Phase 2, Multiple-Site, Open-Label, Randomized, 2-Group, Parallel Study to Assess the Efficacy and Safety of Ryanodex(R) (EGL-4101)as Adjuvant Treatment in Subjects With Psychostimulant Drug-Induced Toxicity (PDIT)
Phase: PHASE2
Conditions: Drug Toxicity Psychotropic Agents Psychostimulants
Sponsor: Eagle Pharmaceuticals, Inc.

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 
Confidential 
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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 
Confidential 
Page 3 of 14 
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 
Confidential 
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 
Confidential 
Page 5 of 14 
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 
Confidential 
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 
Confidential 
Page 7 of 14 
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

Eagle Pharmaceuticals, Inc. 
Protocol EGL-4104-C-1702 
Ryanodex (dantrolene sodium) for Injectable Suspension 
Psychostimulant Drug Induced Toxicity 
Amendment 1 
Confidential 
Page 9 of 14 
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 
Confidential 
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)

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 11 of 14 
•
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. 

Eagle Pharmaceuticals, Inc. 
Protocol EGL-4104-C-1702 
Ryanodex (dantrolene sodium) for Injectable Suspension 
Psychostimulant Drug Induced Toxicity 
Amendment 1 
Confidential 
Page 12 of 14 
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. 

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 13 of 14 
Table 1: Schedule of Assessments 
Screening/ 
Baseline 
Treatment Phase 
Study 
Discharge 

Ryanodex (dantrolene sodium) for Injectable Suspension 
Eagle Pharmaceuticals, Inc. 
Psychostimulant Drug Induced Toxicity 
Protocol EGL-4104-C-1702 
 
Amendment 1 
Confidential 
Page 14 of 14 
Abbreviations: CCM = continuous cardiac monitoring; ETCO2 = end-tidal carbon dioxide; ECG = electrocardiogram; med = medication; min = minutes; PT = prothrombin time 
1.