseline or which worsened after the Baseline were reported as AEs. Post-Baseline 
severe respiratory distress or other medically important emergent events were reported as 
AEs. However, only AEs which occurred or worsened on or after the initiation of first 
administered study treatment were tabulated as TEAEs. 
 
 
.  
9.7.1.10.2 
Clinical Laboratory Evaluations 
 
 
 
. 
Eagle Pharmaceuticals, Inc.
Protocol No. EGL-4104-C-1502
02 November 2016 Final
70


 
9.7.1.10.3 
Exploratory Safety Endpoints 
  
 
 
 
 
 
. 
9.7.1.10.4 
Vital Signs Measurements, Physical Findings and Other Safety 
Evaluations