Conditions: Drug Toxicity Psychotropic Agents Psychostimulants
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 2
Healthy volunteers: no

Brief summary:
Ryanodex is being investigated as a potential adjuvant treatment for people suffering from psychostimulant drug-induced toxicity (PDIT), a life-threatening medical condition that results mainly from the abuse of certain illicit drugs, most notably methamphetamine, and related forms (MDMC or "Molly"; MDMA or "Ecstasy"). Ryanodex is approved for the treatment of malignant hyperthermia in conjunction with appropriate supportive measures and for prevention of malignant hyperthermia in patients at high risk and in this study, will be investigated for the treatment of PDIT. The hypothesis of this study is that administration of Ryanodex as adjuvant treatment to Standard of Care (SOC) will improve the clinical outcome compared with SOC alone, in subjects with psychostimulant drug induced toxicity. Current SOC is defined as body cooling and supportive measures.

Detailed description:
This study will be conducted at pre-hospital emergency care (PHEC) facilities. The PHECs are medical units that are fully equipped and staffed to provide adequate emergency medical care to patients with PDIT. The study is designed to evaluate the safety and efficacy of Ryanodex in an on0site pre-hospital emergency setting where subjects are anticipated to be treated over a short period of time and then transferred to another medical facility or released. After screening and diagnosis of PDIT, SOC treatment will be initiated. Subjects eligible for the study will be randomized to either receive SOC + Ryanodex or to receive SOC only. Study subjects are expected to remain at the study site for a maximum of 6 hours post-baseline.

Arms:
arm 1: Ryanodex (dantrolene sodium) 50 mg/mL suspension to be administered as a rapid IV push of 2.5 mg/kg, added to Standard of Care (SOC). SOC is defined as efficient body cooling by physical methods and supportive measures \[ice packs, evaporative cooling(application of room temperature water via mist with use of a fan\], benzodiazepines to ameliorate shivering, IV fluids, respiratory support, and other treatments deemed necessary to treat complications or comorbidities\]. Administer a single dose of Ryanodex. If a subject does not show an adequate clinical response within 10 - 30 minutes post-dose, a second IV bolus dose of 2.5 mg/kg may be administered. arm 2: Standard of Care is defined as efficient body cooling by physical methods and supportive methods and supportive measures\[ice packs, evaporative cooling (application of room temperature water via mist with use of a fan\], benzodiazepines to ameliorate shivering, IV fluids, respiratory support, and other treatments deemed necessary to treat complications or comorbidities\].

Interventions: intervention 1: Ryanodex (dantrolene sodium) for injectable suspension
Intervention descriptions: intervention 1: Ryanodex (dantrolene sodium) for injectable suspension, 250 mg/vial to be reconstituted in 5 mL of sterile water for injection to yield a 50 mg/mL suspension that will be administered as a rapid IV push of 2.5 mg/mL.

Protocol document:
Prot_001.pdf: 
NCT03189433 
 
Protocol EGL-4104-C-1702:  
Phase 2, Multiple-Site, Open-Label, Randomized, 2-Group, Parallel 
Study to Assess the Efficacy and Safety of Ryanodex® (EGL-4104) as 
Adjuvant Treatment in Subjects With Psychostimulant Drug-Induced 
Toxicity (PDIT) 
 Document Date: September 6, 2017 
 
 
 
 


Eagle Pharmaceuticals, Inc. 
Protocol EGL-4104-C-1702 
Ryanodex (dantrolene sodium) for Injectable Suspension 
Psychostimulant Drug Induced Toxicity 
Amendment 1 
Confidential 
Page 1 of 14 
Clinical Study Protocol 
Amendment 1 
Protocol Title: 
Protocol Number: 
Date of Protocol: 
Product: 
IND No.: 
Study Phase: 
Sponsor: 
Sponsor’s Medical Monitor: 
Principal Investigator: 
Phase 2, Multiple-Site, Open-Label, Randomized, 2-Group, 
Parallel Study to Assess the Efficacy and Safety of 
Ryanodex® (EGL-4104) as Adjuvant Treatment in Subjects 
With Psychostimulant Drug-Induced Toxicity (PDIT) 
EGL-4104-C-1702 
06 SEPTEMBER 2017 
Ryanodex® (EGL-4104) 
2 
Eagle Pharmaceuticals, Inc. 
Adrian J Hepner, MD, PhD 
Phone: +1 (201) 326-5300 
 
 
Confidentiality Statement 
This confidential information in this document is provided to you as an Investigator or 
consultant for review by you, your staff, and the applicable Institutional Review 
Board/Independent Ethics Committee. Your acceptance of this document constitutes 
agreement that you will not disclose the information contained herein to others without 
written authorization from the Sponsor. 


Eagle Pharmaceuticals, Inc. 
Protocol EGL-4104-C-1702 
Ryanodex (dantrolene sodium) for Injectable Suspension 
Psychostimulant Drug Induced Toxicity 
 
Amendment 1 
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SIGNATURES 
PROTOCOL TITLE: Phase 2, Multiple-Site, Open-Label, Randomized, 2-Group, Parallel 
Study to Assess the Efficacy and Safety of Ryanodex® (EGL-4104) as Adjuvant Treatment in 
Subjects With Psychostimulant Drug-Induced Toxicity (PDIT). 
PROTOCOL NO: EGL-4104-C-1702 – Amendment 1 
Adrian J. Hepner, MD, PhD 
Executive Vice President & Chief Medical Officer 
Eagle Pharmaceuticals, Inc. 
Date 


Eagle Pharmaceuticals, Inc. 
Protocol EGL-4104-C-1702 
Ryanodex (dantrolene sodium) for Injectable Suspension 
Psychostimulant Drug Induced Toxicity 
Amendment 1 
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Protocol EGL-4104-C-1702 – Amendment 1 
Summary of Changes 
Section 
Original Protocol 
(12 JUNE 2017) 
Amendment 1 
(06 SEPTEMBER 2017) 
Reason for Change 
Inclusion Criterion
Inclusion Criterion   : 
Core body temperature obtained 
rectally of >39.5° C (103.1° F). 
Inclusion Criterion 
Inclusion Criterion  
Organ dysfunction, as evidenced 
by a LODS score ≥ 6. In the 
event of any delay in obtaining 
the lab results for baseline LODS 
score determination, subject may 
be enrolled 
after enrollment if the pending 
baseline LODS score turns out 
to be < 6, subject will be 
withdrawn from the study and 
subsequently replaced with a 
                                              for 
LODS score    determination.  
Inclusion Criterion  
Inclusion Criterion  
Known or suspected recent use 
of a psychostimulant drug, in the 
judgement of the Investigator. 
Inclusion Criterion  
Inclusion Criterion 
Negative pregnancy test for 
females. 
                                       . In the 
Obtaining pregnancy test results 
in an emergency research setting 
often takes long time and this 
amendment will allow 
potentially eligible subjects to 


Eagle Pharmaceuticals, Inc. 
Protocol EGL-4104-C-1702 
Ryanodex (dantrolene sodium) for Injectable Suspension 
Psychostimulant Drug Induced Toxicity 
 
Amendment 1 
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Page 4 of 14 
Section 
Original Protocol 
(12 JUNE 2017) 
Amendment 1 
(06 SEPTEMBER 2017) 
Reason for Change 
event of any delay in obtaining 
pregnancy test result, subject 
may be enrolled and randomized 
if all the other eligibility criteria 
are met. 
 


Eagle Pharmaceuticals, Inc. 
Protocol EGL-4104-C-1702 
Ryanodex (dantrolene sodium) for Injectable Suspension 
Psychostimulant Drug Induced Toxicity 
 
Amendment 1 
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1.0 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 
Title of Study: 
Phase 2, Multiple-Site, Open-Label, Randomized, 
2-Group Parallel Study to Assess the Efficacy and
Safety of Ryanodex® (EGL-4104) as Adjuvant
Treatment in Subjects With Psychostimulant Drug-
Induced Toxicity (PDIT).
Protocol No: 
EGL-4104-C-1702 – Amendment 1 
Principal Investigator: 
 
Study sites: 
Pre-Hospital Emergency Care (PHEC) units in the 
United States 
Study duration
Phase: 2 
Psychostimulant-Induced Intoxication (PDIT) 
PDIT is a life-threatening condition characterized by sudden onset and fast progression. PDIT occurs secondary 
to illicit use of psychostimulant drugs (e.g., MDMA, methamphetamine, methylone) for recreational purposes, 
often taken at mass gathering events where performing intense physical activity in high ambient temperature 
is commonly observed, such as large music festivals and concerts. The main clinical characteristics of PDIT 
include core body hyperthermia of >39.5° C (103.1° F) and changes in mental status such as agitation, 
delusions, hallucinations, seizures or even coma. Other signs and symptoms often include tachycardia, 
tachypnea, rhabdomyolysis, dehydration, acidosis and hyperkalemia. Current treatment includes cooling 
measures (e.g. ice packs, evaporative cooling, cold water immersion), sedative agents (e.g. benzodiazepines, 
ketamine) and supportive measures. Treatment delay often leads to serious complications including cardiac 
arrhythmias, coagulation disorders and organ dysfunction, which may result in long-term sequelae or even 
death. 
Mass-Gathering Medicine 
Hundreds of mass gatherings, including city marathons, parades, concerts, and music festivals, occur 
throughout the US each year and, in general, they are safe and enjoyable events. However, attendees at these 
events can be isolated from access to regular emergency services and medical care, and illness, injuries, and 
fatalities do occur.  
Mass gatherings require health and medical services, harm-reduction strategies, operational plans, and 
emergency contingency plans to be in place. A mass gathering can be defined as any occasion that attracts 


Eagle Pharmaceuticals, Inc. 
Protocol EGL-4104-C-1702 
Ryanodex (dantrolene sodium) for Injectable Suspension 
Psychostimulant Drug Induced Toxicity 
Amendment 1 
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Page 6 of 14 
sufficient people to strain the planning and resources of the community, city, or nation hosting the event. Mass-
gathering medicine (MGM) is a young and rapidly evolving discipline with ties to emergency medicine, 
disaster medicine, and public health.  
Mass gatherings take place in dynamic environments. Planning and provision of health and emergency medical 
services is challenging. Patterns of injury and illness differ from those typically encountered in the community. 
Medical responses are complicated by logistical challenges, such as weather extremes, crowding, site access, 
geographical barriers and communication difficulties. These unique challenges, along with increased rates of 
morbidity, mean that baseline 911 emergency services alone are not enough to ensure the safety of attendees. 
As well, there is a growing awareness of the impact of mass gatherings on local communities and a requirement 
to avoid compromising baseline emergency services. Consequently, there is a shift away from a standard first-
aid model of care and toward on-site multidisciplinary medical teams (e.g., physicians, nurses, paramedics) 
offering a higher and more complex level of care, which includes similar capabilities as those commonly 
available at an emergency department of a regular community hospital. 
Objectives 
Primary: To evaluate the efficacy of Ryanodex® for the treatment of PDIT, administered as an adjuvant 
treatment to the current standard of care (SOC). 
Secondary: To evaluate the safety and tolerability of Ryanodex® for the treatment of PDIT administered as an 
adjuvant treatment to current SOC. 
Methodology 
Study EGL-4104-C-1702 is a phase 2, multiple-site, open-label, randomized, 2-group parallel study of 
Ryanodex® for the treatment of PDIT, administered intravenously (IV) as adjuvant treatment to the current 
SOC, which is defined as body cooling and supportive measures, including treating related symptoms and any 
existing comorbidities. Due to the acute and serious nature of PDIT, more commonly occurring in young 
individuals attending mass gathering events (e.g. large music festivals and concerts), and the importance of 
early diagnosis and fast implementation of treatment, the study will be conducted at qualified pre-hospital 
emergency care facilities [PHEC]. The PHECs are medical units fully equipped and staffed to provide adequate 
emergency medical care to patients with PDIT.  This study is designed to evaluate the safety and efficacy of 
Ryanodex® in this acutely ill patient population in an emergency setting, where study subjects are anticipated 
to be treated over a short period of time and then transferred to another medical facility or released, depending 
on their overall medical status. In order to standardize subject’s evaluation, data collection and subsequent 
analysis, functioning of each organ system will be assessed individually and will also be conducted using the 
Logistic Organ Dysfunction System (LODS). 
After diagnosis of PDIT, the Investigator should initiate SOC treatment as quickly as possible, and will assess 
the subject’s eligibility for study participation. The Investigator will document subject’s baseline status.  
Body cooling measures should be stopped at the first instance of rectal temperature , to avoid 
hypothermia. 
Enrolled study subjects are expected to remain at the study site for a maximum of 6 hours after screening, prior 
to discharge from the study site. Subjects who require hospitalization beyond 
 after Screening (e.g., 
because of complications, adverse events [AEs], or other reasons) will complete the required study discharge 
procedures prior to their continuation of care outside of the study. The Investigator will make all reasonable 
efforts to obtain subjects’ medical data from these medical facilities. 
Logistic Organ Dysfunction System 
The Logistic Organ Dysfunction System (LODS) provides an objective tool for assessing organ dysfunction 
in critical patients. The LODS identifies organ dysfunction for 6 organ systems: neurologic, cardiovascular, 
renal, pulmonary, hematologic and hepatic, taking into account both the relative severity among organ systems 
and the level of severity within an organ system. 


Eagle Pharmaceuticals, Inc. 
Ryanodex (dantrolene sodium) for Injectable Suspension 
Psychostimulant Drug Induced Toxicity 
Protocol EGL-4104-C-1702 
Amendment 1 
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Standard of Care 
Implementation of standard of care (SOC) should be initiated as quickly as possible after admission of the 
subject to the PHEC. For the purpose of this study, SOC is defined as efficient body cooling by physical 
methods and supportive measures, implemented as following: 
Body Cooling 
•
Ice packs: should be placed to neck, axilla, and inguinal regions.
•
Evaporative cooling: application of water (room temperature) over the body surface, via mist application
with continuous use of a fan. Subjects may be covered with a thin sheet. Do not use ice/cold water
immersion because of concerns with shivering (which could potentially worsen hyperthermia), and the
need for IV access and other monitoring measures and medical procedures.
•
Benzodiazepines: may be administered to ameliorate shivering induced by cooling methods, as deemed
necessary by the Investigator.
Supportive Measures 
Randomized subjects will also receive any other medical treatments and/or supportive measures (IV fluids, 
respiratory support) for the adequate treatment of existing complications or comorbidities (e.g. dehydration, 
seizures, aggressiveness, asthma) following acceptable medical practice, and as deemed necessary by the 
Investigator. 
Treatment Groups 
Upon admission to the PHEC, eligible patients with PDIT will be randomized in a 
 ratio to one of the 
following treatment groups: 
•
Group A: Ryanodex®, as added treatment to SOC
•
Group B: SOC only
The Investigator will make all reasonable efforts to perform the 
 drug screen test during the screening 
process or as soon as feasible after randomization. The 
 drug screen test may not be feasible in some 
subjects, due to the dehydration, use of oxygen therapy and/or endotracheal intubation commonly seen in 
patients with PDIT, which may result in dryness of the oral mucosa. A blood sample for testing for the presence 
of psychostimulant drugs will also be collected after randomization. 
Subjects in Group A will receive SOC immediately followed by an initial dose of Ryanodex® (study drug) of 
2.5 mg/kg administered as an IV bolus. Initial dose of Ryanodex® should be administered within  minutes of 
randomization. The goal is to achieve an adequate clinical response, which is defined as meeting both of the 
following criteria: 
1.
2.
Logistic Organ Dysfunction System (LODS) score ≤ 5
If the subject is not showing adequate clinical response between 10 and 30 minutes after the initial dose, or the 
subject had achieved an adequate response but afterwards signs/symptoms believed to be associated with PDIT 
re-appear                                                                                        a 
second IV bolus dose of 2.5 mg/kg of Ryanodex® may be administered between 10 and 30 minutes following 
the initial dose. This repeat dosing is permitted, as deemed necessary by the Investigator, unless the subject 
demonstrates clinically significant signs/symptoms of dantrolene-related adverse reactions. 
The Investigator must clearly record all clinical assessments and symptoms leading to repeat dosing of 
Ryanodex®. The total administered dose of Ryanodex® in a 24-hour period should not exceed 10 mg/kg. 


Eagle Pharmaceuticals, Inc. 
Protocol EGL-4104-C-1702 
Ryanodex (dantrolene sodium) for Injectable Suspension 
Psychostimulant Drug Induced Toxicity 
 
Amendment 1 
Confidential 
Page 8 of 14 
Individual Subject Stopping Rules 
•
The Investigator may consider stopping study drug if the subject demonstrates clinically significant
signs/symptoms of dantrolene toxicity, which may include, but are not limited to, the following:
increased skeletal muscle weakness; worsening in the state of consciousness (e.g., lethargy, coma);
worsening respiratory status, including increased respiratory muscle weakness, vomiting, diarrhea, or
crystalluria; providing none of these signs/symptoms are not attributable to PDIT, a comorbid condition 
(e.g., asthma, epilepsy, pneumonia) or a concomitant medication (e.g., sedatives).
•
The Investigator may stop study drug at any time for that subject’s well-being if the Investigator
believes that the subject has experienced a serious AE (SAE) possibly related to study drug or a
clinically significant non-serious AE possibly related to study drug.
•
The subject will be withdrawn from the study if a diagnosis had been made for which dantrolene is the
SOC (e.g., malignant hyperthermia [MH]), and treatment with commercially available dantrolene
should be initiated.
•
In case a subject was unable to provide consent at the time of enrollment due to the severity of their
condition (in accordance with the provisions in 21 CFR 50.24), once the subject is able to understand
the nature of the study and the consenting process or the subject’s relative becomes available, the subject 
or relative will be informed that the subject has been enrolled in a clinical study and has been treated
on an emergency basis with either standard of care (SOC) or with SOC plus an investigational drug. If
the subject or relative refuses consent, the Investigator will stop study assessments and procedures at
that time, withdraw the subject from the study, and will not perform any subsequent study assessments.
Study Phases 
The study will include the following phases: Screening/Baseline, Treatment Phase, and Discharge. 
Planned number of subjects: 
An estimated total of 100 subjects will be enrolled 
in the study (approximately 50 per group). 
 
Safety evaluations will be analyzed for 
all randomized subjects who have received study 
treatment.
Diagnosis and 
main criteria for inclusion: 
Male or non-pregnant female subjects, aged 18 
years or older, will be eligible for entry into this 
study if they are diagnosed with PDIT, as 
evidenced by all the following at Screening:  
•
Core body temperature obtained rectally
of >39.5° C (103.1° F).
•
LODS score ≥ 6. In the event of any delay
in obtaining the lab results for baseline
LODS score determination, subject may
be enrolled and randomized if all the other 
eligibility 
criteria 
are 
met; 
after
enrollment if the pending baseline LODS
score turns out to be < 6, subject will be
withdrawn 
from 
the 
study 
and


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Protocol EGL-4104-C-1702 
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Psychostimulant Drug Induced Toxicity 
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subsequently replaced with a new subject 
to complete the ITT population. 
•
Known or suspected recent use of a
psychostimulant drug, in the judgement of
the investigator.
•
Negative pregnancy test for female
subjects. If positive, female subjects must
be excluded from participating in the
study. In the event of any delay in
obtaining pregnancy result, subject may
be enrolled and randomized if all other
eligibility criteria are met.  However,
female subjects randomized to Treatment
Group A (Ryanodex as adjuvant treatment 
to SOC) must not be dosed with
Ryanodex until a negative result of the
pregnancy test is available. If a positive
pregnancy 
test 
is 
noted 
after
randomization, subject will be withdrawn
from the study and subsequently replaced
with a new subject to complete the ITT
population.
Main criteria for exclusion: 
A subject diagnosed with PDIT will be excluded 
from entering the study if he or she presents with 
or, in the judgment of the Investigator, meets any 
of the following criteria at Screening: 
•
Diagnosed with or is suspected to have an
acute clinically severe infection, which in
the opinion of the Investigator may
increase 
the 
subject’s 
risk 
for
participating in the study and/or may
impair the ability of performing and/or
interpreting study assessments.
•
Severe hyperthermia secondary to a
condition 
other 
than 
PDIT 
(e.g.,
thyrotoxicosis, pheochromocytoma, or
brain hemorrhage).
•
Likelihood of head trauma in the past
3 months, or other systemic disease that
might increase the subject’s risk for
participating in the study and/or may
impair the ability of performing and/or
interpreting study assessments.
•
Positive pregnancy test or evidence of
active lactation.
•
Known 
history 
of 
allergy 
or
hypersensitivity to dantrolene.
•
Known history of seizure disorders or
epilepsy.


Eagle Pharmaceuticals, Inc. 
Protocol EGL-4104-C-1702 
Ryanodex (dantrolene sodium) for Injectable Suspension 
Psychostimulant Drug Induced Toxicity 
Amendment 1 
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Page 10 of 14 
•
Current or prior use (within the past 2
weeks) of calcium channel blockers.
Test product, dose, and mode of administration: 
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; to be administered as a rapid IV push 
of 2.5 mg/kg. 
Reference therapy, dose, and mode of 
administration: 
Standard of Care (SOC): all subjects in both 
treatment groups will receive SOC. 
Supportive Measures: all subjects should receive 
adequate supportive measures for treating PDIT, as 
well as medically acceptable treatment for 
complications and comorbidities. 
Endpoints: 
Primary Efficacy Endpoint: 
The primary efficacy endpoint for this study is proportion of subjects achieved a total LODS score ≤ 5 at or 
prior to 60 minutes post-randomization. 
Secondary Efficacy Endpoints: 
•
Proportion of subjects who achieved a LODS total score ≤ 5 at planned time points.
•
 
Dantrolene plasma concentration: 
Plasma sample data will be presented for all subjects with informed consent and/or summarized. 
Safety Assessments: 
•
Adverse events (AEs)
•
Vital signs (blood pressure, respiratory rate, and pulse)
•
Clinical safety laboratory tests (hematology and coagulation parameters, and blood chemistry)
•
Electrocardiogram (ECG)


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Protocol EGL-4104-C-1702 
Ryanodex (dantrolene sodium) for Injectable Suspension 
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•
Physical examination
•
Brief neurological examination
•
Oxygen saturation (measured with pulse oximeter)
•
End-tidal CO2 (ETCO2)
Sample size:  
A planned sample size of 100 (50 per treatment group) fully eligible (for efficacy) subjects are planned to be 
randomized in this study. 
Baseline: 
Baseline body temperature will be the first rectal temperature >39.5° C (103.1° F) taken during the Screening 
Phase. Baseline results for other study assessments will 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 Intent-to-Treat (ITT) population is defined as all randomized subjects whose screening test results for 
presence of a psychostimulant drug was confirmed by blood test. The ITT population will be used as the 
primary efficacy population.  
The Modified Intent-to-Treat (MITT) population is a subset of the ITT population excluding the subjects who 
are intubated or with mechanical ventilation or CPAP.  
The Per Protocol population (PP) is defined as all ITT subjects who met all inclusion/exclusion criteria, have 
a baseline and at least 1 post-baseline LODS score, and have no major protocol deviations that could affect the 
efficacy assessments.  
The Safety population is defined as all randomized subjects who received any study treatment (SOC only or 
SOC with Ryanodex®). The Safety population will be used to analyze all safety endpoints using actual 
treatment received. 


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Protocol EGL-4104-C-1702 
Ryanodex (dantrolene sodium) for Injectable Suspension 
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Efficacy Analysis: The primary analyses of the primary and secondary efficacy endpoints will be conducted 
on the ITT population. The MITT and PP population analyses of primary and secondary endpoints will be 
considered supportive. 
o
Logit model for inferential statistics 
Safety Analysis: 
Safety Population will be used for the safety analysis. No modeling or inferential statistics will be conducted 
on the safety assessments. 


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Table 1: Schedule of Assessments 
Screening/ 
Baseline 
Treatment Phase 
Study 
Discharge 


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Abbreviations: CCM = continuous cardiac monitoring; ETCO2 = end-tidal carbon dioxide; ECG = electrocardiogram; med = medication; min = minutes; PT = prothrombin time 
1.
  

SAP_000.pdf: 
NCT03189433 
 
Protocol EGL-4104-C-1702:  
Phase 2, Multiple-Site, Open-Label, Randomized, 2-Group, Parallel 
Study to Assess the Efficacy and Safety of Ryanodex® (EGL-4104) as 
Adjuvant Treatment in Subjects With Psychostimulant Drug-Induced 
Toxicity (PDIT) 
 Document Date: September 6, 2017 
 
 
 
 


Ryanodex (dantrolene sodium) for Injectable Suspension 
Eagle Pharmaceuticals, Inc. 
Psychostimulant Drug Induced Toxicity  
 
Protocol EGL-4104-C-1702 
 
Amendment 1 
 
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Page 68 of 87 
8.0 STATISTICAL CONSIDERATIONS 
This section presents general information about statistical considerations and concepts such as 
randomization, covariates, statistical power, sample size, and a  brief  discussion on analysis 
methodology, as well as some data conventions. Detailed descriptions of the statistical analysis 
methods  and  data  conventions  will  be  
included  
in  a  separate  document;  
i.e.,  
the  Statistical 
Analysis Plan (SAP). 
8.1 Treatment Groups 
The following treatment groups will be assessed: 
Group 
Description 
Group A 
Ryanodex®,  as adjuvant treatment to 
SOC 
Group B 
SOC only 
8.2 Description of Study Endpoints 
8.2.1 Efficacy Endpoints 
8.2.1.1 Primary Efficacy Endpoint 
Primary endpoint: Proportion of subjects achieving a total LODS score ≤ 5 at or prior to 60 
minutes post-randomization.  
8.2.1.2 Secondary Efficacy Endpoints: 
• Proportion of subjects who achieved a LODS total score ≤ 5 at planned timepoints. 
• 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 


Ryanodex (dantrolene sodium) for Injectable Suspension 
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• 
 
 
8.2.2 Safety Assessments 
• Adverse events (AEs) 
• Vital signs (blood pressure, respiratory rate, and pulse)  
• Clinical safety laboratory tests (hematology and coagulation parameters, and blood 
chemistry) 
• Electrocardiogram (ECG) 
• Physical examination 
• Brief neurological examination 
• Oxygen saturation (measured with pulse oximeter) 
• End-tidal CO
2 (ETCO
2) 
8.3 Sample Size Determination and Rationale 
A total of 100 (50 per treatment group) fully eligible (for efficacy) subjects are planned to be 
randomized in this study. 
 is used for this sample size calculation. The sample 
size calculation is based on the assumption that  
 of subjects who receive SOC therapy and 
Ryanodex®  will  achieve  a  LODS  score  ≤  5  at  or  prior  
to  60  minutes  post-randomization, 
compared with only  
of subjects who receive SOC therapy alone.  
Under the above assumption,   subjects per treatment group will be required to meet the Type 
I error rate of 0.05, 2-sided and more than 90% power; for a total of  
subjects for the study.  
Sample size estimation is depicted in Figure 2. 
Figure 2: Sample Size Yielding More than 90% Power for the Study 
 


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8.4 
Randomization 
Subjects who meet all inclusion and none of the exclusion criteria will be randomly assigned 
in a 1:1 ratio to either Group A (Ryanodex® as adjuvant treatment to SOC) or Group B (SOC 
only) within each study site. The randomization schedule will be generated using an 
appropriate block size to help maintain treatment groups of equal size.  
8.5 
Blinding 
This is an open-label study; no blinding of study drug will be performed.  
8.6 
 
 
8.7 
General Statistical Considerations 
Baseline body temperature will be the first rectal temperature >39.5° C taken during the 
Screening Phase. Baseline results for other study assessments will be the value closest in time 
to the baseline rectal temperature and prior to randomization. The SAP may specify additional 
data handling rules.  
All collected study data will be presented in subject data listings. Statistical analyses will be 
performed using SAS® for Windows, version 9.4 or later. Descriptive statistics (n, mean, 
standard deviation, median, minimum and maximum) will be presented by treatment group for 
continuous variables. Frequencies and percentages will be presented by treatment group for 
categorical variables.  
8.7.1 Data to Be Analyzed 
 will analyze the study data. Data handling will be the 
responsibility of 
. The data will be inspected for inconsistencies by performing 
validation checks. 
All data collected during the study will be reported. All details regarding the statistical analysis 
and the preparation of tables, listings, and figures will be described in the SAP prepared by 
nd approved by the Sponsor before database lock. The statistical analysis will be 
performed by 
 


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8.8 
Analysis Populations 
8.8.1 Intent-to-Treat (ITT) population 
The Intent-to-Treat (ITT) population is defined as
 
 
 
 
. The ITT 
population will be the primary population for the analysis of primary and secondary endpoints.  
8.8.2 Modified Intent-to-Treat (MITT) population 
The Modified Intent-to-Treat (MITT) population is 
 
 
The MITT analysis of primary and secondary endpoints will be considered supportive.  
8.8.3 Per Protocol (PP) Population 
The Per Protocol (PP) population is defined 
 
 
 
  
  
.  
8.8.4 Safety Population 
The Safety population is defined as any subject who received any study treatment (SOC only 
or SOC with Ryanodex®). This population will be used for the analysis of safety parameters. 
8.9 
Covariates  
For efficacy analyses, the baseline values will be used as covariates in the analysis models. 
. 
8.10 Missing Data 
For efficacy evaluation appropriate methods will be used to handle any missing data. The 
details of techniques for handling of missing data will be included in the SAP for the study 
which will be finalized prior to database lock.  


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8.11 Analysis Methods 
A Statistical Analysis Plan (SAP) will be developed and approved before the database is 
locked. The SAP will present the detailed statistical methodology to be used in analyzing the 
efficacy and safety data from this trial. All inferential statistical analysis will be based on a 
two-sided test with a Type I error rate of 0.05. 
All the efficacy analyses presented here will be conducted using the ITT, 
 
populations. All safety analyses will be conducted using the Safety population. Study data 
summaries will include the following:  
8.11.1 Subject Disposition 
The disposition of all subjects screened will be provided.
 
 
. 
8.11.2 Demographic and Baseline Characteristics 
Demographics and baseline characteristics will be summarized by treatment group using 
appropriate descriptive statistics. 
8.11.3 Concomitant Medications/Therapies 
 
 
 
 
 
  
8.11.4 Efficacy Analyses 
8.11.4.1 
Primary Analysis 
The primary analysis will be conducted on the Intent-to-treat (ITT) population.  
Primary Endpoint: 
 will be used to compare the proportion of subjects achieved a total LODS score ≤ 
5 at or prior to 60 minutes post-randomization.  


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Secondary Endpoints:  
• Proportion of subjects who achieved a LODS total score ≤ 5 at planned timepoints. 
•
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All secondary endpoints data will be presented and summarized according to the variable type:  
• Continuous data summaries will include:  
o Number  of  observations,  mean,  standard  deviation,  median,  and  minimum  and 
maximum values.  
o 
 
  
 
 
 
• Categorical data summaries will include: 
o Frequency counts and percentages.  
o 
 
• Time-to-event data summaries will be using 
o Kaplan-Meier  (K-M)  methods  to  depict  the  data  and  Cox  proportional  hazards 
model for inferential statistics.  
8.11.5 Supportive Analysis  
 
 
 


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.  
8.12 Safety Analyses 
The Safety population will be used for the analysis of safety endpoints.  
For continuous variables data will be summarized by treatment using n, mean, SD, minimum 
and maximum values. For categorical variables data will be summarized by treatment using 
frequency and percentage. 
 
8.12.1 Adverse Events 
Adverse events will be coded using the most recent version of Medical Dictionary for 
Regulatory Activities (MedDRA). Treatment Emergent AE’s (TEAE) are defined as events 
with an onset on or after the first randomized treatment. TEAEs will be summarized by 
treatment group, System Organ Class, and preferred term. The following TEAE summaries 
will be provided: 
 Overall (i.e., regardless of severity or relationship to treatment) 
 By severity grade (mild, moderate, severe, or life threatening for SAEs) 
 By relationship to clinical trial treatment according to the mapping scheme below: 
o Potentially related: will include all adverse events with a relationship rating of 
“definitely”, “probably” or “possibly”.  
o Unlikely/not related: will include all adverse events with a relationship rating of 
“unlikely” or “unrelated”. 
In addition, separate summaries of serious adverse events, and adverse events resulting in 
discontinuation of study treatment will be presented. 
8.12.2 Clinical Laboratory Evaluations 
 
. 
8.12.3 Other Safety Data 
 
8.13