A Single-Dose, Randomized, Placebo-Controlled, Cross-Over Study of the Safety and Efficacy of Intranasal Epinephrine After Administration of ARS -1 in Subjects With Frequent Urticaria Flares
Phase: PHASE2
Conditions: Urticaria
Sponsor: ARS Pharmaceuticals, Inc.

                NCT05496465
AUGUST 24, 2022

ARS Pharmaceuticals Inc. 
Protocol EPI U01 
ARS-1 (Epinephrine Intranasal) 
Version: 2.0 
 
 
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TABLE OF CONTENTS 
KEY CONTACTS FOR THE STUDY .......................................................................................... 2 
SPONSOR SIGNATURE PAGE ................................................................................................... 3 
LIST OF TABLES .......................................................................................................................... 8 
LIST OF FIGURES ........................................................................................................................ 8 
LIST OF APPENDICES ................................................................................................................. 8 
INVESTIGATOR STATEMENT ................................................................................................ 12 
PROTOCOL SYNOPSIS.............................................................................................................. 14 
1.0 
INTRODUCTION ............................................................................................................. 19 
1.1 
Background ........................................................................................................................ 19 
1.2 
Clinical Experience with ASR-1 1.0 mg in Healthy Volunteers ....................................... 20 
1.2.1 
Pharmacokinetics of ARS-1 1.0 mg in Healthy Volunteers ............................................ 20 
1.2.1.1 Concentration vs Time Curves – Integrated Analysis ..................................................... 21 
1.2.1.2 Pharmacokinetics Parameters – Integrated Analysis ....................................................... 21 
1.2.2 
Pharmacodynamics of ARS-1 1.0 mg in Healthy Volunteers ......................................... 22 
1.2.2.1 Systolic Blood Pressure – Integrated Analysis ................................................................ 22 
1.2.2.2 Diastolic Blood Pressure – Integrated Analysis .............................................................. 23 
1.2.2.3 Pulse Rate – Integrated Analysis ..................................................................................... 24 
1.2.3 
Overall Pharmacological Conclusions ............................................................................. 25 
1.2.4 
Safety ............................................................................................................................... 25 
1.2.4.1 Clinical Experience with ARS-1 in Adult Subjects ......................................................... 25 
1.2.4.2 Clinical Experience with ARS-1 in Pediatric Subjects .................................................... 27 
1.3 
Study Rationale .................................................................................................................. 27 
2.0 
STUDY OBJECTIVES ...................................................................................................... 28 
2.1 
Study Objectives ................................................................................................................ 28 
3.0 
STUDY DESIGN............................................................................................................... 29 
3.1 
Description of Study Design .............................................................................................. 29 
3.1.1 Randomization/Assignment to Study Drug ....................................................................... 30 
3.2 
Study Drugs ....................................................................................................................... 30 
3.2.1 Test Product ....................................................................................................................... 30 
3.2.2 Dose and Dose Justification ............................................................................................... 31 

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3.3 
Efficacy Assessments ......................................................................................................... 31 
3.4 
Safety Assessments ............................................................................................................ 32 
3.5 
Concomitant Medications .................................................................................................. 32 
3.5.1 Prior and Concomitant Medications .................................................................................. 32 
3.5.2 Prohibited Concomitant Medications ................................................................................ 32 
3.6 
Procedures for Monitoring Subject Compliance ................................................................ 33 
4.0 
STUDY POPULATION .................................................................................................... 34 
4.1 
Inclusion Criteria ............................................................................................................... 34 
4.2 
Exclusion Criteria .............................................................................................................. 35 
4.3 
Stopping or Suspending the Study ..................................................................................... 36 
5.0 
SCREENING ASSESSMENTS ........................................................................................ 37 
5.1 
Complete or Targeted Physical Examination .................................................................... 37 
5.2 
Medical History ................................................................................................................. 37 
5.3 
Vital Signs .......................................................................................................................... 37 
5.4 
Height and Weight ............................................................................................................. 37 
5.5 
ECG.................................................................................................................................... 37 
5.6 
Clinical Laboratory Evaluations ........................................................................................ 38 
5.6.1 Hematology ........................................................................................................................ 38 
5.6.2 Serum Chemistry ............................................................................................................... 38 
5.6.3 Coagulation ........................................................................................................................ 38 
5.6.4 Urinalysis ........................................................................................................................... 38 
5.6.5 Pregnancy Test ................................................................................................................... 38 
6.0 
EFFICACY ........................................................................................................................ 38 
7.0 
PHARMACOKINETICS ................................................................................................... 40 
8.0 
PHARMACODYNAMICS ............................................................................................... 40 
9.0 
SAFETY ASSESSMENTS ................................................................................................ 40 
9.1 
Collection of Adverse Events Data .................................................................................... 40 
9.2 
Complete or Targeted Physical Examination .................................................................... 40 
9.3 
Vital Signs .......................................................................................................................... 40 
10.0 STUDY VISITS AND PROCEDURES ............................................................................ 41 
10.1 Screening (Days -90 to -1) ................................................................................................. 41 
10.2 Pre-dose Evaluations (Treatment Periods 1 - 3) ................................................................ 42 

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10.3 Drug Administration .......................................................................................................... 42 
10.4 Post-dose Evaluations (Treatment Periods 1 - 3) ............................................................... 43 
10.5 Discharge Assessments (Treatment Periods 1 - 3) ............................................................ 43 
11.0 PREMATURE DISCONTINUATION FROM STUDY ................................................... 43 
12.0 PRODUCT SPECIFICATIONS ........................................................................................ 44 
12.1 Description ......................................................................................................................... 44 
12.2 Formulation, Packaging, and Labeling .............................................................................. 44 
12.3 Receipt, Storage and Stability of ARS-1 ........................................................................... 45 
12.4 Administration of Study Drug ........................................................................................... 45 
12.5 Ordering and Distribution of Study Drug .......................................................................... 45 
12.6 Accountability of Study Drugs .......................................................................................... 45 
13.0 SAFETY MONITORING AND ADVERSE EVENTS .................................................... 46 
13.1 Adverse Events .................................................................................................................. 46 
13.2 Serious Adverse Events ..................................................................................................... 48 
13.3 Pregnancy Reporting .......................................................................................................... 49 
13.3.1 Reporting Requirements for Serious Adverse Events ....................................................... 49 
13.3.2 Recording of Serious Adverse Events ............................................................................... 49 
14.0 STATISTICAL CONSIDERATIONS............................................................................... 50 
14.1 Sample Size Determination ................................................................................................ 50 
14.2 Analysis Data Sets ............................................................................................................. 50 
14.3 Efficacy Data Analyses ...................................................................................................... 50 
14.3.1 Primary Efficacy Analyses ................................................................................................ 50 
14.4 Safety Data Analyses ......................................................................................................... 51 
 51 
15.0 DATA COLLECTION, STUDY MONITORING, AND DATA DISCLOSURE ............ 51 
15.1 Data Collection and Reporting ........................................................................................... 51 
15.2 Study Monitoring ............................................................................................................... 52 
15.3 Audit and Inspection .......................................................................................................... 52 
15.4 Deviation from Clinical Trial Protocol .............................................................................. 52 
15.5 Retention of Records .......................................................................................................... 52 
15.6 Data Disclosure and Subject Confidentiality ..................................................................... 53 
16.0 PROTECTION OF HUMAN SUBJECTS ........................................................................ 53 

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16.1 Basic Principles .................................................................................................................. 53 
16.2 Institutional Review Board/Ethics Committee .................................................................. 54 
16.3 Informed Consent............................................................................................................... 54 
16.4 Subject Health Injury and Insurance .................................................................................. 54 
16.5 Completion of the Study .................................................................................................... 55 
17.0 REFERENCE LIST ........................................................................................................... 56 
 

ARS Pharmaceuticals Inc. 
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LIST OF TABLES 
 
 
 
 
 
 
 
 
 49 
 
LIST OF FIGURES 
 
 
 
 
 
 
LIST OF APPENDICES 
Appendix A: Schedule of Study Procedures ................................................................................. 57 
 
 
 

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LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
ADL 
Assisted Daily Living 
AE 
adverse event 
ALT 
alanine aminotransferase 
ARS 
ARS Pharmaceuticals Inc. 
ARS-1 
epinephrine nasal spray suspension manufactured for ARS 
Pharmaceuticals Inc. 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AUC(0-t) 
area under the plasma concentration-time curve to the final sample 
with a concentration ≥ LOQ 
AUEC 
area under the effect curves 
BP 
blood pressure 
bpm 
beats per minute 
BSA 
body surface area 
BUN 
blood urea nitrogen 
BZK 
benzalkonium chloride  
CBC 
complete blood cell count 
CFR 
Code of Federal Regulations  
Cmax 
maximum plasma concentration 
CO2 
carbon dioxide/bicarbonate  
CRF 
case report form 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events (v 5.0) 
CV 
coefficient of variation 
DBP 
diastolic blood pressure 

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ABBREVIATION 
DEFINITION 
DDM 
dodecylmaltoside 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDTA 
ethylenediaminetetraacetic acid 
Emax 
maximum effect  
FDA 
US Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice  
GRAS 
generally recognized as safe 
HbSAg 
Hepatitis B surface antigen  
HIV 
human immunodeficiency virus 
HR 
heart rate 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IFU 
Instructions for Use 
IM 
intramuscular 
IN 
intranasal 
IP 
investigational (medicinal) product  
IRB/EC 
Institutional Review Board/Ethics Committee  
kg 
kilogram(s) 
LDH 
lactate dehydrogenase  
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram(s) 
mL 
milliliter 

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ABBREVIATION 
DEFINITION 
PD 
pharmacodynamics  
PE 
physical exam 
PK 
pharmacokinetics 
PR 
pulse rate 
QTcF 
Fridericia’s correction 
RBC 
red blood cell 
SAE 
serious adverse event 
SBP 
systolic blood pressure 
SC 
subcutaneous  
SOP 
standard operating procedure 
TEAE 
treatment-emergent adverse event 
TEmax 
time to maximum effect 
tmax 
time to maximum plasma concentration 
µL 
microliter 
UAS 
Uniform Assessment System 
UDS 
Unit Dose Sprayer 
US/USA 
United States of America 
VAS 
Visual Analog Scale 
WBC 
white blood cell 
WHODD 
World Health Organization Drug Dictionary 

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INVESTIGATOR STATEMENT 
I have read and understand the protocol and agree to implement the study in accordance with the 
procedures set forth in the protocol and in accordance with the Sponsor's guidelines, all 
applicable government regulations, and the International Conference on Harmonisation Good 
Clinical Practice Guidelines E6 (ICH-GCP). 
I will maintain accurate source documents from which data are transcribed onto case report 
forms and accurate drug accountability records that show the receipt and disposition of all study 
drugs. 
I will provide adequate protocol training to my associates, colleagues, and employees assisting in 
the conduct of the study. 
I will obtain Institutional Review Board/Ethics Committee (IRB/EC) approval of the protocol 
and Informed Consent Form (ICF) prior to enrollment of subjects in the study. I understand that 
any modifications to the protocol made during the course of the study must first be approved by 
the IRB/EC prior to implementation except when such modification is made to remove an 
immediate hazard to the subject. 
I will ensure that a fully executed IRB-approved Informed Consent Form is obtained from each 
subject prior to initiation of any study procedures. 
I will report (within 24 hours) any serious adverse event, regardless of relationship to study drug, 
or pregnancy that occurs during the course of the study, in accordance with the procedures 
described in Section 13.0 of the protocol. I will notify the Sponsor if I become aware that a 
partner of a study subject becomes pregnant while the subject was receiving this study drug. 
I will submit all protocol inclusion/exclusion violations to the Medical Monitor for approval 
prior to enrollment of the subject in the study. 
I will allow the Sponsor, ARS Pharmaceuticals Inc. (ARS) and its agents, as well as the United 
States (US) Food and Drug Administration (FDA) and other regulatory agencies to inspect study 
facilities and pertinent records at reasonable times and in a reasonable manner, ensuring subject 
confidentiality. If I am notified that this study is to be inspected by a regulatory agency, I will 
notify the Sponsor as soon as possible thereafter (no later than one week). 
This protocol contains information that is proprietary to ARS. The information contained herein 
is provided for the purpose of conducting a clinical trial for ARS. 

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The contents of this protocol may be disclosed to study personnel under your supervision and to 
your IRB/EC. The contents of this protocol may not be disclosed to any other parties (unless 
such disclosure is required by government regulations or laws) without the prior written approval 
of ARS. 
 
 
 
__________________________________________ 
_______________________ 
Investigator’s Signature 
Date 
 

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antihistamine) at least 2 weeks before dosing and will remain the same throughout the 
study. 
3. Has body weight more than 30 kilogram (kg) and body mass index between 18 and 
34 kg/m², inclusive. 
4. Has no medical history of hypertension and cardiovascular disease in the last 10 years. 
Controlled hypertension without beta blocker confirmed by the Investigator is 
acceptable.  
5. At screening, has stable vital signs in the following ranges (after 5 minutes of rest): 
• 
Systolic blood pressure (SBP) ≥90 and ≤140 mmHg 
• 
Diastolic blood pressure (DBP) ≥50 and ≤90 mmHg 
• 
Heart rate (HR) ≥45 and ≤100 beats per minute (bpm)   
Note: Each blood pressure (BP) should be taken after at least 5 minutes rest in a chair 
with back supported, legs uncrossed, and upper arm bared (slight recline for comfort is 
permitted).  If vital signs are out of range, the Investigator may obtain two additional 
readings, so that up to 3 consecutive assessments are made within 1 hour. 
6. If female, is not pregnant or breastfeeding based on the following: 
a. 
agree to the use of highly effective contraceptive methods for at least 2 weeks 
before baseline until 7 days after the last day of study drug and a negative urine 
pregnancy test at baseline; or  
b. is of nonchildbearing potential defined as clinically infertile as the result of 
surgical sterilization (hysterectomy, bilateral tubal ligation, bilateral 
salpingectomy and/or bilateral oophorectomy); or  
c. 
is confirmed postmenopausal status (defined as either having amenorrhea for ≥ 
12 consecutive months without another cause and documented serum follicle-
stimulating hormone (FSH) level > 40 mIU/mL or another documented medical 
condition (e.g., was born without a uterus)). 
NOTE: The following are considered highly effective contraceptive methods: 
abstinence, hormonal oral contraceptives, injectables, and patches; intrauterine 
devices; double-barrier methods (synthetic condom, diaphragm, or cervical cap used 
with spermicidal foam, cream, or gel); Nexplanon contraceptive implant (if 
implanted within 3 years); and male partner sterilization. 
7. If male (with or without vasectomy), agree to the use of highly effective contraceptive 
methods (as listed in Criterion #6 above) at screening until 7 days after the last day of 
study drug. 
8. Is able to communicate clearly with the Investigator and staff; able to read, complete 
questionnaires, and understand study procedures. 
9. Is willing and able to provide written informed consent prior to participating in the study. 
Main Exclusion 
Criteria  
Subjects must NOT meet any of the following Exclusion criteria to be eligible for 
enrollment: 
1. Has a history of clinically significant gastrointestinal, renal, hepatic, neurologic, 
hematologic, endocrine, oncologic, pulmonary, immunologic, psychiatric, or 
cardiovascular disease or any other condition which, in the opinion of the Investigator, 
would jeopardize the safety of the subject or impact the validity of the study results. 
2. Patients receiving beta blocker due to potential interaction with the study drug.  
3. Has prior nasal fractures, severe nasal injuries or history of nasal disorders (e.g., polyps, 
polyposis, recurrent epistasis [>1 nosebleed per month], clinically meaningful deviated 
septum, nasal piercing or any nasal passage abnormality based on the Investigator’s 
judgement).  
4. Has any clinically significant medical condition or physical exam (PE) finding as 
deemed inappropriate by the Investigator. 
5. Has abnormal cardiovascular exam at screening including any prior history of 
myocardial infarction or clinically significant abnormal electrocardiogram (ECG) (e.g., 

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1.0 INTRODUCTION 
1.1 
Background 
Urticaria, also known as hives, is a common dermatologic condition which presents with the 
rapid appearance of pale to brightly colored wheals of various sizes ranging from several 
millimeters to several centimeters, with or without surrounding erythema, pruritus or occasional 
burning sensations, and the skin returning to normal typically within one to twenty-four hours (1) 
(2). The pathophysiologic mechanism involves the release of histamine and other mediators from 
mast cells and basophils; release in the dermis results in urticaria while release in the deeper 
dermis and subcutaneous tissues results in angioedema (2). Most commonly, symptoms are 
caused by exposure to allergens, foods, insect venom, medications, and viral infections. Persons 
of any ages may present with urticaria, with a lifetime prevalence of between 15% and 25% (2) 
(3)(4).  
Acute urticaria is defined as urticaria persisting less than 6 weeks, whereas chronic urticaria 
persists 6 weeks or longer (2)(5)(6). Second-generation H1 antihistamines are first-line 
medication for the treatment of acute urticaria. In some cases, they may be titrated to two or even 
four times the normal dose to control symptoms followed by H2 antihistamines and 
corticosteroid for severe cases (1)(2). Indication for epinephrine includes emergency treatment of 
type 1 hypersensitivity reactions (7) and epinephrine injection is recommended in medical 
prescribing guidelines in the United States (US) for the management of acute flares with 
associated angioedema in patients with urticaria. Acute urticaria is treated with but often 
unresponsive to antihistamines and corticosteroids. Intramuscular (IM) epinephrine is typically 
efficacious in alleviating urticarial flares. 
Epinephrine, illustrated in Figure 1 below, is a sympathomimetic catecholamine. Chemically, 
epinephrine is B-(3, 4dihydroxyphenyl)-a-methyl-aminoethanol. Epinephrine solution 
deteriorates rapidly on exposure to air or light, turning pink from oxidation to adrenochrome and 
brown from the formation of melanin. It is a colorless to light yellow crystalline compound, 
insoluble in water. The formula is C9H13NO3 and the molecular weight is 183.20442. 
Figure 1:  Epinephrine 
 

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3.0 
STUDY DESIGN 
3.1 
Description of Study Design 
This is a Phase 2, single-dose, randomized, placebo-controlled, crossover study that will consist 
of a screening period and an open-label treatment period. Subjects enrolled will have acute 
urticaria with known etiology or have chronic spontaneous urticaria with unknown etiology at 
least two (2) times a week while on a chronic treatment.   
Each subject will be randomized to receive either a single treatment of ARS-1 (1 mg and 2 mg 
dose) or placebo nasal spray and then will be crossed over to receive other treatments during an 
acute urticaria flare. Efficacy will be primarily assessed using a patient reported pruritus/hive 
score and VAS for pain. Clinical assessments will also be conducted by the Investigator after 
dosing ARS-1. 
 eligible male or female subjects, 18 to 65 years of age, with urticaria who 
experience acute flares while on a chronic treatment regimen or chronic spontaneous urticaria 
with unknown etiology at least two (2) times a week will be randomized to receive ARS-1 (1 mg 
dose), ARS-1 (2 mg dose), or placebo. After screening subjects will return to the clinical site 
when experiencing an acute flare of urticaria symptoms or chronic spontaneous urticaria. 
Screening Period: Subjects will be screened to assess eligibility for the clinical trial. All subjects 
will undergo safety screening evaluations within 90 days prior to treatment. 
Open-Label Treatment Period:  Subjects will return to the site when experiencing an acute flare 
of urticaria symptoms or chronic spontaneous urticaria before taking other acute medications. 
Urticaria symptoms and severity will be assessed based on both patient-reported and clinician-
based assessments. After baseline safety assessments, subjects will be randomized to receive the 
following treatments at each of the three Treatment Periods: 
• 1 mg per 100 µL dose of ARS-1, 
• 2 mg per 100 µL dose of ARS-1, or  
• placebo (100 µL)  
If possible, rescue medication should be avoided for 15 minutes after dosing. Subjects will be 
monitored for both safety and symptom relief. Safety assessments will be performed after dosing 
and will include AEs and vital signs. Concomitant medications will be recorded. 
Subjects should remain in the clinic as below:  
• Acute flare: at least 2 hours after dosing and can discharge when the discharge criteria is 
met (the time when symptoms of acute urticaria have been effectively treated based on 
the investigator’s or his/her designee’s opinion will be recorded, not necessarily when 

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subjects discharged). If no relief of pruritus symptoms after 2 hours, other acute 
interventions may be administered as rescue. 
• Chronic spontaneous urticaria: until the urticaria symptoms returns to the baseline.
 
 
   
 
 
3.1.1 
Randomization/Assignment to Study Drug 
 subjects with urticaria who experience acute flares while on a chronic treatment 
regimen or chronic spontaneous urticaria with unknown etiology at least two (2) times a week 
will be enrolled and randomized to receive the following treatments in each Treatment Period: 
• 1 mg/100 µL dose of ARS-1, 
• 2 mg/100 µL dose of ARS-1, 
• placebo 
To ensure proper wash-out between the IN doses, each subject will be randomized to one of the 
following sequences: 
• 1 mg ARS-1 IN: placebo: 2 mg ARS-1 IN 
• 2 mg ARS-1 IN: placebo: 1 mg ARS-1 IN 
The side (right or left) of dosing will be alternated per randomization. 
3.2 
Study Drugs 
3.2.1 
Test Product 
ARS-1 is a solution formulation of epinephrine intended for nasal administration. 
 
 
ARS-1 will be administered by IN 
administration using the commercial sprayer device at a dose of 1 mg and 2 mg epinephrine per 
spray delivered in a volume of 100 μL aqueous solution. 
 
 
. 
Placebo is saline to be administered by IN administration using the commercial sprayer device 
delivered in a volume of 100 μL aqueous solution. 
 
 
Dosing will be conducted according to the Instructions for Use (IFU) (Appendix B). 

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3.6 
Procedures for Monitoring Subject Compliance 
Subjects will be admitted to the clinical trial site when experiencing an acute flare of urticaria 
symptoms or chronic spontaneous urticaria and will remain in the clinic for at least 2 hours to 
complete efficacy assessments and safety assessments. Subjects may be discharged once the 
discharge criteria is met. 

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4.0 STUDY POPULATION 
The study population will be male or female adult volunteers aged 18 to 65 years diagnosed with 
urticaria who experience an acute flare of symptoms or have chronic spontaneous urticaria at 
least two (2) times a week while on a chronic treatment regimen and who have consented to 
participate in this study.  
4.1 
Inclusion Criteria 
For a subject to be eligible for this study, he or she must meet all of the following criteria:  
1. Is a male or female subject between the ages of 18 and 65 years, inclusive. 
2. Has been clinically diagnosed with acute flares or with chronic spontaneous urticaria with 
unknown etiology and have urticaria symptom (patient-rated pruritus and hive severity 
score ≥2) at least two (2) times a week while on a chronic treatment (e.g., antihistamine) 
at least 2 weeks before dosing and will remain the same throughout the study.  
3. Has body weight more than 30 kg and body mass index between 18 and 34 kg/m², 
inclusive.  
4. Has no medical history of hypertension and cardiovascular disease in the last 10 years. 
Controlled hypertension without beta blocker confirmed by the Investigator is acceptable.  
5. At screening, has stable vital signs in the following ranges (after 5 minutes of rest): 
• 
SBP ≥90 and ≤140 mmHg 
• 
DBP ≥50 and ≤90 mmHg 
• 
HR ≥45 and ≤100 bpm   
Note: Each BP should be taken after at least 5 minutes rest in a chair with back 
supported, legs uncrossed, and upper arm bared (slight recline for comfort is permitted). 
If vital signs are out of range, the Investigator may obtain two additional readings, so 
that up to 3 consecutive assessments are made within 1 hour. 
6. If female, is not pregnant or breastfeeding based on the following:  
a. agree to the use of highly effective contraceptive methods for at least 2 weeks before 
baseline until 7 days after the last day of study drug and a negative urine pregnancy 
test at screening; or 
b. is of nonchildbearing potential defined as clinically infertile as the result of surgical 
sterilization (hysterectomy, bilateral tubal ligation, bilateral salpingectomy and/or 
bilateral oophorectomy); or 

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c. is confirmed postmenopausal status (defined as either having amenorrhea for 
≥ 12 consecutive months without another cause and documented serum follicle-
stimulating hormone (FSH) level > 40 mIU/mL or another documented medical 
condition (e.g., was born without a uterus)). 
NOTE: The following are considered highly effective contraceptive methods: 
abstinence, hormonal oral contraceptives, injectables, and patches; intrauterine 
devices; double-barrier methods (synthetic condom, diaphragm, or cervical cap 
used with spermicidal foam, cream, or gel); Nexplanon contraceptive implant (if 
implanted within 3 years); and male partner sterilization.   
7. If male (with or without vasectomy), agree to the use of highly effective contraceptive 
methods (as listed in Criterion #6 above) at screening until 7 days after the last day of 
study drug. 
8. Is able to communicate clearly with the Investigator and staff; able to read, complete 
questionnaires, and understand study procedures. 
9. Is willing and able to provide written informed consent prior to participating in the study. 
4.2 
Exclusion Criteria 
Subjects must NOT meet any of the following Exclusion criteria to be eligible for enrollment: 
1. Has a history of clinically significant gastrointestinal, renal, hepatic, neurologic, 
hematologic, endocrine, oncologic, pulmonary, immunologic, psychiatric, or cardiovascular 
disease or any other condition which, in the opinion of the Investigator, would jeopardize the 
safety of the subject or impact the validity of the study results. 
2. Patients receiving beta blocker due to potential interaction with the study drug.  
3. Has prior nasal fractures, severe nasal injuries or history of nasal disorders (e.g., polyps, 
polyposis, recurrent epistasis [>1 nosebleed per month], clinically meaningful deviated 
septum, nasal piercing or any nasal passage abnormality based on the Investigator’s 
judgement). 
4. Has any clinically significant medical condition or physical exam (PE) finding as deemed 
inappropriate by the Investigator. 
5. Has abnormal cardiovascular exam at screening including any prior history of myocardial 
infarction or clinically significant abnormal ECG (e.g., second- or third-degree heart block, 
uncontrolled arrhythmia, QTcF [Fridericia’s correction] interval >450 msec for male subjects 
and >470 msec for female subjects). 

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6. Has mucosal inflammatory disorders (e.g., pemphigus or Sjogren’s syndrome or fungal 
sinusitis). 
7. Has had significant traumatic injury, major surgery or open biopsy within 30 days prior to 
study screening. 
8. Has donated blood or had an acute loss of blood (>50 mL) during the 30 days before study 
drug administration or intends to donate blood or blood products within 30 days after the 
completion of the study. 
9. Known hypersensitivity to any compound in the test product, or any other closely related 
compound (e.g., dihydropyridine-derived molecules). 
10. Has participated in a clinical trial within 30 days prior to the first dose of study drug. 
Participation in an observational (non-interventional) study is not excluded as long as there 
are no scheduling conflicts with this study. 
11. Has had treatment with any epinephrine or norepinephrine containing products within 7 days 
of Day -1.  
12. At screening is positive for human immunodeficiency virus (HIV), Hepatitis B surface 
antigen (HbSAg), or Hepatitis C, or a positive urine screen for drugs of abuse or cotinine or a 
positive saliva test for alcohol. 
13. Has an immediate family member of the Investigator, or an employee of the study center, 
with direct involvement in the proposed study, or other studies under the direction of the 
Investigator or study center or is in a dependent relationship with a study center employee 
who is involved in the conduct of this study (e.g., spouse, parent, child, sibling), or may 
consent under duress. 
4.3 
Stopping or Suspending the Study 
If the trial is prematurely terminated or suspended for any reason, the Investigator/Institution 
should promptly inform the trial subjects, should assure appropriate therapy and follow-up for 
the subjects, and, where required by the applicable regulatory requirement(s), should inform the 
regulatory authority(ies).  
In addition, if the Investigator or the Sponsor terminates or suspends a trial,  
• the Investigator should inform the Institution where applicable, and the 
Investigator/Institution should promptly inform the Institutional Review Board/Ethics 
Committee (IRB/IEC) (and the Sponsor, if applicable) and should provide the Sponsor 
and/or the IRB/IEC a detailed written explanation of the termination or suspension. 

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• the Sponsor should promptly inform the Investigators/Institutions, and the regulatory 
authority(ies) of the termination or suspension and the reason(s) for the termination or 
suspension. 
5.0 SCREENING ASSESSMENTS 
5.1 
Complete or Targeted Physical Examination 
The Investigator will perform a complete PE at screening. A targeted PE will be performed at 
pre-dose in each Treatment Period. Results will be recorded on the appropriate page of the 
electronic case report form (eCRF). 
5.2 
Medical History 
A medical history will be obtained at screening. Medical history will include demographic data 
(age, sex, race/ethnicity, etc.). The medical history will be confirmed at pre-dose in Treatment 
Period 1.  
5.3 
Vital Signs  
Vital signs (BP, pulse rate [PR], respiratory rate, and temperature) are to be obtained at screening 
and pre-dose each Treatment Period. 
5.4 
Height and Weight 
Height will be reported in centimeters at screening. Body weight will be reported in kilograms at 
screening.  
5.5 
ECG 
Subjects will be in a sitting or slightly reclined position and kept comfortable for a standard 
(after resting for at least 5 minutes) 12-lead ECG that will be performed in triplicate by a trained 
technician at screening.  
All ECGs are obtained in triplicate. ECG assessments will be conducted by taking a 10 second 
reading in triplicate, each 1 to 2 minutes apart for screening and baseline and within the window 
before and after dosing. Subjects will be in a sitting or slightly reclined position and kept 
comfortable. 
ECGs will be assessed by the Investigator, Sub-Investigator or a cardiologist. The ECG report 
must be reviewed, signed, and dated by the Investigator or cardiologist. The original ECG results 
will be kept on file at the site as source documentation. 

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5.6 
Clinical Laboratory Evaluations 
Blood samples and urine specimens for laboratory evaluation will be collected at screening per 
Schedule of Study Procedures (Appendix A).  
Urine samples will be collected at screening for amphetamines, barbiturates, benzodiazepine 
metabolites, cocaine metabolites, methadone, opiate metabolites, phencyclidine, marijuana 
metabolites, and cotinine. For alcohol, saliva test will be utilized. 
The presence of HIV antibody, HbSAg, and Hepatitis C antibody will be assessed at screening. 
5.6.1 
Hematology 
Complete blood cell count (CBC) will include a standard red blood cell (RBC), hemoglobin, 
hematocrit, white blood cell (WBC) with differential, and platelet count. 
5.6.2 
Serum Chemistry 
Comprehensive metabolic panel will include serum alkaline phosphatase, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), glucose, calcium, phosphorus, 
chloride, sodium, potassium, blood urea nitrogen (BUN), creatinine, total bilirubin, albumin, 
total protein, amylase, bicarbonate/carbon dioxide (CO2), uric acid, and lactate dehydrogenase 
(LDH).  
5.6.3 
Coagulation 
Coagulation will include PT and aPTT.  
5.6.4 
Urinalysis 
Urinalysis will include pH, specific gravity, glucose, protein, ketones, blood and a detailed 
microscopic analysis. Microscopic analysis will be performed and will include the following: 
WBC, RBC and bacteria. 
5.6.5 
Pregnancy Test 
A urine pregnancy test will be administered to females of childbearing potential at screening. 
6.0 EFFICACY 
Efficacy assessments will be evaluated based on self-reported and clinical assessments of 
pruritus at pre-dose, and at 5 (± 2 min), 10 (± 2 min), 15 (± 3 min), 30 (± 5 min), 45 (± 5 min), 
60 (±10 min), 120 (±10 min) minutes, and every 60 minutes (±10 min) after dosing until the 
discharge criteria (the time when symptoms of acute urticaria have been effectively treated based 
on the Investigator’s or his/her designee’s opinion will be recorded, not necessarily when 

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7.0 PHARMACOKINETICS 
No PK measures will be assessed during this study. 
8.0 PHARMACODYNAMICS 
No PD measures will be assessed during this study. 
9.0 SAFETY ASSESSMENTS 
9.1 
Collection of Adverse Events Data 
Data regarding TEAEs will be collected in this study. TEAEs are events that are not present at 
baseline, or if present at baseline, have worsened in severity. AEs will be assessed while the 
subjects are in the study. AEs assessed by the Investigator as related to study drug and “ongoing” 
at discharge will be monitored by the Investigator until resolved or until the subject is deemed 
“lost to follow-up”. 
Any AEs reported by the subject or noted by the Investigator or his/her designee will be recorded 
on the eCRF regardless of the Investigator opinion of causality. The following information will 
be recorded for each AE: description of the event, date and time of onset, date and time of 
resolution, severity, causal relationship to study drug, outcome, action taken with the study drug 
and any treatment given. 
All abnormal changes from baseline will be collected, graded with regards to severity or clinical 
significance, assessed for causal relationship and recorded on the eCRF. 
Refer to Section 13.0 for further details.  
9.2 
Complete or Targeted Physical Examination  
The Investigator will perform a complete PE at screening. A targeted PE will be performed pre-
dose in each Treatment Period. Results will be recorded on the appropriate page of the eCRF.  
9.3 
Vital Signs 
Vital signs (BP, PR, respiratory rate, and temperature) will be assessed at screening and at pre-
dose and at 5 (± 2 min), 20 (± 2 min), 30 (± 2 min), 60 (± 5 min), and 120 (± 5 min) minutes 
after dosing in each Treatment Period.  
Actual reading time at the measurement by hour/minutes/seconds will be recorded for each 
assessment. 
The Investigator will assess vital signs on an ongoing basis and make sure the BP is within 
normal limit before study drug dosing. 

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10.0 
STUDY VISITS AND PROCEDURES 
Refer to Appendix A for the Schedule of Study Procedures. 
10.1 
Screening (Days -90 to -1)  
The Investigator or his/her approved designee must explain the nature of the study protocol and 
associated risks to the potential study participant. The potential participant must be allowed to 
review the study information and to ask questions before being asked to sign the Informed 
Consent Form (ICF). Written informed consent must be provided by the potential study 
participant prior to initiation of any screening evaluations or other study-related procedures. The 
signature date and the name of the individual at the site who obtained the informed consent will 
be recorded in the subject’s medical record. 
After written informed consent is obtained, the subject will be assigned a screening number and 
will undergo the designated screening procedures listed in Appendix A. The Investigator, Sub-
Investigator or delegate will assess the results of these screening evaluations to determine 
eligibility for entry into the study according to the inclusion/exclusion criteria listed in 
Section 4.0. 
Screening evaluations may be performed up to 90 days in advance of dosing but must be 
completed at least one (1) day prior to Day 0. 
The following study evaluations and procedures are required to determine eligibility: 
• Obtain and record a medical history, including demographics, prior medications, and 
concomitant medications. 
• Complete PE 
• Vital signs  
• Height and weight measurements 
• Blood and serum samples for the following laboratory evaluations: 
o Hematology 
o Serum chemistry 
o Coagulation  
o HIV antibody 
o Hepatitis screening 
• Urinalysis, urine drug, alcohol and cotinine screen (Saliva test for alcohol may be 
utilized) 
• Urine pregnancy test 

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• 12-lead ECG (performed in triplicate) 
10.2 
Pre-dose Evaluations (Treatment Periods 1 - 3) 
Subjects will return to the site when experiencing an acute flare of urticaria symptoms or chronic 
spontaneous urticaria before taking other acute medications. Urticaria symptoms and severity 
will be assessed based on both patient-reported and clinician-based assessments. Pre-dose 
assessments include the following: 
• Admission to clinical site 
• Confirm eligibility (Treatment period 1 only) 
• Confirm medical history (Treatment period 1 only) 
• Targeted PE 
• Concomitant medications 
• Vital signs  
• Patient-reported pruritus/hive score and VAS for pain 
• Investigator-rated extent of urticaria and erythema score 
10.3 
Drug Administration 
After baseline safety assessments, subjects will be randomized to receive the following 
treatments at each of the three Treatment Periods: 
• 1 mg per 100 µL dose of ARS-1, 
• 2 mg per 100 µL dose of ARS-1, or  
• placebo (100 µL)  
ARS-1 or placebo will be dosed to the nostril by the medical professional in a clinical setting per 
IFU (Appendix B). 
  
Subjects will be 
monitored for both safety and symptom relief. Safety assessments will be performed after dosing 
and will include AEs and vital signs. Concomitant medications will be recorded. 
Subjects should remain in the clinic as below: 
• Acute flare: at least 2 hours after dosing and can discharge when the discharge criteria is 
met (the time when symptoms of acute urticaria have been effectively treated based on 
the investigator’s or his/her designee’s opinion will be recorded, not necessarily when 
subjects discharged). If no relief of pruritus symptoms after 2 hours, other acute 
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• 
Chronic spontaneous urticaria: until the urticaria symptoms returns to the baseline.
 
 
   
The calendar date and 24-hour clock time of all doses will be recorded on the eCRF. 
10.4 
Post-dose Evaluations (Treatment Periods 1 - 3)  
Post-dose assessments include the following: 
• Vital signs 
• Concomitant medication 
• AEs 
• Patient reported pruritus/hive score and VAS for pain 
• Investigator-rated extent of urticaria and erythema score 
• 
 
 
 
 
 
10.5 
Discharge Assessments (Treatment Periods 1 - 3) 
Discharge assessments will be completed by the Investigator or his/her designee once symptoms 
of urticaria have been effectively treated for an acute flare or returned to baseline for chronic 
spontaneous urticaria. Actual time by hours and minutes will be recorded. In addition, AEs and 
concomitant medication will also be recorded. 
 
 
11.0 
PREMATURE DISCONTINUATION FROM STUDY 
A premature discontinuation from study will occur when a subject who signed informed consent 
ceases participation in this study, regardless of circumstances, prior to completion of the 
protocol. Subjects can be prematurely discontinued from the study for one of the following 
reasons:  
• Failure to meet inclusion/exclusion criteria before receiving first dose of study drug has 
been administered 
• Death 
• Significant safety event that in the opinion of the Investigator warrants discontinuation 

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• Lost to follow-up after every attempt has been made to contact the subject, including 
sending a registered letter 
• Subject withdraws consent 
The Principal Investigator and the IRB/EC reserve the right to prematurely terminate the study in 
the interest of subject safety and welfare. The Sponsor reserves the right to prematurely 
terminate the study at any time for administrative reasons. 
12.0 
PRODUCT SPECIFICATIONS 
12.1 
Description 
Epinephrine, illustrated in Figure 1, is a sympathomimetic catecholamine. Chemically, 
epinephrine is B-(3, 4dihydroxyphenyl)-a-methyl-aminoethanol. Epinephrine solution 
deteriorates rapidly on exposure to air or light, turning pink from oxidation to adrenochrome and 
brown from the formation of melanin. In addition to oxidation, epinephrine is also susceptible to 
racemization at very low pH and photolysis. 
ARS-1 is a solution formulation of epinephrine intended for nasal administration. 
 
  
 
12.2 
Formulation, Packaging, and Labeling 
 
 
 
 single label panel 
containing the following information: 
ARS-1 (Intranasal Epinephrine) 
Single-Use Spray 
1.0 mg (100 µL at 10 mg/mL) 
Lot Number: XXXXXXX 
Manufacturing Date: MMMYYYY 
Storage Conditions: Protect from light – store in package until ready to use 
 
OR 
 
ARS-1 (Intranasal Epinephrine) 
Single-Use Spray 
2.0 mg (100 µL at 20 mg/mL) 

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The study drug supplied for this study is for use only in subjects properly consented and enrolled 
into this protocol. Study drugs must be kept in a secure location physically separated from 
standard clinic or office drug supplies. 
13.0 
SAFETY MONITORING AND ADVERSE EVENTS 
13.1 
Adverse Events 
Data regarding TEAEs will be collected in this study. TEAEs are events that are not present at 
baseline, or if present at baseline, have worsened in severity. 
Definition of Adverse Events and Adverse Drug Reactions: 
AEs in the eCRF will be classified according to the most recent FDA definitions and in a manner 
consistent with International Conference on Harmonization (ICH) guidelines. As such the 
following definitions will be used: 
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with 
the use of an investigational (medicinal) product (IP) or other protocol-imposed intervention, 
regardless of attribution. An AE may include intercurrent illnesses or injuries that represent an 
exacerbation (increase in frequency, severity, or specificity) of pre-existing conditions (e.g., 
worsening of asthma). A laboratory abnormality will be reported on the “Adverse Event” case 
report forms only if it is associated with clinical sequelae or requires therapeutic intervention. 
 
 
Whenever possible, it is preferable to record a diagnosis as the AE term rather than a series of 
symptoms relating to a diagnosis.  AEs will be coded according to the Medical Dictionary for 
Regulatory Activities (MedDRA) and graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) v 5.0 (Appendix C).  
The reporting period for AEs starts after dosing and continues until discharge.
 
 
If an AE remains unresolved at discharge, the subject will be followed, at the Investigator’s 
discretion, until resolution of the event or until the subject is deemed “lost to follow-up”. AEs 
assessed by the Investigator as related to study drug and “ongoing” at discharge will be 
monitored by the Investigator until resolved or until the subject is deemed “lost to follow-up”. 
SAEs must be followed until resolution by the PI, even if this extends beyond the study-reporting 

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period. Resolution is defined as the return to baseline status or stabilization of the condition with 
the expectation that it will remain chronic. 
The Investigator will assess AEs for severity, relationship to IP, and as to whether the event 
meets one or more of the definitions of an SAE. The assessments will be recorded on the source 
documents and AE case report form (CRF), using the categories defined below.  
Causality 
Category 
Description 
Unlikely 
A clinical event, including laboratory test abnormality, with a 
temporal relationship to drug administration which makes a causal 
relationship improbable, and in which other drugs, chemicals or 
underlying disease provide plausible explanations. For the purpose of 
this protocol, the term unlikely will be considered not related to study 
medication and an “Adverse Event”. 
Possible 
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, but which 
could also be explained by concurrent disease or other drugs or 
chemicals. Information on drug withdrawal may be lacking or unclear. 
For the purpose of this protocol, an event that has possible relationship 
to study medication will be defined as a “Suspected Adverse Drug 
Reaction”.   
Probable 
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, unlikely to be 
attributed to concurrent disease or other drugs or chemicals, and which 
follows a clinically reasonable response on withdrawal. For the 
purpose of this protocol, an event that has probable relationship to 
study medication will be defined as an “Adverse Drug Reaction”.  
In order to classify AEs and diseases, preferred terms will be assigned by the Sponsor or its 
designee to the original terms entered on the eCRF, using MedDRA. 

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For those AEs that are not described on the CTCAE v 5.0 (Appendix C), such AEs will be 
graded on a 5-point scale (mild, moderate, severe, life-threatening, death) and reported as 
indicated on the CRF. Intensity of such an AE is defined as follows: 
Table 8:  Severity Assessment Terminology for Reporting Adverse Events 
Grade 
Common 
Term 
 Description 
1 
Mild 
Mild; asymptomatic or mild symptoms; clinical or 
diagnostic observations only; intervention not indicated. 
2 
Moderate 
Moderate; minimal, local or noninvasive intervention 
indicated; limiting age-appropriate instrumental Assisted 
Daily Living (ADL). 
3 
Severe 
Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; limiting self-care 
ADL. 
4 
Life-
Threatening 
Life-threatening consequences: urgent intervention 
indicated. 
5 
Death 
Death related to AE 
13.2 
Serious Adverse Events 
According to the ICH Guidelines for Good Clinical Practice (E6), an SAE is any untoward 
medical occurrence during the course of a clinical investigation that is characterized by one or 
more of the following: 
• Results in death 
• Is life-threatening 
• Requires in-subject hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Important medical events 
Hospitalization admissions scheduled prior to the study are not considered SAEs unless the 
hospitalization is prolonged due to an AE. However, such hospitalization should be documented 
in the Investigator’s comment in the eCRF. Hospitalizations for scheduled treatments of a 

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preexisting condition that has not worsened or hospitalization for fewer than 24 hours does not 
meet the category of “New or prolonged hospitalization”. 
13.3 
Pregnancy Reporting 
Although not an SAE, exposure to study drug during pregnancy, even if no AE is reported in the 
mother, should be reported within 24 hours. 
13.3.1 
Reporting Requirements for Serious Adverse Events 
All SAEs must be reported to the Sponsor by the Investigator, study coordinator, other 
designated study personnel, or clinical research associate within 24 hours of notification of the 
SAE. To report such events, an SAE form must be completed by the Investigator and sent within 
24 hours by email or fax with relevant information. 
Within the 48 hours following the initial report, the Investigator must provide further information 
on the SAE if available. This should include a copy of the completed SAE form, and any other 
information that will assist the understanding of the event. Significant new information on 
ongoing SAEs should be provided promptly as a follow-up. 
The Investigator also must report all SAEs promptly to the appropriate IRB/EC as required by 
the institution within 24 hours or 48 hours if on weekend/holiday. 
 
 
Table 9:  Contact Information for SAE Reporting 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
13.3.2 
Recording of Serious Adverse Events 
All SAE information must be recorded on the SAE form provided by the Sponsor. Additional 
follow-up information (e.g., test results, autopsy, and discharge summary) must be obtained to 
supplement the SAE report form. A copy of all initial and follow-up reports must be filed with 
the subject’s eCRF. 

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14.0 
STATISTICAL CONSIDERATIONS 
14.1 
Sample Size Determination 
The sample size is based on practical consideration.
 
  
14.2 
Analysis Data Sets 
Data Analysis Set 
Definition 
Analysis 
Intent-To-Treat (ITT) 
analysis set 
Any subjects who are randomized and 
received at least one treatment. Subjects 
will be analyzed per randomization scheme.  
Demographics 
 
Modified ITT (mITT) 
analysis set 
A subset of the ITT analysis set that 
includes subjects who received treatment 
and have post-treatment efficacy data from 
at least two treatments.  
Efficacy 
 
Safety analysis set 
Subjects who are randomized and received 
at least one treatment. Subjects will be 
analyzed based on the treatment received at 
each treatment period. 
Safety 
 
14.3 
Efficacy Data Analyses 
14.3.1 
Primary Efficacy Analyses 
The baseline for the primary endpoints will be the pre-dose at each visit.  
Superiority comparison of ARS-1 1 mg vs. placebo and ARS-1 2 mg vs. placebo at each 
timepoint will be tested at the two-sided 0.05 significance level. If both ARS-1 1 and 2 mg are 
statistically superior to placebo, comparison between the ARS-1 doses will be conducted. 
Time to effect is defined to be the time that it takes to lower one grade, two grades, and three 
grades.  
Duration of effect is defined as the time from when the grade becomes above baseline until the 
grade returned to baseline. 

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14.4 
Safety Data Analyses 
Safety variables to be monitored include AEs and vital signs. Safety data will be collected 
throughout the study and summarized using descriptive statistics.  
The incidence and severity of AEs reported during the study and their relationship to study drug 
will be tabulated. AEs will be coded using MedDRA™ and will be presented by body system. 
The incidence of laboratory abnormalities as determined by CTCAE v 5.0 will be summarized 
for each dose cohort and time point. 
The World Health Organization Drug Dictionary (WHODD) will be used to classify prior and 
concomitant medications by therapeutic class and preferred term. Prior and concomitant 
medication usage will be summarized by the number and percentage of subjects receiving each 
medication within each therapeutic class by dose cohort. 
14.5 
 
 
 
  
 
 
 
  
 
 
  
  
  
15.0 
DATA COLLECTION, STUDY MONITORING, AND DATA DISCLOSURE 
15.1 
Data Collection and Reporting 
An eCRF will be completed for each subject who receives at least one dose of study drug. All 
entries on the eCRF must be supported by original source documentation (e.g., laboratory 
reports, medical records) maintained at the investigational site.  
The Investigator will make all safety assessments (AEs and vital signs) on an ongoing basis. The 
Investigator is required to review all entries on the eCRF and sign at appropriate time intervals. 

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15.2 
Study Monitoring 
All aspects of the study will be monitored carefully by the Sponsor’s designees with respect to 
current Good Clinical Practice (GCP) and Standard Operating Procedures (SOP) for compliance 
with applicable government regulations. It is the responsibility of the Investigator to provide all 
study records, including eCRFs, source documents, etc., for review and source document 
verification by the clinical monitor. 
All eCRFs will be 100% source verified against corresponding source documentation (e.g., 
office and clinical laboratory records) for each subject. Clinical monitors will evaluate 
periodically the progress of the study, including the verification of appropriate consent form 
procedures, review of drug accountability and preparation procedures, adherence to dosing 
procedures, and the verification of the accuracy and completeness of eCRFs. Clinical monitors 
will also ensure that all protocol requirements, applicable FDA regulations, other requirements, 
and Investigator’s obligations are being fulfilled. 
15.3 
Audit and Inspection 
The Sponsor or representative may conduct audits at the trial site(s). Audits will include, but are 
not limited, to protocol compliance, drug supply, presence of required documents, the informed 
consent process, and comparison of eCRFs with source documents. The Investigator agrees to 
participate with audits conducted at a reasonable time in a reasonable manner. 
Regulatory authorities worldwide may inspect the trial site during or after the trial. The 
Investigator should contact the Sponsor immediately if this occurs and must fully cooperate with 
the inspections conducted at a reasonable time in a reasonable manner. 
15.4 
Deviation from Clinical Trial Protocol 
Deviations from the protocol are to be avoided. If a deviation occurs, the Investigator must 
promptly report the deviation to the study monitor. 
The Investigator (or designee) will record any failure to follow the protocol because of any other 
medical unavoidable reason to avoid the subject's urgent risk and record a document as soon as 
possible stating this and the reason. It must be submitted to the Sponsor and the director of the 
study site. 
15.5 
Retention of Records 
The Investigator must retain all study records required by ARS and by the applicable regulations 
in a secure and safe facility. The Investigator must notify ARS of any change in the location, 
disposition, or custody of the study files. The Investigator/Institution must take measures to 
prevent accidental or premature destruction of essential documents, that is, documents that 
permit evaluation of the conduct of a study and the quality of the data produced, including paper 

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copies of study records (e.g., subject charts) as well as any original source documents that are 
electronic as required by applicable regulatory requirements. 
All study records must be retained until whichever is the later day in the following: (1) At least 
the date of approval for the drug or (2) the date when 3 years have passed since the 
discontinuation or completion of the study. No records relating to this study should be disposed 
of without the written approval of ARS. It is the responsibility of ARS to inform the 
Investigator/Institution as to when these documents no longer need to be retained. 
15.6 
Data Disclosure and Subject Confidentiality 
Subject medical information and video recordings obtained as a result of this study is considered 
confidential and used only for study evaluation purposes. Disclosure to third parties other than 
those noted below is prohibited. All reports and communications relating to subjects in this study 
will identify each subject only by number. Medical information resulting from a subject’s 
participation in this study may be given to the subject’s personal physician or to the appropriate 
medical personnel responsible for the subject’s welfare. Data generated as a result of this study 
are to be available for inspection on request by FDA or other government regulatory agency 
auditors, the Sponsor clinical monitor (or designee), and the IRB/EC. 
All laboratory specimens, evaluation forms, reports, and other records that leave the site will be 
identified by a coded number to maintain subject confidentiality. All records will be kept in a 
locked and secured area. All computer entry and networking programs will be identifiable only 
by coded numbers. Clinical information will not be released without written permission from the 
subject, except as necessary for monitoring by the IRB, the FDA, or the study Sponsor. 
Any information, inventions, or discoveries (whether patentable or not), innovations, 
suggestions, ideas, and reports, made or developed by the Investigator(s) as a result of 
conducting this study shall be promptly disclosed to the Sponsor and shall be the sole property of 
the Sponsor. The Investigator agrees, upon the Sponsor’s request and at the Sponsor's expense, to 
execute such documents and to take such other actions, as the Sponsor deems necessary or 
appropriate, to obtain patents in the Sponsor’s name covering any of the foregoing. 
The results of this study will be published under the direction of the Sponsor. Results will not be 
published without prior review and approval by the Sponsor and Study Investigator. 
16.0 
PROTECTION OF HUMAN SUBJECTS 
16.1 
Basic Principles 
The study will be conducted in accordance with the relevant regulatory requirements, this 
protocol, and ethical principles that are consisted with the GCP guideline developed by the 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH). This clinical trial will also be conducted in compliance 

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with Declaration of Helsinki, protocol, Standard specified in the relevant local regulations. Prior 
to initiation of the study, the Investigator and the Sponsor should obtain approval from the 
IRB/IEC on this protocol and any further amendments, and the subject information and informed 
consent form. 
Any suspected serious breaches must be immediately reported to the Sponsor. A serious breach 
is a breach of the conditions and principles of GCP in connection with the study or the protocol, 
which is likely to affect, to a significant degree, the safety of the subjects or the scientific value 
of the study. 
Personnel involved in the study will be qualified by education, training, and experience to 
perform their respective tasks. 
16.2 
Institutional Review Board/Ethics Committee 
The Investigator or designee agrees to provide the IRB/EC with all appropriate material, 
including a copy of the ICF. The study will not be initiated until the Investigator obtains written 
approval of the research plan and the ICF from the appropriate IRB/EC and copies of these 
documents are received by the Sponsor. Appropriate reports on the progress of this study will be 
made by the Investigator to the IRB/EC and Sponsor in accordance with applicable government 
regulations and in agreement with the policies established by the Sponsor. The Sponsor ensures 
that the IRB/EC complies with the requirements set forth in 21 CFR Part 56 (Code of Federal 
Regulations). 
16.3 
Informed Consent 
The Investigator is responsible for: 
• Explain the subject of the study, the risks and benefits expected from participating in the 
study, and that the participation is voluntary so that the subject can understand. 
• Obtain informed consent to participate in the trial from the subject by signing or signing 
the consent form and entering the date before starting the study procedure and study 
drugs. 
• Properly answer questions from subjects at any time during the trial and if new 
information that can affect the subject's intention to continue the trial is obtained while 
the subject is participating in the trial, the information is promptly communicated to the 
subject. 
• Give a copy of the written consent form to the study participants and keep one copy at the 
study site. 
16.4 
Subject Health Injury and Insurance 
In general, if a subject is health-injured as a direct result of the investigational products, the 
Sponsor or its contracted insurance company will pay for reasonable and necessary medical 

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treatment for the health-injury. If laws or regulations of the locality in which the study is taking 
place require additional payment of expenses, the Sponsor should comply with such laws or 
regulations. Where applicable, the Sponsor will arrange for specific insurance coverage. If health 
damage occurred to a subject participating in the clinical trial due to the willful or gross 
negligence of Investigator’s site, indemnification will be discussed based on the contract with the 
site. The indemnification for the health damage and the payment to subjects will be described in 
the ICF. 
16.5 
Completion of the Study 
If the clinical trial is completed at the study site, the Investigator will notify the director of the 
study site that the trial has been completed and provide an approximate summary in writing. The 
director of the study site will promptly notify the IRB/EC and the Sponsor in writing about the 
completion. 

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17.0 
REFERENCE LIST 
1. 
Frigas E, Park M. Acute urticaria and angioedema. Am J Clin Dermatol. 2009;10(4):239-
250. 
2.  
Schaefer P. Acute and chronic urticaria: Evaluation and treatment. Am Fam Phys. 
2017;95(11):717-724. 
3. 
American College of Allergy, Asthma, and Immunology - https://acaai.org 
4. 
Kanani A, Betschel SD, Warrington R. Urticaria and angioedema. Allergy Asthma Clin 
Immunol. 2018;14(Suppl 2):59:115-127. 
5.  
Zuberbier T, et al. The EAACI/GA2LEN/EDF/WAO guideline for the definition, 
classification, diagnosis and management of urticaria. Allergy. 2018;73:1393-1414.  
6.  
Radonjic-Hoesli S, Hofmeier KS, Micaletto S, Schmid-Grendelmeier P, Bircher A, 
Simon D. Urticari and angioedema: an update on classification and pathogenesis. Clin Rev 
Allergy Immunol. 2018;54(1):88-101. 
7.  
Prescription Information of epinephrine injection USP – 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205029s000lbl.pdf 
8.  
Arnold JJ, Ahsan F, Meezan E, Pillion DJ. Correlation of tetradecylmaltoside induced 
increases in nasal peptide drug delivery with morphological changes in nasal epithelial cells. 
Journal of pharmaceutical sciences. 2004;93(9):2205-13. 
9.  
Oswalt ML, Kemp SF. Anaphylaxis: office management and prevention. Immunology 
and allergy clinics of North America. 2007;27(2):177-91, vi. 
10. 
KJ S, FE S. - Epinephrine and its use in anaphylaxis: current issues. D - 100936359. (- 
1473-6322 (Electronic)):T - publish. 
11. 
Yamada T. The Potential of the Nasal Mucosa Route for Emergency Drug 
Administration Via a High-Pressure Needleless Injection System. Anesth Prog. 2004;5(2):56–61. 
12. 
Bleske BE, Rice TL, Warren EW, Giacherio DA, Gilligan LJ, Massey KD, et al. Effect of 
dose on the nasal absorption of epinephrine during cardiopulmonary resuscitation. Am J Emerg 
Med. 1996; 14:133-38.  
13.  
Spack EG, Wehner NG, Winkelhake JL. Preclinical and Pharmacological Studies of 
AG284, a Soluble HLA-DR2:Myelin Basic Protein Peptide Complex for the Treatment of 
Multiple Sclerosis. CNS Drug Reviews. 1998;4(3):225-46. 
 

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Appendix A: Schedule of Study Procedures 

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Appendix B: Instructions for Use 
 
 
 
 

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Appendix C: Common Terminology Criteria for Adverse 
Events (CTCAE) Version 5.0 
 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quick_refere
nce_5x7.pdf