Conditions: Exertional Heat Stroke
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 17
Healthy volunteers: no

Brief summary:
A double-blind, parallel study of Ryanodex for the adjuvant treatment of exertional heat stroke (EHS) compared to current Standard of Care (SOC) for EHS.

Detailed description:
Following triage and primary assessment in the emergency medical facility, subjects will be randomized to 1 of 2 treatment arms, SOC plus Ryanodex or SOC only. Subjects will be dosed and followed for up to 6 hours post-randomization. Current SOC is limited to body cooling and supportive measures.

Arms:
arm 1: In addition to Standard of Care measures, Ryanodex (dantrolene sodium) for injectable suspension; 250 mg/vial will be administered. arm 2: Standard of Care treatment will consist of the immediate start of cooling measures.

Interventions: intervention 1: Ryanodex and Standard of Care intervention 2: Standard of Care
Intervention descriptions: intervention 1: Ryanodex to be administered as a rapid IV push intervention 2: Body cooling measures and supportive measures

Protocol document:
Prot_000.pdf: 
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 

SAP_001.pdf: 
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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9.7 
STATISTICAL METHODS PLANNED IN THE PROTOCOL  
9.7.1 Statistical and Analytical Plans 
 
 lock for the clinical trial protocol EGL-4104-C-
1801. Highlights from the statistical analyses proposed for this study are discussed below. 
  
9.7.1.1 General Statistical Considerations 
All collected study data was to be presented in subject data listings. Statistical analyses 
were to be performed using SAS® for Windows, version 9.4 or later. Descriptive statistics 
(n, mean, standard deviation, median, minimum and maximum) were to be calculated by 
treatment group for continuous variables. Frequencies and percentages were to be 
presented by treatment group for categorical variables. 
9.7.1.2 Data Convention and Related Definitions 
9.7.1.2.1 
Baseline Definition 
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. 
9.7.1.2.2 
Duplicate Data 
For unplanned duplicate data within a protocol-specified time point, the last measured 
value was to be used for the analysis. If it is not possible to identify the “last measured 
value”, the average of the duplicate values was to be used. 


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9.7.1.2.3 
Outliers 
Data  points  
that  appear  to  be  outliers  (i.e.,  clinically  
identified  
to  be  
too  small  or too 
large)  were  to  be  investigated  and  were  not  to  be  excluded  from  the  listings.  If  the 
clinician confirms that a data point was truly an outlier and was not clinically possible, 
two  analyses  were  
to  be  performed,  one  with  
the  outlier  data  point  and  one without  
it. 
Any such analysis was to be clearly indicated and footnoted. 
9.7.1.2.4 
Handling of Missing Data 
Every  effort  was  
to  be  made  
to  obtain  required  data  at  each  scheduled  evaluation 
from  all  subjects  who  have  been  randomized  to  minimize  missing  data.  The 
following  methods  were  to  be  used  to  handle  missing  data  for  efficacy  and  safety 
evaluations. 
9.7.1.2.4.1 Handling of Missing Data for Efficacy Evaluations 
For efficacy data points the following methods were to be used for the post baseline time 
points with missing assessments:  
• If the data point was categorical in nature then the result from the missing data point 
was to be considered as failure (i.e., non responder) for analysis purposes  
•  If  the  missing  data  point  was  continuous  in  nature,  then  Mixed  Model  Repeated 
Measures (MMRM) was to be used to adjust for the missing values  
• If the data point was  a time-to-event endpoint then the result from the missing data 
point  was  to  be  considered  no  event  and  censored  based  on  the  last  available 
date/time  
9.7.1.2.4.2 Handling of Missing Data for Safety Evaluations 
With  
respect  
to  summaries  of  AEs,  only  AEs  
that  were  
treatment  emergent  were  
to  be 
tabulated. Treatment–emergent AEs were defined as AEs with start date and time ≥ date 
of randomization.  
9.7.1.2.5 
Sensitivity Analysis 
A  sensitivity  analysis  using  multiple  imputations  or  tipping  point  analysis  was  to  be 
conducted on the ITT population to assess the likelihood that missing data could bias the 
conclusion of the primary endpoint (i.e., proportion of subjects achieved a GCS score ≥ 
13 at or prior to 90 minutes post-randomization) of the study. 


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9.7.1.2.6 
Multicenter Clinical Trials 
This study was a multicenter clinical trial. All the data collected from the different study 
centers was to be presented as a by-subject listing. 
9.7.1.2.7 
Multiple Comparisons and Type I Error Rate Multiplicity 
Adjustments 
For the primary endpoint only one (1) hypothesis was to be tested, hence there was to be 
no adjustment for Type I error rate. 
For the secondary endpoints, the closed test procedure was to be used to protect the trial-
wise error rate. 
. 
9.7.1.2.8 
Covariates and Prognostic Factors 
For efficacy analyses, baseline values were to be used as covariates in the analysis 
models. 
9.7.1.2.9 
Stratification Factors 
The randomization for the study was stratified by study center. This stratification was 
used to ensure a balanced distribution of subjects among the two treatment groups. 
9.7.1.2.10 
Subgroup Analysis 
Subgroup analyses were to be conducted for the predefined stratification factors 
presented in Section 9.7.1.2.9 above. Additional subgroup analysis for all the efficacy 
endpoints was to be conducted using the subgroup of subjects that did not require 
endotracheal intubation at post-randomization. 
9.7.1.2.11 
Standard Calculations 
Age 
Age was to be calculated as the number of completed years between the date of 
randomization and the subject’s birth date as per the formula listed below: 
Age (years) = integer of [(date of randomization – date of birth) / 365.25 + 0.5] 
Change from Baseline 
Change from baseline for a given measurement was to be calculated using below 
formula. 


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Change From Baseline =  Post baseline result at time t – Baseline result 
Percent Change from Baseline 
Percent change from baseline for a given measurement was to be calculated using below 
formula. 
Percent Change =  [(Post baseline result at time t)/Baseline result– 1]*100 
Temperature 
For summary purposes, temperature was expressed in Celsius. Entries made in Fahrenheit 
(° F) was to be converted to Celsius (° C) using below formula. 
Temperature (° C)  =  (Temperature (° F) – 32)*(5/9) 
Time to first rectal temperature ≤ 37° C and ≤ 38° C 
Time (minutes) to first rectal temperature ≤ 37° C was to be calculated using below 
formula. 
Time to first rectal temperature ≤ 37° C =   
Time of first rectal temperature ≤ 37° C– Time of baseline rectal temperature 
Time (minutes) to first rectal temperature ≤ 38° C was to be calculated using below 
formula. 
Time to first rectal temperature ≤ 38° C =   
Time of first rectal temperature ≤ 38° C– Time of baseline rectal temperature 
9.7.1.3 Analyses Populations 
9.7.1.3.1 
Intent-to-Treat (ITT) Population 
The Intent-to-Treat (ITT) population was defined as all randomized subjects who 
received any study treatment. Subjects who achieved a GCS total score of ≥ 13 prior to 
receiving any study treatment were to be excluded from the ITT population. The ITT 
population was to be the primary population for the analysis of the primary and 
secondary efficacy endpoints.  


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9.7.1.3.2 
Per Protocol (PP) Population 
The Per Protocol (PP) population was defined as 
 
 
 
 
9.7.1.3.3 
Safety Population 
The Safety population was defined as all randomized subjects who received any study 
treatment (SOC with Ryanodex or SOC only). This population was to be used for 
analysis of all safety endpoints using actual treatment received.  
9.7.1.4 Analysis of Efficacy Data 
All inferential statistical analysis was to be based on a two-sided test with a Type I error 
rate of 0.05.  
The primary analyses of the primary and secondary efficacy endpoints were to be 
conducted on the ITT population.
 
 
 
 
9.7.1.4.1 
Primary Endpoint 
The primary efficacy endpoint for this study was cumulative incidence of subjects 
achieving a GCS score ≥ 13 at or prior to 90 minutes post-randomization.  
The number and percentage of subjects who achieved a GCS score ≥ 13 at or prior to 90 
minutes post-randomization was to be presented by treatment arm. The 
 
adjusting for baseline GCS score was to be used to analyze the percentage of subjects 
achieving GCS score ≥ 13 at or prior to 90 minutes post-randomization and the 95% CI 
for the treatment difference and p-value for the treatment effect was to be reported. 
9.7.1.4.2 
Secondary Endpoints 
As discussed in Section 9.7.1.2.7, to protect the type I error rate for the secondary 
endpoints, the closed test procedure was to be used. Discussed below are the approaches 
that were to be taken for each of the secondary endpoints. These endpoints are presented 
in the order that were to be tested. 


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9.7.1.4.2.1 
Cumulative incidence of subjects who achieve a GCS score ≥13 at 
planned time points 
The number and percentage of subjects who achieved a GCS score ≥ 13 at each planned 
time point was to be presented by treatment arm. 
 
. 
9.7.1.4.2.2 
Actual values, changes from baseline, and percent changes from baseline 
in GCS scores over time 
Actual values, changes from baseline and percent changes from baseline in GCS scores 
were to be calculated (see Section 9.7.1.2.11 for calculation). Descriptive summary of 
number of observations, mean, standard deviation, median, and minimum and maximum 
values was to be presented.  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 


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9.7.1.5 Planned Analysis for Safety Data 
All safety analyses were to be conducted using the Safety population. All data collected 
was to be summarized according to the variable type.  
For  continuous  variables,  data  was  to  be  summarized  by  treatment  using  n,  mean, 
standard deviation, minimum, and maximum values. For categorical variables, data was 
to be summarized by treatment using frequency and percentage. No inferential statistics 
were planned. 
9.7.1.5.1 
Adverse Events 
Adverse events were to be coded using the most recent version of Medical Dictionary for 
Regulatory  Activities  (MedDRA).  Treatment  Emergent  AE’s  (TEAE)  were  defined  as 
events  which  started  on  or  after  the  start  date  and  time  of randomization,  or  which 
worsened after the start date and time of randomization. TEAEs were to be summarized 
by  treatment  group,  System  Organ  Class,  and  preferred  term.  The  following  TEAE 
summaries were to be provided:  
• Overall (i.e., regardless of severity or relationship to treatment)  
• By severity grade (mild, moderate, or severe)  
• By  
investigators  causality  assessment  (related,  possibly  related,  probably  related  or 
unrelated)  
In addition, separate summaries of serious adverse events, and adverse events resulting in 
study discontinuation will be presented. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


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clinically significant) and Abnormal (clinically significant)) with counts and percentages 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.7.2 Determination of 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 is used for this sample size calculation. 
The sample size calculation is based on the assumption that 50% of subjects who receive 
SOC therapy and Ryanodex will 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 assumption, 50 subjects per treatment group were required to meet the 
Type I error rate of 0.05, 2-sided and over 95% statistical power; for a total of 100 
subjects for the study.  
Figure 9-3 depicts the statistical power and sample size based on the above specified 
assumptions with a Type I error rate of 0.05 and 2-sided test. 


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Figure 9-3: 
Study Sample Size Estimation