Open-label Study of Safety and Tolerability of Chronic Intermittent Usage for 24 or 52 Weeks of Intranasal Dihydroergotamine Mesylate (DHE) Administered Using the I123 Precision Olfactory Delivery (POD®) Device [INP104, POD-DHE] in Patients With Migraine Headache
Phase: PHASE3
Conditions: Migraine Headache
Sponsor: Impel Pharmaceuticals

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CLINICAL STUDY PROTOCOL 
Protocol Title 
Open-label Study of Safety and Tolerability of Chronic 
Intermittent Usage for 24 or 52 Weeks of Intranasal 
Dihydroergotamine Mesylate (DHE) Administered using 
the I123 Precision Olfactory Delivery (POD®) Device 
[INP104, POD-DHE] in Patients with Migraine Headache 
STOP 301 Trial (Safety and Tolerability of POD-DHE) 
Protocol Number 
INP104-301 
Product 
INP104 [POD-DHE] 
Indication 
Migraine 
Development Phase 
Phase 3 
Sponsor 
Impel NeuroPharma Inc. 
201 Elliott Ave West, Suite 260 
Seattle, Washington 98119 
USA  
Medical Monitor 
Dr Andrew Graber MD 
PPD Medical Monitor 
PPD Pharmacovigilance Hotline: +1-(888) 483-7729 
Safety Email: wilsafety@ppdi.com 
Version  
Amendment 03 (A03) - Final v4.0 
Effective Date 
26 April 2019 
This document contains privileged, proprietary and confidential information. Neither the document nor the 
information contained herein should be used, disclosed or reproduced, in whole or in part, for any purpose 
other than to the extent necessary to obtain required regulatory and ethics approvals, informed consent, or 
as required by applicable laws and regulations. Disclosures for purposes other than as authorized above 
must obtain prior written consent of Impel NeuroPharma Inc. 
NCT: 03557333  This NCT number has been applied to the document for the purposes
of posting on clinicaltrials.gov.

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TABLE OF CONTENTS 
TABLE OF CONTENTS .....................................................................................................2 
TABLE OF TABLES ..........................................................................................................6 
PROTOCOL AUTHORIZATION.......................................................................................7 
DECLARATION OF THE INVESTIGATOR ....................................................................8 
FACILITIES AND PERSONNEL ......................................................................................9 
STUDY SYNOPSIS ..........................................................................................................10 
LIST OF TERMS AND ABBREVIATIONS ....................................................................14 
1 
BACKGROUND ............................................................................................15 
1.1 
Introduction .....................................................................................................15 
1.2 
Clinical overview ............................................................................................16 
1.3 
Summary of potential risks and benefits ........................................................16 
1.4 
Proposed dosage and treatment period ...........................................................16 
1.5 
Patient population ...........................................................................................16 
2 
OBJECTIVES .................................................................................................18 
2.1 
Primary objectives ..........................................................................................18 
2.2 
Secondary objectives ......................................................................................18 
3 
STUDY DESIGN ...........................................................................................19 
3.1 
Overview .........................................................................................................19 
3.2 
Primary endpoints ...........................................................................................20 
3.3 
Secondary endpoints .......................................................................................20 
3.4 
Exploratory endpoints .....................................................................................20 
4 
STUDY POPULATION .................................................................................22 
4.1 
Population size ................................................................................................22 
4.2 
Inclusion criteria .............................................................................................22 
4.3 
Exclusion criteria ............................................................................................23 
4.4 
Concomitant medications ...............................................................................24 
4.5 
Diet, activity, and other restrictions ................................................................25 
4.6 
Contraceptive requirements ............................................................................26 
5 
INVESTIGATIONAL PRODUCTS ..............................................................27 
5.1 
Study medication identification ......................................................................27 
5.2 
Dosage and administration .............................................................................27 

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5.2.1 
Study supplies .................................................................................................27 
5.2.2 
Investigational product storage, dispensing, and accountability ....................28 
6 
STUDY PROCEDURES ................................................................................29 
6.1 
Medical history ...............................................................................................29 
6.2 
Demographics .................................................................................................29 
6.3 
Body weight and height or body mass index ..................................................29 
6.4 
Safety assessments ..........................................................................................29 
6.4.1 
Physical examination ......................................................................................29 
6.4.2 
Nasal endoscopic examination .......................................................................30 
6.4.3 
Olfactory changes (UPSIT) ............................................................................31 
6.4.4 
Electrocardiogram ...........................................................................................32 
6.4.5 
Vital signs .......................................................................................................32 
6.4.6 
Laboratory investigations ...............................................................................32 
6.4.6.1 
Hematology and serum chemistry ..................................................................32 
6.4.6.2 
Urinalysis ........................................................................................................33 
6.4.6.3 
Serology ..........................................................................................................34 
6.4.6.4 
Urine drug screen ............................................................................................34 
6.4.6.5 
Pregnancy testing ............................................................................................34 
6.5 
Efficacy assessments ......................................................................................35 
6.5.1 
MIDAS and HIT-6 questionnaires..................................................................35 
6.5.2 
Migraine diary ................................................................................................35 
6.5.3 
Subject’s impression of INP104 usability/effectiveness ................................35 
7 
STUDY SCHEDULE .....................................................................................36 
7.1 
Study flow .......................................................................................................36 
7.2 
Study activities ................................................................................................38 
7.2.1 
Consent and screening ....................................................................................38 
7.2.2 
Baseline ...........................................................................................................39 
7.2.3 
Treatment period visits ...................................................................................39 
7.2.4 
End-of-treatment visits ...................................................................................40 
7.2.5 
Post-treatment follow-up visits .......................................................................41 
8 
SAFETY .........................................................................................................42 
8.1 
Definition of an adverse event ........................................................................42 
8.1.1 
Severity of an adverse event ...........................................................................44 

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8.1.2 
Causal relationship of an adverse event ..........................................................44 
8.1.3 
Action taken with investigational products ....................................................45 
8.1.4 
Outcome ..........................................................................................................45 
8.2 
Definition of a serious adverse event ..............................................................45 
8.2.1 
Notification of a serious adverse event ...........................................................47 
8.3 
Clinical laboratory abnormalities and other abnormal assessments as adverse 
events and serious adverse events ...................................................................47 
8.4 
Documenting adverse events ..........................................................................48 
8.5 
INP104 combination product technical complaints ........................................48 
8.6 
Regulatory authorities .....................................................................................49 
8.7 
Follow-up of adverse events and serious adverse events ...............................49 
8.8 
Pregnancy .......................................................................................................49 
8.9 
Safety data review ...........................................................................................50 
9 
STUDY DURATION .....................................................................................51 
9.1 
Subject withdrawal .........................................................................................51 
9.2 
Subject replacement ........................................................................................52 
10 
STUDY CLOSURE ........................................................................................53 
11 
STUDY MONITORING AND DATA MANAGEMENT .............................54 
11.1 
Study monitoring ............................................................................................54 
11.2 
Access to study documents and personnel ......................................................54 
11.3 
Source document and data verification ...........................................................54 
11.4 
Data management ...........................................................................................55 
12 
STATISTICAL ANALYSES .........................................................................56 
12.1 
Sample size calculation ...................................................................................56 
12.2 
Subjects to analyze .........................................................................................56 
12.3 
Study endpoints ..............................................................................................57 
12.4 
Exploratory efficacy analysis .........................................................................57 
12.5 
Safety analysis ................................................................................................57 
12.6 
Exploratory analysis .......................................................................................59 
13 
REGULATORY REQUIREMENTS .............................................................60 
13.1 
Regulatory approvals ......................................................................................60 
13.2 
Ethics committees ...........................................................................................60 
13.3 
Subject informed consent ...............................................................................60 

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13.4 
Data protection ................................................................................................60 
14 
ADMINISTRATIVE PROCEDURES ...........................................................61 
14.1 
Liability/indemnity/insurance .........................................................................61 
14.2 
Recording of data and retention of records .....................................................61 
14.3 
Publication of results ......................................................................................61 
14.4 
Disclosure and confidentiality ........................................................................62 
15 
QUALITY CONTROL AND QUALITY ASSURANCE .............................63 
15.1 
Compliance with Good Clinical Practice .......................................................63 
15.2 
Archiving and regulatory inspection ..............................................................63 
16 
CLINICAL STUDY REPORT .......................................................................64 
17 
SPONSOR AND INVESTIGATOR OBLIGATIONS ..................................65 
17.1 
Protocol amendments ......................................................................................65 
17.2 
Protocol deviations .........................................................................................65 
18 
REFERENCES ...............................................................................................66 
19 
APPENDICES ................................................................................................67 
19.1 
Appendix 1 – List of Permitted Migraine Medications ..................................67 
19.2 
Appendix 2 – Examples of CYP3A4 Inhibitors .............................................68 
19.3 
Appendix 3 – Nasal Examination Manual ......................................................69 
19.4 
Appendix 4 – Migraine Disability Assessment Test (MIDAS) ......................70 
19.5 
Appendix 5 – Headache Impact Test (HIT-6TM) ............................................71 
19.6 
Appendix 6 – Product Acceptability Questionnaire .......................................72 
 
 
 

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TABLE OF TABLES 
Table 6-1:  Quantitative Scoring Scale for Evaluation of the Nasal Mucosa (QSS-NM) .30 
Table 7-1:  Time and Event Schedule ................................................................................36 
 

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PROTOCOL AUTHORIZATION 
Title: Open-label Study of Safety and Tolerability of Chronic Intermittent Usage for 24 
or 52 Weeks of Intranasal Dihydroergotamine Mesylate (DHE) Administered using the 
I123 Precision Olfactory Delivery (POD®) Device [INP104, POD-DHE] in Patients with 
Migraine Headache 
 
This study protocol was subjected to critical review. The information it contains is 
consistent with current knowledge of the risks and benefits of the investigational product, 
as well as with the moral, ethical, and scientific principles governing clinical research, as 
set out in the current Declaration of Helsinki and the guidelines on Good Clinical Practice 
(GCP), as per ICH Integrated Addendum to ICH E6(R1): Guideline for GCP E6(R2) 
(2015) and applicable local regulations. 
 
 
 
 
 
Dr. Stephen Shrewsbury (MD), Chief Medical Officer,  
Impel NeuroPharma Inc. 
 
Date 
26-Apr-2019 | 14:40 PDT

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DECLARATION OF THE INVESTIGATOR 
Title: Open-label Study of Safety and Tolerability of Chronic Intermittent Usage for 24 
or 52 Weeks of Intranasal Dihydroergotamine Mesylate (DHE) Administered using the 
I123 Precision Olfactory Delivery (POD®) Device [INP104, POD-DHE] in Patients with 
Migraine Headache 
All documentation for this study that is supplied to me and that has not been previously 
published will be kept in the strictest confidence. This documentation includes this study 
protocol, Investigator's Brochure(s) (IB), Case Report Forms (CRFs), and scientific data 
not in the public domain. 
The study will not be commenced without the prior written approval of a properly 
constituted Institutional Review Board (IRB). No changes will be made to the study 
protocol without the prior written approval of the Sponsor and the IRB, except where 
necessary to avert an immediate hazard to the subjects. 
I have read the protocol and agree that the study will be conducted in compliance with the 
protocol and in accordance with the principles of the current version of the Declaration of 
Helsinki, concerning medical research in humans (recommendations guiding physicians 
in biomedical research involving human subjects), ICH Integrated Addendum to ICH 
E6(R1): Guideline for GCP E6(R2) (2015) and applicable local regulations. 
I acknowledge that I am responsible for the overall study conduct. I agree to personally 
conduct or supervise the described clinical study. I agree to ensure that all associates, 
colleagues, and employees assisting in the conduct of the study at my site are informed 
about their obligations. Mechanisms are in place to ensure that site staff receive the 
appropriate information throughout the study. 
 
 
 
 
 
Investigator Name (Print) 
 
Investigational Site / Site 
Number 
 
 
 
 
Investigator Signature 
 
Date 

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FACILITIES AND PERSONNEL 
Medical Monitor 
Dr Andrew Graber, MD 
PPD Medical Monitor 
 
Phone: +1 919-380-2000 
Email: wilsafety@ppdi.com 
 
Sponsor’s Medical Officer and 
Medical Expert 
Dr Stephen B Shrewsbury, MD 
Chief Medical Officer & Medical Monitor 
 
Phone: 
 
Email: sshrewsbury@impelnp.com 
 
SAE Reporting 
Phone: +1 800-201-8725 
Fax: +1 888-488-9697 
 

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STUDY SYNOPSIS 
Title 
Open-label Study of Safety and Tolerability of Chronic Intermittent Usage for 
24 or 52 Weeks of Intranasal Dihydroergotamine Mesylate (DHE) 
Administered using the I123 Precision Olfactory Delivery (POD®) Device 
[INP104, POD-DHE] in Patients with Migraine Headache 
Protocol number 
INP104-301 
Sponsor 
Impel NeuroPharma Inc. 
Seattle, Washington USA 
Study medication 
INP104 (POD-DHE) 
Clinical phase 
3 
Study sites 
Approximately 40 sites in the United States of America 
Study objectives 
Primary Objectives: 
Safety and tolerability as assessed by: 
• 
Number of subjects with serious and non-serious treatment emergent 
adverse events 
• 
Change in nasal mucosa 
• 
Change in olfactory function. 
Secondary Objectives: 
• 
Efficacy of INP104 as assessed by change from baseline in migraine 
measures at 24 and 52 weeks of treatment 
• 
Additional safety and tolerability as assessed by: 
o 
Change in vital signs 
o 
Change in physical examinations 
o 
Change in 12-lead electrocardiogram 
o 
Change in laboratory evaluations (hematology, clinical 
chemistry, and urinalysis). 
Patient population 
Adult male and female subjects 18 to 65 years of age, with a minimum of 
2 migraine attacks per month. 
Number of subjects 
 
Approximately 300 to 340 subjects will be enrolled: 
• 
At least 150 subjects will receive 24 weeks of treatment 
• 
At least 60 subjects (of the 300 to 340 enrolled) will receive up to 
52 weeks of treatment 
At least 30 of each gender will be enrolled. 
Study design 
Interventional, open-label, single-group assignment, safety, tolerability and 
exploratory efficacy study. The study will comprise a 4-week screening period, 
a 24-week treatment period, and a 2-week post-treatment follow-up period for 
all subjects. A subset of these subjects will complete a 52-week treatment 
period. 
Methodology 
Study assessments will include evaluations of clinical measures, laboratory 
findings, and safety reporting. 
• 
Specific assessments to evaluate treatment safety will include nasal 
endoscopy, University of Pennsylvania Smell Identification Test, and 
the frequency and type of adverse events 

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• 
Clinical evaluations will include collection of medical history, 
concomitant medication use, height and weight, physical examination, 
12-lead electrocardiograms, and vital signs 
• 
Laboratory evaluations will include hematology, serum chemistry, 
urinalysis, serology, and pregnancy testing for women of childbearing 
potential 
Key inclusion 
criteria 
1. Adult males and females, 18 to 65 years of age at the time of screening. 
2. Documented diagnosis of migraine (by International Classification of 
Headache Disorders version 3 beta criteria) with or without aura, with at 
least 2 attacks/month for previous 6 months. 
3. At least two migraine attacks during the 28-day screening period (treated 
with subject’s usual treatment). Subjects who cannot meet this criteria 
cannot be rescreened. 
4. Participants must be in good general health, with no significant medical 
history (excluding migraine), and have no clinically significant 
abnormalities on physical examination at screening or baseline visits. 
Key exclusion 
criteria 
1. Subjects with trigeminal autonomic cephalalgias (including cluster 
headache, hemicrania syndromes and short-lasting, unilateral, 
neuralgiform headache attacks with conjunctival injection and tearing), 
migraine aura without headache, hemiplegic migraine or migraine with 
brainstem aura (previously referred to as basilar migraines), as per by 
International Classification of Headache Disorders version 3 beta criteria. 
2. Subjects with chronic migraines, medication overuse headache or other 
chronic headache syndromes, as per International Classification of 
Headache Disorders version 3 beta criteria. 
3. Positive test for human immunodeficiency virus, hepatitis B surface 
antigen, or hepatitis C antibodies. 
4. Subjects with ischemic heart disease or subjects who have clinical 
symptoms or findings consistent with coronary artery vasospasm, 
including Prinzmetal’s variant angina. 
5. Subjects with significant risk factors for coronary artery disease or medical 
history of diabetes or smoking, known peripheral arterial disease, 
Raynaud’s phenomenon, sepsis or vascular surgery (within 3 months prior 
to study start), or severely impaired hepatic or renal function. Subjects 
with a history of hypertension may be enrolled if the hypertension is stable 
and well-controlled on current therapies for > 6 months, provided no other 
risk factors for coronary artery disease are present. 
6. Significant nasal congestion, physical blockage in either nostril, 
significantly deviated nasal septum, septal perforation, or any pre-existing 
upper nasal mucosal abnormality on endoscopy scoring 1 or more (except 
score 1 allowed for mucosal edema). 
7. Subjects who have previously shown hypersensitivity to ergot alkaloids or 
any of the ingredients in the drug product. 
8. Subjects who have previously failed to respond to intravenous DHE for 
treatment of migraine. 
9. Use of > 12 days per month of triptan or ergot-based medication in the 
2 months prior to screening or during screening period 
Study drug 
administration 
INP104 drug-device combination product will be used to administer 1.45 mg 
DHE intranasally. 

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Subjects will be instructed to use no more than 2 doses of INP104 within a 
24-hour period, 3 doses in a 7-day period, and 12 doses per 4-week period.  
Treatment 
assignment 
Single group: All study subjects will receive INP104. 
Outcome measures 
Primary Endpoints: 
• 
Number of subjects with serious and non-serious treatment emergent 
adverse events 
• 
Change in nasal mucosa as detected by nasal endoscopy 
• 
Change in olfactory function 
Secondary Endpoints (including additional safety and tolerability 
endpoints): 
• 
Change from baseline in vital signs 
• 
Change from baseline in physical examinations 
• 
Change from baseline in 12-lead electrocardiogram 
• 
Change from baseline in laboratory evaluations (hematology, clinical 
chemistry and urinalysis) 
Exploratory Endpoints: 
• 
Change from baseline in healthcare utilization for migraine 
• 
Product acceptability questionnaire  
Exploratory Efficacy Endpoints: 
• 
Change from baseline in rate of freedom from headache pain at 
2 hours after INP104 administration 
• 
Change from baseline in Most Bothersome Symptom (MBS) at 
2 hours after INP104 administration 
• 
Change from baseline in frequency and severity of headache pain 
(over other time points) after INP104 administration 
• 
Change from baseline in MBS at other time points after INP104 
administration 
• 
Change from baseline in frequency and severity of migraine 
(measured by headache pain, nausea, phonophobia and photophobia) 
by diary 
• 
Incidences of pain relapse within 24 and 48 hours after INP104 
administration 
• 
Change from baseline in Migraine Disability Assessment (MIDAS) 
and Headache Impact Test (HIT)-6 questionnaires 
• 
Change in concomitant migraine medication use 
Statistical analysis 
Statistical analyses will be descriptive in nature. All subjects who receive any 
amount of study drug (Safety Population) will be included in the analyses. 
Safety and tolerability will be analyzed based upon the reporting of adverse 
events, nasal endoscopy, laboratory findings, vital sign assessments, and 
electrocardiogram parameters. Continuous safety data will be summarized with 
descriptive statistics (arithmetic mean, standard deviation, median, minimum, 
and maximum). Categorical safety data will be summarized with frequency 
counts and percentages. 

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Exploratory efficacy analyses will focus on summarizing the following over 
time: 
• 
Frequency and severity of migraine symptoms captured in the 
migraine diary 
• 
MIDAS and HIT-6 questionnaire scores 
• 
Use of concomitant migraine medications 
Study duration 
Maximum of 30 weeks for subjects receiving 24 weeks of treatment and 
58 weeks for subjects receiving 52 weeks of treatment  

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LIST OF TERMS AND ABBREVIATIONS 
AE 
adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BMI 
body mass index 
CRO 
contract research organization 
CSR 
Clinical study report 
DHE 
dihydroergotamine mesylate 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EDC 
Electronic data collection 
eDiary 
electronic diary  
EOT 
end-of-treatment 
FDA 
United States Food and Drug Administration 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
HBsAG 
Hepatitis B surface antigen 
HCV 
Hepatitis C Virus 
HFA 
hydrofluoroalkane-134a (propellant) 
HIT-6 
Headache Impact Test 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator Brochure 
ICH 
International Council for Harmonisation 
ICHD3b 
International Classification of Headache Disorders version 3 beta 
IFU 
Instructions For Use 
IHS 
International Headache Society 
IM 
Intramuscular 
IP 
investigational product 
IRB 
Institutional Review Board 
IV 
Intravenous 
LPLV 
Last patient last visit 
MBS 
Most Bothersome Symptom 
MedDRA 
Medical Dictionary for Regulatory Affairs 
MIDAS 
Migraine Disability Assessment 
NSAID 
Non-steroidal anti-inflammatory drug 
PI 
Principal Investigator 
POD 
Precision Olfactory Delivery 
PPD 
Pharmaceutical Product Development, LLC 
PRN 
as necessary 
PVG 
Pharmacovigilance 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
SD 
standard deviation 
SP 
Safety Population 
SSRI 
selective serotonin reuptake inhibitor 
TEAE 
Treatment Emergent Adverse Event 
UPSIT 
University of Pennsylvania Smell Identification Test 
WHO 
World Health Organization 
WOCBP 
women of childbearing potential 
 

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1 BACKGROUND 
1.1 
Introduction 
Migraine is experienced by more than 80 million people in the United States and 
European Union. It is a common and disabling neurologic disorder (Hansen 2016; 
Manzoni 2010). Acute treatment of migraine remains a clinical challenge despite the 
availability of multiple treatment options. More than 40% of respondents in a population 
survey of acute migraine claimed to have at least one unmet need in their acute migraine 
treatment, and a large percentage (37.4%) of respondents report dissatisfaction with 
current treatment options, suggesting the opportunity for outcome improvement in acute 
migraine subjects (Lipton 2013). 
The purpose of this study is to evaluate the investigational product (IP; INP104 or 
POD-DHE), which is a drug-device combination product comprised of the active 
ingredient, dihydroergotamine mesylate (DHE), administered intranasally by a Precision 
Olfactory Delivery (POD®) device (I123 POD device). The indication for INP104 is for 
the treatment of acute migraine headache with or without aura. 
D.H.E. 45® (dihydroergotamine mesylate) Injection, USP is the brand name of the 
dihydroergotamine mesylate product first approved in 1946 for injection (D.H.E. 45® 
Prescribing Information). DHE, in all current formulations, is an acute (abortive) therapy 
and will not prevent headaches. Common side effects of D.H.E. 45 Injection include 
dizziness, drowsiness, headache, nausea, vomiting, diarrhea, flushing (redness or tingly 
feeling under the skin), increased sweating, anxiety, or skin rash. Though effective, many 
patients do not like injections, and they commonly require a healthcare professional to 
administer them. 
Migranal® Nasal Spray is the brand name of a DHE product administered by a nasal 
spray applicator and was approved by the United States Food and Drug Administration 
(FDA) in August 1997 (Migranal US Prescribing Information). Unfortunately, the 
bioavailability of DHE via intranasal spray (32%) is poor compared to the injectable 
product, and side effects of taste disturbance and rhinitis are frequent (Migranal US 
Prescribing Information). It is hypothesized that absorption of drug could be improved 
with a targeted delivery of drug to the upper nasal cavity in a manner that avoids loss of 
drug through dripping out from the nose or into the throat. 
The INP104 product utilizes hydrofluoroalkane-134a (HFA) propellant to deliver the 
same formulation of DHE as contained in Migranal Nasal Spray, for a total target dose of 
1.45 mg (administered in two sprays, one per nostril), after which the product is 
discarded. The I123 POD device used in INP104 has been specifically designed to propel 
liquid formulations in a focused stream, as a narrow plume, to the nasal epithelium. This 
narrow stream is intended to minimize deposition in the nasal vestibule and to avoid loss 
of drug before absorption. 

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1.2 
Clinical overview 
One clinical trial (Protocol INP104-101) was completed with DHE delivered by the I123 
POD device (i.e., with INP104). This study compared the bioavailability of DHE 
following single dose administration by INP104 to that of D.H.E. 45 (dihydroergotamine 
mesylate) Injection, USP and to Migranal® Nasal Spray in healthy adult subjects. Safety 
data indicate that when DHE is delivered by intranasal administration, adverse events 
(AEs) other than increased nausea tend to be localized to the nose and throat and include 
minor nose and throat irritation, nasal congestion, and bad taste in the mouth. In the 
phase I study (Protocol INP104-101), administration of INP104 or Migranal resulted in 
fewer AEs compared to D.H.E. 45 for Injection administered intravenously. The 
established safety of Migranal Nasal Spray and D.H.E. 45 (dihydroergotamine mesylate) 
Injection, USP supports further clinical development of the INP104 product. 
1.3 
Summary of potential risks and benefits 
The risk/benefit profile of DHE is well known and is described in the D.H.E. 45 
(dihydroergotamine mesylate) Injection, USP and Migranal US Prescribing Information. 
INP104 drug substance and drug product are manufactured by the same contract 
manufacturer using the same equipment and same process as the approved drug substance 
and drug product in Migranal Nasal Spray. Given that there are no differences to the 
chemistry and manufacturing of these two products, no additional toxicology risks due to 
sourcing are anticipated by the Sponsor. 
1.4 
Proposed dosage and treatment period 
D.H.E. 45 (dihydroergotamine mesylate) Injection, USP is approved for intravenous (IV), 
intramuscular (IM), and subcutaneous (SC) injections at a dose of 1 mg. This dose can be 
repeated at 1 hour intervals up to a maximum of 3 mg by IM or SC injection, or a 
maximum of 2 mg by IV injection per any 24-hour period. The total dose should not 
exceed 6 mg in a week. Migranal Nasal Spray is approved for dosing with 2 mg with a 
maximum dose of 3 mg per 24-hour period and 4 mg in any 7-day period. 
It is proposed that INP104 will be administered using the I123 POD device where the 
dose will be 1.45 mg of DHE. Subjects will be allowed to self-administer a maximum 
number of 3 doses in a 7-day period (with no more than 2 doses in a 24-hour period). The 
minimum planned treatment period for all enrolled subjects will be 24 weeks, with a 
subset of at least 60 (of an estimated 80 enrolled into this period) continuing through to 
52 weeks of treatment. 
1.5 
Patient population 
This study will be conducted in subjects diagnosed with a history of migraine per 
International Headache Society (IHS) criteria (Headache Classification Committee of the 
International Headache Society, 2018) with or without aura, with an average of at least 2 
migraine attacks per month in the previous 6 months, and who meet all of the inclusion 
criteria and none of the exclusion criteria. This population is appropriate for a Phase 3 

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study investigating safety and tolerability, as well as changes in migraine frequency and 
severity, changes in the disabling effects of migraine, and changes in concomitant 
medication use. 

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2 OBJECTIVES 
2.1 
Primary objectives 
Safety and tolerability as assessed by: 
• Number of subjects with serious and non-serious treatment emergent adverse 
events 
• Change in nasal mucosa 
• Change in olfactory function. 
2.2 
Secondary objectives 
• Efficacy of INP104 as assessed by change from baseline in migraine measures 
(Section 3.3) at 24 and 52 weeks of treatment 
• Additional safety and tolerability as assessed by: 
o Change in vital signs 
o Change in physical examinations 
o Change in 12-lead electrocardiogram (ECG) 
o Change in laboratory evaluations (hematology, clinical chemistry, and 
urinalysis). 

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3 STUDY DESIGN 
 
3.1 
Overview 
This is an interventional, open-label, single-group assignment, safety, tolerability, and 
exploratory efficacy study. The study will comprise a 4-week screening period, a 
24-week treatment period for all subjects, with a treatment continuation to 52 weeks  for 
a subset of the subjects, and a 2-week post-treatment follow-up period. Approximately 
300 to 340 subjects will be enrolled to allow for a 25% drop-out rate over the 24-week 
study, to achieve at least 150 completing treatment at 24 weeks and 80 subjects 
continuing with the aim of at least 60 subjects completing 52 weeks of exposure. Suitable 
subjects continuing to the 52-week endpoint will be re-consented at 24 weeks. 
The study is an outpatient study in frequent migraineurs (currently suffering a minimum 
of 2 migraines per month) but not diagnosed with chronic headache by International 
Classification of Headache Disorders version 3 beta (ICHD3b) criteria. During the 
screening period, they will be required to complete a daily migraine diary and record at 
least 2 migraine attacks. If they are eligible at Visit 2, they will be enrolled and provided 
with a POD device for training purposes and a supply of INP104 (up to 3 doses per week) 
and instructed to use INP104 when they experience a recognizable migraine. They will be 
instructed to use no more than 2 doses within a 24-hour period, 3 doses in a 7-day period, 
and 12 doses per 4-week period for their usual migraines. All subjects will 
self-administer INP104 intranasally (1.45 mg in a divided dose, one actuation per nostril).  
During the treatment period, all subjects will record all migraines experienced over 
24 weeks. A subset of subjects suffering from an average of at least 2 migraines per 
28-day period between Weeks 12 and 24 (i.e., each subject will record a minimum of 
6 migraine attacks over this 12-week period) and demonstrating at least 80% diary 

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compliance will enter an extension treatment period to allow data collection for 52 weeks 
of total exposure. Study subjects will record all migraine attacks (frequency and severity) 
in a migraine diary and undergo periodic evaluation by Migraine Disability Assessment 
(MIDAS; Appendix 4) and Headache Impact Test (HIT-6TM; Appendix 5) questionnaires. 
Subjects will also return to the clinic for periodic evaluations of safety, which will 
include collection of vital signs, physical examinations, nasal endoscopy, UPSIT smell 
test, electrocardiography, and recording of AEs, laboratory evaluations, and concomitant 
medications. 
After the last study treatment visit, subjects will return two weeks later for a 
post-treatment follow-up visit. 
If a higher than anticipated drop-out rate is experienced or enrolled subjects experience 
fewer than 2 migraine events per 28 days on treatment, consideration will be given to 
amending the protocol to increase the number of enrolled subjects, or to modify the 
inclusion criteria to require a higher frequency of migraines, or both. 
3.2 
Primary endpoints 
The primary endpoints for the study are listed below: 
• Number of subjects with serious and non-serious treatment emergent adverse 
events 
• Change in nasal mucosa as detected by nasal endoscopy 
• Change in olfactory function. 
3.3 
Secondary endpoints 
The secondary endpoints for the study include additional safety and tolerability endpoint: 
• Change from baseline in vital signs 
• Change from baseline in physical examinations 
• Change from baseline in 12-lead ECG 
• Change from baseline in laboratory evaluations (hematology, clinical chemistry, 
and urinalysis). 
3.4 
Exploratory endpoints 
The exploratory endpoints for the study include: 
• Change from baseline in healthcare utilization for migraine  
• Product acceptability questionnaire. 

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Exploratory efficacy endpoints include:  
• Change from baseline in rate of freedom from headache pain at 2 hours after 
INP104 administration 
• Change from baseline in Most Bothersome Symptom (MBS) at 2 hours after 
INP104 administration  
• Change from baseline in frequency and severity of headache pain (over other time 
points) after INP104 administration 
• Change from baseline in MBS at other time points after INP104 administration 
• Change from baseline in frequency and severity of migraine (measured by 
headache pain, nausea, phonophobia and photophobia) by diary 
• Incidence of pain relapse within 24 and 48 hours after INP104 administration 
• Change from baseline in MIDAS and HIT-6 questionnaires 
• Change in concomitant migraine medication use. 

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4 STUDY POPULATION 
4.1 
Population size 
Approximately 300 to 340 subjects in the United States will be enrolled in the study at 
approximately 40 study sites. All 300 to 340 subjects are planned for the 24-week 
treatment period (the primary safety assessment period), to ensure that at least 150 will 
complete that period. At least 80 of these subjects will be enrolled into an extension of 
the treatment period to ensure 60 will complete a total of 52 weeks of treatment. At least 
30 subjects of each gender will be enrolled in the initial 300 to 340 subjects enrolled. 
4.2 
Inclusion criteria 
In order to be eligible for participation in this study, potential subjects must meet all of 
the following criteria: 
1. Adult male and females, 18 to 65 years of age (inclusive) at the time of screening. 
2. Documented diagnosis of migraine (by ICHD3b criteria) with or without aura, with at 
least 2 attacks/month for previous 6 months. 
3. Must have experienced at least 2 migraine attacks as defined by ICHD3b criteria 
during the 28 days of screening prior to Visit 2. All migraines experienced during the 
screening period must be recorded in the diary. Subjects who do not meet this 
criterion cannot be rescreened. 
4. Must have completed daily diary entries on 23 of the 28 days of screening prior to 
Visit 2. 
5. Participants must be in good general health, with no significant medical history 
(excluding migraine), have no clinically significant abnormalities on physical 
examination or laboratory value at baseline visit. 
6. Negative urine drug screen at screening. Positive urine drug screens with a medical 
explanation may be discussed with the Medical Monitor for potential inclusion. 
7. Participants must have the ability and willingness to attend the necessary visits to the 
study center. 
8. Written informed consent must be given, signed, and documented prior to entry into 
the study. 
9. Female subjects of childbearing potential must agree to use adequate contraception 
(as defined in the protocol) during the study and for 30 days after the last dose of 
study drug. 
10. Male subjects and their partners must agree to use effective contraception (as defined 
in the protocol) during the study and for 30 days after study completion. Males must 
refrain from sperm donation for 30 days after study completion. 

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4.3 
Exclusion criteria 
In order to be eligible for participation in this study, potential subjects may not meet any 
of the following criteria: 
1. Subjects with trigeminal autonomic cephalalgias (including cluster headache, 
hemicrania syndromes and short-lasting, unilateral, neuralgiform headache attacks 
with conjunctival injection and tearing), migraine aura without headache, hemiplegic 
migraine or migraine with brainstem aura (previously referred to as basilar 
migraines), as per ICHD3b criteria. 
2. Subjects with chronic migraines, medication overuse headache or other chronic 
headache syndromes (and/or subjects with ≥ 15 headache days per 28 days in 
screening), as per ICHD3b criteria. 
3. Subjects with status migrainosus in the 3 months prior to screening or during 
screening period. 
4. Positive test for human immunodeficiency virus (HIV), hepatitis B surface antigen 
(HBsAg), or hepatitis C antibodies (HCV). 
5. Subjects with ischemic heart disease or subjects who have clinical symptoms or 
findings consistent with coronary artery vasospasm, including Prinzmetal’s variant 
angina. 
6. Subjects with significant risk factors for coronary artery disease, current use of 
tobacco products, smoking history (of at least 10 or more cigarettes per day within the 
last 12 months prior to screening), or history of diabetes, known peripheral arterial 
disease, Raynaud’s phenomenon, sepsis or vascular surgery (within 3 months prior to 
study start), or severely impaired hepatic or renal function. Subjects with a history of 
hypertension may be enrolled if the hypertension is stable and well-controlled on 
current therapies for > 6 months, provided no other risk factors for coronary artery 
disease are present. 
7. Subjects with potentially unrecognized coronary arterial disease as demonstrated by 
history, physical examination, or screening ECG. 
8. Abnormal, clinically significant laboratory tests at screening, including but not 
limited to: 
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2X upper 
limit of normal. 
• Serum creatinine > 1.5X upper limit of normal. 
9. Any acute illness or uncontrolled infection within 28 days prior to Day 1; however, 
potential subjects who have experienced a mild self-limiting illness that has resolved 
at least 7 days prior to Day 1 may be included. 
10. Subjects with recurrent sinusitis or epistaxis, or chronic rhinosinusitis with nasal 
polyp (unless surgically resolved > 3 months prior to screening). 

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11. Significant nasal congestion, physical blockage in either nostril, significantly deviated 
nasal septum, septal perforation, or any pre-existing upper nasal mucosal abnormality 
on endoscopy scoring 1 or more (except score 1 allowed for mucosal edema). 
12. Subjects who have previously shown hypersensitivity to ergot alkaloids or any of the 
ingredients in the drug product. For ingredients, refer to the INP104 Investigational 
Brochure. 
13. Subjects who have previous documented failure of response to IV DHE for treatment 
of migraine. 
14. Use of any triptan or ergot-based medication or medication strongly or moderately 
affecting CYP3A4 Cytochrome P450 metabolic pathway within 2 days prior to the 
Baseline Visit (Visit 2). This exclusion criteria does not apply to prescription 
contraceptives. 
15. Use of any medications prohibited by protocol (see Section 4.4). 
16. Use of > 12 days per month of triptan or ergot-based medication in the 2 months prior 
to screening or during screening period. 
17. Use of barbiturates/barbiturate containing compounds or opiates (including tramadol 
or tapentadol) greater than 7 days per month (cumulative) or unstable usage pattern in 
the 2 months prior to screening or during screening. 
18. History or presence of alcoholism or drug abuse within the 2 years prior to the first 
study drug administration or a positive result on the urine drug test at the Screening 
Visit (positive urine drug screens with a medical explanation may be discussed with 
the Medical Monitor for potential inclusion). 
19. Females who are pregnant, or planning to get pregnant, or are lactating while 
participating in this clinical study. 
20. Treatment with another investigational drug, investigational device, or approved 
therapy for investigational use within 28 days or 5 half-lives (whichever is longer) 
prior to screening is prohibited. 
21. Subjects with any underlying physical, psychological, or medical condition that, in 
the opinion of the investigator, would make it unlikely that they would comply with 
the study. 
22. Failure to satisfy the Investigator of fitness to participate for any other reason. 
4.4 
Concomitant medications 
A list of permitted concomitant migraine medications is provided in Appendix 1. 
All medications including over-the-counter medications and herbal supplements taken 
during the 28 days prior to the Screening Visit (Visit 1) and continuing through the 
screening period will be recorded and reviewed by the Investigator to determine whether 
the subject is suitable for inclusion. In addition, all migraine medications taken within 12 
months before the Screening Visit will be recorded.  

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Routine migraine prevention treatment (e.g., beta-blocker or tricyclic antidepressant) may 
be continued if stable > 30 days prior to screening unless they are contraindicated for 
concomitant use with an ergot derivative. Other acute migraine treatment may be used in 
the screening period. 
While on study, only non-ergot, non-triptan acute migraine treatment may be used and 
only after 2 hours from study drug administration has elapsed. After 2 hours, non-ergot, 
non-triptan analgesics may be used as rescue medication for subjects who still have 
headache pain. Alternatively, a single further dose of Investigational Product may be 
taken at 2 hours. The use of such rescue medications must be recorded in the diary. 
Use of any triptan or ergot (other than IP) acute migraine treatment within 2 days prior to 
Baseline Visit (Visit 2) and through end of study treatment is prohibited. 
Intranasal use of saline is allowable. Intranasal use of corticosteroids and antihistamines 
are allowable if usage pattern is stable for at least 2 months prior to screening and 
throughout trial. Other concomitant medications via intranasal route are prohibited during 
trial. 
Macrolide antibiotics, protease inhibitors, and other medications affecting the CYP3A4 
metabolite pathway (including verapamil) are prohibited, with the exception of oral 
contraceptives, during the course of this study (Appendix 2). 
Peripheral vasoconstrictors are prohibited, as well as nicotine from smoking or other 
sources. 
Caution should be advised when a selective serotonin reuptake inhibitor (SSRI) is being 
used due to rare events with weakness, hyperreflexia and incoordination when 5-HT 
agonists have been co-administered with SSRIs (e.g., fluoxetine, fluvoxamine, 
paroxetine, sertraline). There have been no spontaneous reported cases of drug interaction 
between SSRIs and Migranal Nasal Spray or D.H.E. 45 for Injection. 
Beta-blockers are allowed (if being taken for migraine prophylaxis, but not for 
hypertension), however caution should be advised due to their potential to block the 
vasodilatory properties of epinephrine. 
All medications including over-the-counter medications and herbal supplements (other 
than the IP) taken by subjects during the course of the study will be recorded. 
Concomitant medications will be recorded and will be coded using the most current 
World Health Organization (WHO) drug dictionary. 
4.5 
Diet, activity, and other restrictions 
The are no diet or activity restrictions; however, dosing with INP104 more than twice in 
24 hours, and more than 3 times within a 7-day period is not allowed. 

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4.6 
Contraceptive requirements 
Subjects must be willing to comply with the contraceptive requirements of the study as 
detailed below: 
(a) Female subjects 
Women will be defined as of non-childbearing potential if post-menopausal (12 months 
of spontaneous amenorrhea or 6 months of spontaneous amenorrhea with FSH levels 
> 40 mIU/ml or 6 weeks postsurgical bilateral oophorectomy or hysterectomy). 
Women of childbearing potential (WOCBP) must not become pregnant and must use 
adequate contraceptive during the study and for 30 days after the last dose of IP. 
Adequate contraception is defined as one of: 
• Birth control pills 
• Depo Shot or injectable birth control (e.g., Implanon) 
• Intrauterine Device 
• Condom with spermicide 
• Diaphragm with spermicide 
• NuvaRing® 
• Documented evidence of surgical sterilization at least 6 months prior to Screening 
Visit, i.e., tubal ligation or hysterectomy for women or vasectomy of a male 
partner. 
These allowed methods of contraception are only effective when used consistently, 
correctly, and in accordance with the product label. The Investigator is responsible for 
ensuring subjects understand how to properly use these methods of contraception. 
(b) Male subjects 
To prevent pregnancy in a female (WOCBP) partner, male subjects must agree to use 
effective contraception (as defined in the protocol) during the study and for 30 days after 
study completion for all sexual intercourse (see Section 8.8).  
Males must also not donate sperm during the study or for 30 days after study completion. 

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5 INVESTIGATIONAL PRODUCTS 
The IP is INP104. INP104 is a drug-device combination product that includes a drug 
component: DHE drug product and a device component: I123 POD® Device. Specific 
instructions regarding the storage, preparation, and administration of INP104 are 
provided in the Investigator’s Brochure, Pharmacy Manual, and Instructions For Use 
(IFU). The IFU will be provided to all participating subjects. 
5.1 
Study medication identification 
The device component, I123 POD device, is a handheld, manually actuated, metered-
dose administration device intended to deliver a drug solution to the nasal cavity. 
The drug component, DHE drug product, is a 3.5-mL amber glass vial filled with 1 mL of 
DHE 4 mg/mL solution. The DHE drug product vial attaches to the I123 POD device 
forming the fully assembled INP104 product. A single manual actuation of INP104 by 
the user results in delivery of the DHE solution to the nasal cavity of the user. INP104 is 
designed to be disposed of after single-dose drug delivery of 1.45 mg DHE delivered as 
two actuations, one to each nostril. 
Additional information about INP104 and its components are provided in the INP104 
Investigational Brochure. 
5.2 
Dosage and administration 
INP104 will be self-administered. The dose will be split between nostrils, with one spray 
in each nostril delivering a target total dose of 1.45 mg DHE. 
Subjects will be instructed to use INP104 when they experience a recognizable migraine. 
Study drug should be the first acute treatment medication administered unless daily or 
weekly dosage limits have been reached. INP104 should not be used as second-line 
therapy for acute migraines. 
Rescue medication: While on study, only non-ergot, non-triptan acute migraine 
treatment may be used and only after 2 hours from study drug administration has elapsed. 
After 2 hours, non-ergot, non-triptan analgesics may be used as rescue medication for 
subjects who still have headache pain. The use of such rescue medications must be 
recorded in the diary. Subjects will be instructed to use no more than 2 doses of INP104 
within a 24-hour period, 3 doses in a 7-day period, and 12 doses per 4-week period. 
5.2.1 
Study supplies 
The Sponsor will supply all IP through a third-party vendor, Almac Group (Craigavon, 
Northern Ireland), to the investigational site(s). The DHE drug product provided for this 
study will be manufactured under current Good Manufacturing Practices, will be subject 
to release, and will be suitable for human use. The I123 POD device will be 
manufactured under controlled conditions and assembled into kits under clean room 
conditions. 

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Almac will be responsible for the packaging and labelling of the IP. The Sponsor will be 
responsible for providing details of batch numbers, safety, and stability data. 
Almac will label the products in accordance with local regulatory requirements. 
5.2.2 
Investigational product storage, dispensing, and accountability 
Investigational product must be stored at controlled room temperature, between 15°C and 
25°C, in original packaging as provided (not refrigerated or frozen) upon receipt at the 
investigational site. A record will be maintained by the investigational site, which will 
account for all dispensing and return of any used and unused IP. At the end of the study, 
the IP will be reconciled, and a copy of the record given to the Study Monitor. 
Upon completion of the study, any surplus IP will be returned to an appropriate storage 
facility as indicated by the Sponsor. If no supplies remain, this will be documented in the 
disposition record. 
The Investigator will be fully responsible for the security, accessibility, and storage of the 
IP while it is at the investigational site. 
Subjects may be assigned a POD training device to assist with training. The training 
device will not contain any study medication, however, while training with the POD 
device, subjects may be exposed to HFA gas (the propellant of the POD device) if the 
device is actuated while the tip is placed in the naris. 
Following training on the use of INP104 by an authorized Sponsor trainer, the 
Investigator is responsible for the education of study staff and study subjects in the 
correct administration of the IP. 

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6 STUDY PROCEDURES 
6.1 
Medical history 
Medical history (focused on migraine diagnosis) and concomitant medication use 
(especially for the prevention or treatment of migraine; see Section 4.4) will be recorded 
at screening and will include the collection of previous and current illnesses and 
surgeries, as well as a medication history. Any ongoing events should be recorded as 
baseline medical history. 
Information about healthcare utilization over the previous 12 months (for migraine) will 
be collected if available. 
6.2 
Demographics 
Date of birth, age (calculated), sex, ethnicity, and race will be recorded at screening. 
6.3 
Body weight and height or body mass index 
Body mass index is calculated by dividing the subject’s body weight in kilograms by the 
subject’s height in meters squared (BMI = kg/m2). Body height (centimeters) and body 
weight (kilograms) will be measured at the time points delineated in the study schedules. 
Body weight and height will be obtained with the subject’s shoes and jacket or coat 
removed. 
6.4 
Safety assessments 
This study will assess the safety and tolerability of INP104. Safety will be determined by 
evaluating physical examination findings, nasal endoscopy, and testing of olfactory 
function, ECGs, vital signs, clinical laboratory parameters, concomitant medication 
usage, and AEs. 
6.4.1 
Physical examination 
Complete physical examinations may be performed by a licensed physician (or by a nurse 
practitioner or physician’s assistant delegated by the Principal Investigator if permitted 
by local law), at the time points specified in Table 7-1. 
Complete physical examinations include: general appearance, head, ears, eyes, nose, 
throat, dentition, thyroid, chest (heart, lungs), abdomen, skin, neurological, extremities, 
back, neck, musculoskeletal, and lymph nodes. 
Directed physical examinations include: head, ears, eyes, nose, throat, chest (heart, 
lungs), abdomen, skin, musculoskeletal, lymph nodes, and any pertinent system based on 
any prior findings. 
Physical examinations may be performed at various unscheduled time points if deemed 
necessary by the Investigator. 

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6.4.2 
Nasal endoscopic examination 
Nasal endoscopic examinations will be performed by a board certified/board eligible 
otolaryngologist at the specified visits (or within specified nasal endoscopy time 
windows). 
The nasal endoscopy will include endoscopic evaluation of both the lower and upper 
nasal mucosa, using either a flexible or rigid 30-degree nasal endoscope (with a diameter 
between 2.5 and 4 mm), with special attention paid to identifying any trauma, 
inflammation, crusting, epistaxis, ulceration, or other changes to the mucosa as listed in 
Table 6-1. Every attempt must be made to ensure the same investigator assess the same 
subject at each visit with the same equipment. 
Nasal endoscopy will be performed in all subjects during Screening (before visit 2) and 
then at 4, 8, and 12 weeks. If no adverse changes to the upper nasal cavity mucosa are 
detected on nasal endoscopy, and the subjects have not reported any AEs related to the 
nose, then all subjects will have further nasal endoscopy at 24 weeks and at 36 and 
52 weeks for those continuing through 52 weeks of treatment. For those subjects who are 
noted to have clinically significant changes on nasal endoscopy or have reported a 
clinically significant AE related to the nose, and nasal endoscopy will be repeated at 
2-week intervals until the change has resolved or been otherwise explained. If the 
changes have not resolved or have worsened at the first repeat endoscopy, treatment 
should be discontinued, unless changes are otherwise explained and approved by medical 
monitor to continue treatment. 
Otolaryngologists will conduct the nasal endoscopy and will follow the study Nasal 
Examination Manual (Appendix 3) and scoring grid outlined in Table 6-1.  
Table 6-1:  Quantitative Scoring Scale for Evaluation of the Nasal Mucosa 
(QSS-NM) 
Finding 
Grading Criteria 
Score 
Mucosal Irritation 
0 = None 
0 
Grade 1A = focal irritation 
1 
Grade 1B = superficial mucosal erosion 
2* 
Grade 2 = moderate mucosal erosion 
3* 
Grade 3 = ulceration 
4* 
Grade 4 = septal perforation 
5* 
Epistaxis (frank bleeding or 
dried blood clot) 
None 
0 
Mild = self-limited 
1 
Moderate = significant, prevents daily activity 
2* 
Severe = Emergency Room visit or hospitalization 
3* 

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Table 6-1:  Quantitative Scoring Scale for Evaluation of the Nasal Mucosa 
(QSS-NM) 
Finding 
Grading Criteria 
Score 
Mucosal Edema 
 
None 
0 
Mild 
1 
Moderate 
2* 
Severe 
3* 
Nasal Discharge 
None 
0 
Mild 
1 
Moderate 
2* 
Severe 
3* 
Mucosal Crusting 
None 
0 
Mild 
1 
Moderate 
2* 
Severe 
3* 
* A total score exceeding 7 (summed from left + right upper nasal cavity scores), or an individual score of 2 
or more on any one of the 5 items at any time point will trigger a repeat examination 2 weeks later. 
All endoscopic examinations will be scored and summed for the upper nasal cavity (left 
side + right side) using the scale above. The lower nasal cavity scores will not be 
summed or used for making study treatment discontinuation decisions. Follow-up of any 
changes in the lower nasal space will be at the discretion of the otolaryngologist. 
Findings (in the upper nasal cavity) causing a change in score as defined above will 
require a follow-up endoscopy within 14 days. The purpose of the endoscopic 
examination is to ensure subjects are not experiencing untoward events that may be 
associated with the POD delivery of DHE, and that any subject with endoscopic findings 
considered clinically significant will be followed for 28 days or until resolution (refer to 
Section 8.7). The purpose of the scale is to quantify changes from baseline. 
Procedures conducted by otolaryngologists are not required to be carried out on the same 
day as those carried out by the investigational site, provided all study procedures are 
carried out within the specified visit windows. 
Further details of the nasal endoscopy procedure and scoring can be found in the Nasal 
Examination Manual (Appendix 3). 
6.4.3 
Olfactory changes (UPSIT) 
Olfactory changes will be assessed using the University of Pennsylvania Smell 
Identification Test (Doty 1984), as described in the Nasal Examination Manual 
(Appendix 3). 

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The full test consists of 4 booklets with a total of 40 scratch-and-sniff odorants to 
correctly identify in a multiple-choice format. The full 40-question examination will be 
administered at screening and at 0, 12, and 24 weeks. Absent any significant changes in 
test scores at any of these time points (where a significant change will be defined as 
greater than or equal to a 5-point reduction in absolute test score compared to averaged 
screening and baseline UPSIT scores for that subject), thereafter the test will be 
administered at 36 and 52 weeks for the subset of subjects enrolled through 52 weeks of 
the study. A reduction in absolute test score of greater than or equal to 5 points on any 
single test will be recorded as an AE and will trigger a repeat test 4 weeks later. If the 
UPSIT score is still 5 or more points below baseline for that subject 4 weeks later, the 
subject will be discontinued from any further treatments with INP104 but will continue to 
return for scheduled study visits until olfaction returns to baseline or they have completed 
their participation in the study (whichever occurs sooner). 
6.4.4 
Electrocardiogram 
A 12-lead ECG will be collected at the time-points delineated in the study schedule 
Table 7-1. Additional ECG monitoring may be performed at other times if deemed 
necessary. 
ECGs will be performed with subjects in a supine position. Subjects must be in this 
position for at least 5 minutes before the reading is taken. When the time of ECG 
monitoring coincides with a blood draw, the ECG will be conducted first. 
All ECG tracings will be reviewed by the PI or his/her designate. 
6.4.5 
Vital signs 
Subjects should rest for at least 3 minutes prior to and during the collection of vital signs. 
Blood pressure and heart rate should be measured when the subject is in a supine or 
seated position. When the time of vital signs measurement coincides with a blood draw, 
the vital signs will be taken before the scheduled blood draw. 
Additional vital signs may be performed at other times if deemed necessary. 
6.4.6 
Laboratory investigations 
Safety laboratory tests (hematology, chemistry, and urinalysis) will be performed at the 
time points specified in Table 7-1. 
Medically indicated laboratory tests (emergency) can be conducted at a local laboratory, 
but repeat and unscheduled tests should be conducted at the central laboratory. 
6.4.6.1 
Hematology and serum chemistry 
A blood sample will be taken from each subject for hematology and serum chemistry 
analysis at the time points delineated in the study schedule in Table 7-1. Laboratory 
parameters will include: 

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• hematology 
• hemoglobin 
• hematocrit 
• erythrocytes 
• platelets 
• leukocytes with differential (including eosinophils, neutrophils, basophils, 
lymphocytes, monocytes, and reticulocytes) 
Serum chemistry 
• blood urea nitrogen 
• creatinine 
• total bilirubin and direct bilirubin 
• urate 
• albumin 
• total protein 
• alkaline phosphatase 
• creatine kinase 
• gamma-glutamyl transferase 
• aspartate aminotransferase 
• alanine aminotransferase 
• glucose 
• sodium 
• potassium 
• calcium 
• chloride 
• phosphate 
• bicarbonate 
Additional clinical laboratory tests may be performed at other times if deemed necessary. 
6.4.6.2 
Urinalysis 
A urinalysis test (dipstick) will be performed for each subject. Urinary analyses will be 
performed at the Screening Visit and at other times according to the study schedule 
(Table 7-1). 

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Macroscopic 
• pH 
• specific gravity 
• protein 
• glucose 
• ketones 
• total bilirubin 
• occult blood 
• nitrite 
• urobilinogen 
• leukocytes 
If an abnormality is noted for protein, blood, nitrite or leukocyte esterase, a microscopic 
examination of red blood cells, white blood cells, bacteria, and casts will be performed. 
6.4.6.3 
Serology 
Serologic testing for HBsAg, anti-HCV, and HIV antibody testing will be performed at 
the Screening Visit. 
6.4.6.4 
Urine drug screen 
A urine drug screen will be performed at the Screening Visit. This will include screening 
for: 
• Cocaine 
• Amphetamines 
• Barbiturates 
• Opiates 
6.4.6.5 
Pregnancy testing 
A serum pregnancy test will be performed at screening and urine pregnancy tests will be 
performed at all other study visits for women of childbearing potential only, according to 
the study schedule (Table 7-1). Serum FSH will be measured in post-menopausal women 
(who have not had a period for at least 12 months). 

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6.5 
Efficacy assessments 
6.5.1 
MIDAS and HIT-6 questionnaires 
The MIDAS (Appendix 4) and HIT-6 (Appendix 5) Questionnaires provide tools for the 
assessment of headache-related disability. The MIDAS questionnaire (Stewart 1999) 
includes 5 scored questions that measure the number of days in the past 3 months that the 
subject experienced limitations in daily activities resulting from migraine. The HIT-6 
questionnaire (Yang 2011) includes 6 scored questions that measure the impact 
headaches have on activities of daily living, with 3 of the questions asking for data from 
the past 4 weeks. These questionnaires will be completed by study subjects at baseline, 
selected study visits (Table 7-1), and end-of-treatment (EOT). 
6.5.2 
Migraine diary 
The primary modality for diary data collection will be a validated electronic diary 
(eDiary), though a paper diary may be implemented as a back-up if needed (eg, if 
technology issues interfere with eDiary data collection). An eDiary (or, alternatively, a 
paper diary if needed) entry will be completed by subjects for every migraine they 
experience during the study, whether or not they treat it. 
At least 2 such migraines must be experienced in the 28-day screening period, and the 
subject must record details about them in the migraine diary. Only subjects who 
successfully complete their diary during at least 2 migraines during the screening period 
will be enrolled. 
Once enrolled, subjects will record all headaches experienced. When a subject 
experiences a recognizable migraine, it will be recorded in the diary and the subject will 
take the study medication (or alternative, if they have already reached their maximum 
permitted use of IP). Subjects will answer a series of questions about the severity of 
headache and presence and severity of associated symptoms (nausea, phonophobia, and 
photophobia). These questions will be used to determine if the headache qualifies as a 
migraine as per ICHD-3b. The same questions will be answered and recorded in the diary 
at various time points post-dosing. 
If the migraine has not resolved at 2 hours post IP administration, subjects are allowed to 
take their usual (non-ergot, non-triptan) migraine treatment and will then continue 
scoring the headache diary up to 48 hours. 
At each visit, staff will check that all migraines have been recorded in the diary and 
whether the subject has any questions or concerns. 
6.5.3 
Subject’s impression of INP104 usability/effectiveness 
A questionnaire asking subjects to assess the usability and effectiveness of the INP104 
product will be administered at the 24-week and 52-week time points (Appendix 6). 
 

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7 STUDY SCHEDULE 
7.1 
Study flow 
A tabular display of study events is provided in Table 7-1. 
Table 7-1:  Time and Event Schedule 
Period 
Screening 
Baseline 
Treatment Period 
Follow-up 
Week 
-4 
0 
4 
8 
12 
16 
20 
24/EOT 
261 
36 
42 
52/EOT 
54 
Days 
-28 
0 
28 
56 
84 
112 
140 
168 
182 
252 
294 
364 
378 
Window (days) 
-12 
 
±5 
±5 
±5 
±5 
±5 
±5 
±10 
±10 
±10 
±10 
+ 14 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9a 
9b 
10 
11 
12 
Informed consent 
X 
 
 
 
 
 
 
X8 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Confirmation of eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
Vital signs2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG2 
X 
X 
 
 
 
 
 
X9 
 
 
 
X9 
 
Physical examination 
X 
 
 
 
 
 
 
X 
X 
 
 
X 
X 
Directed exam 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
 
 
Nasal endoscopy3 
X3 
 
X 
X 
X 
 
 
X 
 
X 
 
X 
 
UPSIT4 
X 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
MIDAS and HIT-6 
X 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
Hematology and chemistry 
labs5 
X 
X 
 
 
X 
 
 
X 
X 
X 
 
X 
X 
Urinalysis5 
X 
X 
 
 
X 
 
 
X 
X 
X 
 
X 
X 
Serology  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test6  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum FSH7 
X 
 
 
 
 
 
 
 
 
 
 
 
 

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Table 7-1:  Time and Event Schedule 
Period 
Screening 
Baseline 
Treatment Period 
Follow-up 
Week 
-4 
0 
4 
8 
12 
16 
20 
24/EOT 
261 
36 
42 
52/EOT 
54 
Days 
-28 
0 
28 
56 
84 
112 
140 
168 
182 
252 
294 
364 
378 
Window (days) 
-12 
 
±5 
±5 
±5 
±5 
±5 
±5 
±10 
±10 
±10 
±10 
+ 14 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9a 
9b 
10 
11 
12 
Diary training & distribution 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Diary check 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Training on POD  
 
X 
 
 
 
 
 
 
 
 
 
 
 
Diary Review 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Dispense IP 
 
X 
X 
X 
X 
X 
X 
 X10 
 
X 
X 
  
 
Collect unused IP 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
AE collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant (and rescue) 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Diary collection 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
IP questionnaire (usability 
and effectiveness) 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
Abbreviations: AE = adverse event; ECG = electrocardiogram; EOT = end-of-treatment; FSH = follicle stimulating hormone; HIT-6 = Headache Impact Test; 
IP = investigational product; MIDAS = Migraine Disability Assessment; POD = Precision Olfactory Delivery; UPSIT = University of Pennsylvania Smell 
Identification Test 
1.   Follow-up visit for subjects not continuing through 52 weeks treatment 
2.   Participants should be rested in a supine position for ≥ 5 minutes prior to recording of ECGs. Participants should be seated or supine for ≥ 3 minutes prior to 
taking vital signs. ECGs and vital signs should be assessed prior to blood draws. 
3.   Nasal endoscopy will be performed by a trained otolaryngologist within visit windows as specified. The baseline endoscopy may be performed at any time 
between Visit 1 and Visit 2. Procedures conducted by otolaryngologists are not required to be carried out on the same day as those carried out by the 
investigational site provided all study procedures are carried out within the specified visit windows. Off schedule assessments triggered by findings on the nasal 
endoscopy, or as a result of reported AEs are specified in Section 6.4.2 of this protocol. 
4.   UPSIT testing will be performed at visits as specified. Off schedule assessments triggered by findings on the UPSIT, or as a result of reported AEs are specified 
in Section 6.4.3 of this protocol. 
5.   Blood samples will be collected for hematology and chemistry tests, and a urine sample will be collected for urinalysis. 
6.  Women of childbearing potential only. 
7.   Post-menopausal women only. 
8.   Subjects continuing on to 52 weeks of treatment will be re-consented at their 24-week visit. 
9.  If ECG at Week 24 (for subjects ceasing treatment at that visit) or Week 52 shows potentially significant abnormalities, this should be repeated at Week 26 or 
Week 54, respectively.  
10. IP dispensed to subjects continuing on to 52 weeks of treatment only. 

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7.2 
Study activities 
7.2.1 
Consent and screening 
Prior to enrolling in the study, and before performing any study-related procedures, 
potential subjects will attend a Screening Visit within 28 days (-12 days) of the start of 
the treatment period, at which time they will be provided with the Informed Consent 
Form. Prior to being asked to sign the consent form, subjects will be given time to review 
study information and ask any questions. Subjects continuing on through 52 weeks of 
treatment will be reconsented at their 24-week visit. This option will be offered to those 
subjects complying with diary completion criteria (at least 80% compliance) and 
recording on average a minimum of 2 migraine diaries per 4-week period during the 
period from 12 to 24 weeks (i.e., each individual subject records at least 6 migraine 
attacks over the 12-week period). Once approximately 80 subjects have agreed to 
continue through to 52 weeks, to allow for 60 to complete this period of the study, no 
further subjects will be enrolled in this period. 
After the consent form is signed, subjects will be sequentially assigned a subject 
identification number. The subject identification number will remain the same throughout 
the study. Screening assessments will be carried out as follows: 
• Review of all prior and concomitant medications for the 28 days prior to 
screening (12 months for migraine medications), medical history, and 
inclusion/exclusion criteria 
• Measurement of height and weight 
• Recording demographic information 
• Complete physical examination 
• Nasal endoscopy (to occur once anytime between the Screening and Baseline 
Visits) 
• UPSIT evaluation, MIDAS, and HIT-6 questionnaires 
• Vital signs (body temperature, blood pressure, heart rate, and respiratory rate) 
• 12-lead ECG 
• Clinical laboratory testing (hematology, serum chemistry and urinalysis) 
• HIV, Hepatitis B, and Hepatitis C screen 
• Urine drug screen 
• Serum pregnancy test (women of childbearing potential only) 
• Follicle stimulating hormone (FSH; post-menopausal women only) 
• Collection of pre-treatment AEs 
• Distribution of the migraine diary and training in its use 

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Data from screen failures (basic demographics, migraine history and reason for screen 
fail) will be recorded in the electronic case report form (eCRF). 
7.2.2 
Baseline 
Subjects who qualify for inclusion in the study but are not enrolled within 28 days 
(+12 days), may be re-consented, assigned a new screening number, and re-screened 
once. Subjects who do not qualify for inclusion in the study for reasons other than failing 
to meet screening period migraine attack requirement may be re-screened once if 
approved by the study Medical Monitor. Subjects who do not qualify for inclusion in the 
study because of failure to meet screening period migraine attack requirement may not be 
re-screened. 
Enrolled subjects will undergo the following procedures to collect baseline (Day 0) data: 
• Review to determine whether the subject continues to satisfy the study inclusion 
and exclusion criteria (including diary record of at least 2 migraines during 
screening period) 
• 12-lead ECG 
• Vital signs (body temperature, blood pressure, heart rate, and respiratory rate) 
• Directed physical examination 
• UPSIT evaluation, MIDAS and HIT-6 questionnaires 
• Clinical laboratory testing (hematology, serum chemistry, and urinalysis) 
• Urine pregnancy test (women of childbearing potential only) 
• Pre-treatment AEs 
• The subject’s concomitant medications, including non-prescription medications 
including complementary medicines and herbal preparations 
• Demonstration and training in use of POD device 
• Dispensation of IP. 
7.2.3 
Treatment period visits 
Treatment period visits will occur on Week 4 (±5 days), Week 8 (±5 days), 
Week 12 (±5 days), Week 16 (±5 days) and Week 20 (±5 days), and additionally at 
Week 24 (±5 days), Week 36 (±10 days) and Week 42 (±10 days) for those subjects who 
receive 52 weeks of treatment. The following procedures will be performed at each visit: 
• Vital signs (body temperature, blood pressure, heart rate, and respiratory rate) 
• Directed physical examination 
• Nasal endoscopy performed at selected visits as specified in Table 7-1 

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• UPSIT evaluation, MIDAS and HIT-6 questionnaires (at selected visits as 
specified in Table 7-1) 
• Clinical laboratory testing (hematology, serum chemistry, and urinalysis) (at 
selected visits as specified in Table 7-1) 
• Urine pregnancy test (women of childbearing potential only) 
• Adverse events 
• The subject’s concomitant medications, including rescue medications, non-
prescription medications including complementary medicines and herbal 
preparations 
• Check of the migraine diary 
• Collect unused IP and dispense new supply. IP to be dispensed at 
Week 24 (±5 days) only for subjects continuing to 52 weeks of treatment. 
7.2.4 
End-of-treatment visits 
End-of-treatment (EOT) visits will take place at Week 24 (± up to 5 days) for those 
subjects who receive 24 weeks of treatment and at Week 52 (± up to 10 days) for those 
subjects who receive 52 weeks of treatment. In case a subject is withdrawn from 
treatment at any time (Early Termination), these procedures should be undertaken and the 
subject asked to return 2 weeks later for an early termination follow-up. The following 
procedures will be performed at each EOT visit: 
• Body weight 
• Vital signs (body temperature, blood pressure, heart rate, and respiratory rate) 
• 12-lead ECG 
• Complete physical examination 
• Nasal endoscopy 
• UPSIT evaluation, MIDAS and HIT-6 questionnaires 
• Clinical laboratory testing (hematology, serum chemistry, and urinalysis) 
• Urine pregnancy test (women of childbearing potential only) 
• Adverse events 
• The subject’s concomitant medications, including non-prescription medications 
including complementary medicines and herbal preparations 
• Check and collection of the migraine diary. The diary should only be collected at 
Week 24 from subjects who are not continuing to 52 weeks of treatment.  
• Extension informed consent for subjects continuing to 52 weeks of treatment 
• INP104 Product Questionnaire 

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• Return of unused study medication. 
7.2.5 
Post-treatment follow-up visits 
Safety follow-up visits will take place 2 weeks following the EOT visits, at Week 26 
(+ up to 10 days) for those subjects who only receive 24 weeks of treatment and at 
Week 54 (+ up to 14 days) for those subjects who receive 52 weeks of treatment, or 
2 weeks after last dose for subjects who have an early termination from the study. The 
following procedures will be performed at each safety follow-up visit: 
• Vital signs (body temperature, blood pressure, heart rate, and respiratory rate) 
• Complete physical examination 
• Clinical laboratory testing (hematology, serum chemistry and urinalysis) 
• 12 lead ECG, if preceding ECG showed a potentially clinically significant 
abnormality 
• Urine pregnancy test (women of childbearing potential only) 
• Adverse events 
• The subject’s concomitant medications, including non-prescription medications 
including complementary medicines and herbal preparations. 

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8 SAFETY 
In this study, AEs will be reported by all subjects from time of consent until the 
completion of the last study follow-up visit. Serious adverse events will be reported in all 
subjects (enrolled and not enrolled) from the time of consent. However, AEs recorded 
during the screening period or prior to first dose of IP will not be listed as treatment-
emergent AEs (TEAEs). TEAEs will be evaluated from first exposure to IP until the end 
of study visit. Adverse events that are ongoing at the end of study visit will be marked as 
ongoing on the AE eCRF page. 
Specific TEAEs of olfactory test abnormal (measured by UPSIT) or a significant change 
in Quantitative Scoring Scale for Evaluation of the Nasal Mucosa (QSS-NM, as detected 
on nasal endoscopy) – as outlined in the Nasal Examination Manual (Appendix 3) will be 
recorded and the following medication stopping rules applied: 
• A TEAE will be recorded for any change in UPSIT score of 5 points or more. If 
the change is unresolved at a repeat UPSIT 4 weeks later, study medication will 
be discontinued. 
• A TEAE will be recorded for any QSS-NM score of ≥ 2 in any one criterion, or a 
total score > 7 summed from left + right upper nasal cavity scores. If the change 
remains unresolved at the first follow-up endoscopy 2 weeks later, study 
medication will be discontinued. 
All spontaneously volunteered and enquired for, as well as observed, AEs will be 
recorded in the subject’s medical records and the eCRF. Migraine headaches will be 
recorded separately from the AE eCRF pages; they will not be recorded as AEs but as 
manifestations of the underlying disease unless they are more severe than generally 
experienced by that subject. 
The primary safety analysis will take place when all subjects have completed at least 
24 weeks of treatment. Additional safety analyses will also be performed when all 
subjects who undergo 52 weeks of treatment have completed their treatment. 
8.1 
Definition of an adverse event 
As stated above, for the purposes of this study, a migraine will not meet the 
definition of an AE. 
An AE is any event, side-effect, or other untoward medical occurrence that is temporally 
associated with a study intervention, whether or not considered related to the study 
intervention. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
Events meeting the definition of an AE include: 

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• Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not 
related to progression of underlying disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either 
an increase in frequency and/or intensity of the condition. 
• New condition detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae. 
• "Lack of efficacy" or "failure of expected pharmacological action" per se will not 
be reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting 
from lack of efficacy will be reported as AE or SAE if they fulfill the definition of 
an AE or SAE. 
Events that do not meet the definition of an AE include: 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by 
the investigator to be more severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 
• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition 
that leads to the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
• Hospitalization for elective procedures scheduled prior to start of trial 
participation, or for treatment of the target disease for the study unless associated 
with worsening of the condition. 
If there is evidence of an AE through report or observation, the Investigator or designee 
will evaluate further and record the following information: 
• Time of onset and resolution 

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• Severity 
• Causality/relation to IP 
• Causality/relation to study procedures or participation 
• Action taken regarding IP 
• Outcome. 
8.1.1 
Severity of an adverse event 
Severity of adverse events will be graded by the Investigator as one of: 
• Mild: A type of AE that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with 
usual activities of daily living. 
• Moderate: A type of AE that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm to the 
research subject. 
• Severe: A type of AE that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic 
intervention. 
8.1.2 
Causal relationship of an adverse event 
The Investigator will assess the relationship between IP or study procedures/participation 
and the occurrence of each AE. The Investigator’s assessment of the relationship of each 
AE to IP will be recorded in the source documents and the eCRF. Alternative causes, 
such as medical history, concomitant therapy, other risk factors, and the temporal 
relationship of the event to the IP should be considered and investigated, if appropriate. 
The following definitions are general guidelines to help assign grade of attribution: 
• Not related: The event is clearly related to other factors such as the subject’s 
environment or clinical state, therapeutic interventions or concomitant drugs 
administered to the subject. This is especially so when an event occurs prior to the 
commencement of treatment with the study medication. 
• Unlikely: The event was most likely produced by other factors such as the 
subject’s environment or clinical state, therapeutic interventions, or a concomitant 
drug administered to the subject and does not follow a known response to the 
study medication. 
• Possible: The event follows a reasonable temporal sequence from the time of 
study medication administration or follows a known response to the study 
medication but could have been produced by other factors such as the subject's 
clinical state, other therapeutic interventions, or concomitant drugs administered 
to the subject. 

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• Probable: The event follows a reasonable temporal sequence from the time of 
study medication administration and follows a known response to the study 
medication and/or cannot be reasonably explained by other factors such as the 
subject's clinical state, other therapeutic interventions, or concomitant drugs 
administered to the subject. 
Events assessed as not related or unlikely related will be considered unrelated for 
reporting purposes, and events assessed as possibly or probably related will be assessed 
as related for reporting purposes 
8.1.3 
Action taken with investigational products 
Should the Investigator need to alter the administration of the IP from the procedure 
described in the protocol due to the well-being and safety of the subject, then the action 
taken with IPs will be recorded on the AE eCRF page, as one of the following options: 
• Dose Reduced 
• Dose Interrupted 
• Dose Withdrawn 
• Not Applicable 
• Unknown 
8.1.4 
Outcome 
Outcome of an AE will be recorded on the AE eCRF as follows: 
• Recovered / Resolved or attributable to other (defined) cause 
• Recovering / Resolving 
• Recovered / Resolved with Sequelae 
• Not Recovered / Not Resolving, up to a 28-day follow-up period 
• Fatal 
• Unknown (or subject lost to follow-up after 4 attempts at contact over a period of 
28 days). 
8.2 
Definition of a serious adverse event  
An SAE is any untoward medical occurrence that at any dose meets any of the following 
criteria: 
• Results in death. 
• Is life-threatening. The term 'life-threatening' in the definition of 'serious' refers to 
an event in which the participant was at risk of death at the time of the event. It 

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does not refer to an event, which hypothetically might have caused death, if it 
were more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization. In 
general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
• Results in persistent or significant disability/incapacity. The term disability means 
a substantial disruption of a person’s ability to conduct normal life functions. This 
definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) which may interfere with 
or prevent everyday life functions but do not constitute a substantial disruption. 
• Is a congenital anomaly/birth defect. 
• Other situations. Medical or scientific judgment should be exercised in deciding 
whether SAE reporting is appropriate in other situations such as important 
medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the participant or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious. Examples of such 
events include invasive or malignant cancers, intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that 
do not result in hospitalization, or development of drug dependency or drug 
abuse. 

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8.2.1 
Notification of a serious adverse event 
In order to meet the requirements for expedited reporting of serious adverse events 
(SAEs) to applicable regulatory authorities and IRBs, all SAEs must be entered on the 
appropriate AE eCRF in the electronic data collection (EDC) system within 24 hours 
from the time the site investigational team first become aware of the event. Should the 
EDC system not be available, the SAE can be reported via paper SAE report form and 
faxed to Pharmaceutical Product Development, LLC (PPD) Pharmacovigilance (PVG). In 
the event of fax failure or any questions, the site investigational team should contact PPD 
PVG via the SAE hotline. 
SAE Hotline: 800-201-8725 
SAE Faxline: 888-488-9697 
As further information regarding the SAE becomes available, such follow-up information 
should be updated in the EDC system. After review by the Medical Monitor, additional 
information may be requested. Any requested source documentation should be faxed to 
PPD PVG accordingly. 
Withdrawal from the study in the event of an SAE and the therapeutic measures taken 
shall be at the discretion of the Investigator. A full explanation for the discontinuation 
from the study should be made in the subject’s medical records and in the eCRF. 
8.3 
Clinical laboratory abnormalities and other abnormal assessments 
as adverse events and serious adverse events 
Abnormal laboratory findings (e.g., clinical chemistry, hematology, and urinalysis) or 
other abnormal assessments (e.g., ECG and vital signs) are not reported as AEs. 
However, those abnormal findings that are deemed clinically significant or are associated 
with signs and/or symptoms must be recorded as AEs if they meet the definition of an AE 
(and recorded as an SAE if they meet the criteria of being serious) as described 
previously. Clinically significant abnormal laboratory or other abnormal findings that are 
detected after consent or that are present at baseline and worsen after consent are to be 
included as AEs (and SAEs if serious). 
The Investigator should exercise his/her medical and scientific judgment in deciding 
whether an abnormal laboratory finding or other abnormal assessment is clinically 
significant. Usually, the abnormality should be associated with a clinically evident sign or 
symptom, or be likely to result in an evident sign or symptom in the near term, to be 
considered clinically significant. A clinically significant laboratory abnormality in the 
absence of clinical symptoms may jeopardize the subject and may require intervention to 
prevent immediate consequences. For example, a markedly low serum glucose 
concentration may not be accompanied by coma or convulsions, yet be of a magnitude to 
require glucose administration to prevent such sequelae. 

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8.4 
Documenting adverse events 
Any AE occurrence during the study must be documented in the subject’s medical 
records in accordance with the Investigator’s normal clinical practice and on the AE page 
of the eCRF where applicable. Serious adverse events that occur during the study must be 
documented in the subject’s medical record, on the AE eCRF, and on the SAE report 
form. 
Migraine headaches will be recorded separately from the AE eCRF pages; they will not 
be recorded as AEs but as manifestations of the underlying disease unless they are more 
severe than expected for the participant’s condition. 
The Investigator should attempt to establish a diagnosis of the event based on the signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE (and SAE if serious) and not the individual signs/symptoms. If a 
diagnosis cannot be made, a syndrome may be specified in the case of several related 
symptoms, rather than the individual symptoms. 
If a clinically significant abnormal laboratory finding or other abnormal assessment 
meets the definition of an AE, then the AE eCRF page must be completed as appropriate. 
In addition, if the abnormal assessment meets the criteria for being serious, the SAE 
report form must also be completed. A diagnosis (if known, or clinical signs or 
symptoms, if the diagnosis is unknown, rather than the clinically significant laboratory 
finding or abnormal assessment) should be used to complete the AE/SAE page. If no 
diagnosis is known and clinical signs or symptoms are not present, then the abnormal 
finding should be recorded. If an SAE report form is completed, pertinent laboratory data 
should be recorded on the SAE report form, preferably with baseline values and copies of 
other relevant laboratory reports. 
The SAE page should be completed as thoroughly as possible and signed by the 
Investigator before transmittal to PPD. It is very important that the Investigator provide 
an assessment of the causal relationship between the event and the IP at the time of the 
initial report, as this is required for submissions to regulatory authorities. 
8.5 
INP104 combination product technical complaints 
An INP104 product technical complaint will be defined as: 
• Any malfunction or deterioration in the characteristics and/or performance of 
INP104 as well as any inadequacy in the labeling or the instructions for use. 
Documentation of an INP104 product incident will include: 
• Completion of a technical complaint form and follow-up documentation. 
• For incidents fulfilling the definition of an AE or an SAE, the appropriate 
AE/SAE eCRF page and an SAE report form (if meets SAE criteria) will be 
completed. 

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8.6 
Regulatory authorities 
The reporting of any SAEs to applicable regulatory authorities will be the responsibility 
of Impel in compliance with applicable country regulations. 
All SAEs must be reported to the IRB by the Investigator in accordance with their 
reporting requirements. 
8.7 
Follow-up of adverse events and serious adverse events 
All AEs and SAEs will be followed for 28 days after the last visit of the dosing period, 
until the condition resolves or stabilizes, until the event is otherwise explained, or until 
the subject dies or is lost to follow-up (whichever happens first). The Investigator is 
responsible for ensuring that follow-up includes any supplemental investigations as may 
be indicated to elucidate as completely as practical the nature and/or causality of the 
AE/SAE. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
The Sponsor may request that the Investigator perform or arrange for the conduct of 
supplemental measurements and/or evaluations. If a subject dies during participation in 
the study or during a recognized follow-up period, it should be reported to the Sponsor 
immediately. The Sponsor should be provided with a copy of any post-mortem findings, 
including histopathology. 
8.8 
Pregnancy 
Any pregnancy that occurs during the treatment period and at any time during the 28 days 
following the last dose of IP must be reported using a clinical trial pregnancy form. To 
ensure subject safety, each pregnancy must be reported to PPD within 24 hours of the 
Investigator learning of its occurrence. The pregnancy should be followed up to 
determine outcome (including premature termination) and status of mother and child. The 
subject will be requested to provide written informed consent to enable collection of 
information pertaining to the outcome of the pregnancy. Pregnancy complications and 
elective terminations for medical reasons must be reported as an AE or SAE. 
Spontaneous abortions must be reported as an SAE. 
Any SAE occurring in association with a pregnancy brought to the Investigator’s 
attention after the subject has completed the study and considered by the Investigator as 
possibly related to the IP must be promptly reported to PPD. 
In addition, the Investigator must attempt to collect pregnancy information on any female 
partners of male study subjects who become pregnant while the subject is enrolled in the 
study. Pregnancy information must be reported to PPD as described above. 
All pregnancy related events must be communicated by the Investigator to PPD within 
24 hours of receipt of notification of an event. 

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8.9 
Safety data review 
Study progress and safety will be reviewed by the Medical Monitor and Sponsor’s 
Medical Expert on an ongoing basis (at not less than monthly frequency) as described in 
the Safety and Medical Management Plan and Data Validation Manual. At a minimum, 
safety review will focus on adverse events (AEs) with cross reference to medical history 
and concomitant medication. Additional safety parameters that will be reviewed include 
nasal endoscopic examination grading and olfactory changes. 
There will be two safety analysis time points in this study:  
1) A Primary Safety Analysis will be conducted once all 300 to 340 enrolled subjects 
have completed (or withdrawn early from) the 24-Week Treatment Period. This will 
include the 26-Week visit for those subjects exiting the study after the 24-Week 
Treatment Period (who do not continue on into the 52-Week Treatment Period).  
2) A Secondary Safety Analysis will be conducted once the subset of 80 subjects 
continuing into the 52-Week Treatment Period have completed (or withdrawn early from) 
the study through the 54-Week follow-up visit.  
All subjects who receive any amount of study drug will be included in these analyses.  
In addition to the routine medical monitoring safety reviews, an independent evaluation 
with specific attention to the nasal examination grading and olfactory changes, will be 
performed as part of each of the two safety analysis time points noted above. This review 
will be performed centrally by three independent otolaryngologist consultants to the 
study. A summary of relevant review findings will be provided in an expert report and 
included in the interim and the final clinical study report(s). 
 
 

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9 STUDY DURATION 
The study will comprise 3 periods: screening, treatment, and safety follow-up. The 
screening period will occur 28 days prior to the start of treatment. The treatment period 
will provide for 24 weeks of treatment for all 300 to 340 enrolled subjects entering the 
study (to ensure at least 150 complete) and 52 weeks of treatment for approximately 80 
subjects entering the 52-week treatment period to ensure 60 complete. The safety follow-
up period will extend for 2 weeks after the cessation of treatment for each group of 
subjects. The overall study duration will be 58 weeks (+ up to a 14-day window) 
maximum per subject, with the majority completing 30 weeks. 
All subjects will complete 9 visits, with the subjects continuing treatment through 
52 weeks completing 12 visits in total. 
In the event a subject discontinues the study early for any reason after Visit 2, an Early 
Termination Visit (see Section 7.2.4) will be performed (as per Table 7-1). The subject 
should also return 2 weeks after the last dose of study drug to complete the Post-
Treatment Follow-up Visit procedures (see Section 7.2.5). 
9.1 
Subject withdrawal 
In accordance with applicable regulations, a subject has the right to withdraw from the 
study at any time and for any reason, without prejudice to his/her future medical care. 
Subjects may be withdrawn from the study for any of the following reasons: 
• Subject is unable or unwilling to continue participation in the study 
• Adverse event (whether or not related to IP) that precludes further participation in 
the study in the judgment of the investigator and/or sponsor 
• Protocol noncompliance 
• A male subject’s partner becomes pregnant 
• The investigator considers that it is in the subject’s best interest for the subject not 
to continue participation in the study. 
Subjects must be withdrawn from the study in the event that: 
• A subject becomes pregnant 
• Informed consent is withdrawn. 
If a subject is withdrawn because of an AE, the Investigator must arrange for the subject 
to have appropriate follow-up care until the AE is resolved, has been attributed to another 
cause or has stabilized. Unresolved AEs will be followed until the last scheduled follow-
up visit or until the PI and Medical Monitor determine that further follow-up is no longer 
indicated. In addition to AEs, other reasons for removal of subjects from the study might 
include, but are not limited to: 

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• Withdrawal of consent 
• Administrative decision by the investigator or the sponsor 
• Protocol deviation 
• Subject noncompliance. 
If a subject asks or decides to withdraw from the study, all efforts will be made to 
complete and report the observations, especially the listed primary and secondary 
objectives, as thoroughly as possible up to the date of withdrawal. The primary reason for 
withdrawal will be identified and recorded on the appropriate eCRF, along with the date 
of withdrawal. 
9.2 
Subject replacement 
Once subjects initiate the dosing period of the study they will not be replaced if 
discontinued for any reason. 

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10 STUDY CLOSURE 
The Sponsor, Investigator, and the IRB reserve the right to terminate or suspend the study 
at any time; however, this should be discussed between the relevant parties beforehand 
and the reason for such decision recorded. Should this occur, all data available will be 
recorded in the eCRFs. The Investigator should notify the relevant institutional IRB in 
writing of the study’s completion or early discontinuation. 
In the event of a study closure, the Sponsor and Investigator will arrange appropriate 
follow-up care for any subject who has an ongoing AE. 

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11 STUDY MONITORING AND DATA MANAGEMENT 
11.1 Study monitoring 
The Sponsor has appointed a qualified CRO (PPD) to manage and monitor the study so 
as to assure the adequate conduct of the study and to act as the contact with the 
investigational site. Study Monitors will be identified and will be responsible for liaison 
with, and for support of, investigational sites. 
The Study Monitors and regulatory authority inspectors will contact and visit 
investigational sites for the purpose of inspecting the facilities and, upon request, 
inspecting the various records of the study (e.g., eCRFs, essential documentation, and 
other pertinent data) provided that subject confidentiality is respected. 
11.2 Access to study documents and personnel 
The Sponsor, Sponsor’s agents, CRO Study Monitors, IRB, and applicable regulatory 
agencies may require access to all study documents held at the investigational site, as 
well as access to all members of the investigational site personnel. It is expected that such 
access would normally be arranged by agreement with the investigational site. 
11.3 Source document and data verification 
The Study Monitor will visit the investigational site periodically where s/he shall: 
• Meet with the Investigator and any other applicable site staff. 
• Verify adherence to the protocol; completeness, accuracy, and consistency of the 
data; and adherence to local regulations on the conduct of clinical research. 
• Review subject medical records and other study-related records needed to perform 
source verification of data entered into the eCRFs. The Study Monitor will raise 
queries for correction by the site and ensure that details of changes are recorded 
accordingly. The Investigator will cooperate with the monitor to ensure that any 
problems detected in the course of these monitoring visits are resolved and that 
eCRF data entry is performed in a timely manner. The monitor will identify any 
data to be recorded directly into the eCRFs (i.e., no prior written or electronic 
record of data) and to be considered to be source data. 
• Review the investigational site file and regulatory documentation. 
• Collect relevant documents for use by the appointed data management group and 
retention by the Study Sponsor. 
• Verify disposition of the IP, ensuring that IPs have been stored and handled 
appropriately, and have been administered correctly to eligible subjects. 

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11.4 Data management 
All data will be recorded in individual source documents. An eCRF will be created using 
a validated system for recording of the required data in the study database. All eCRF 
information is to be filled in by site staff. If an item is not available or is not applicable, 
this fact should be indicated. Blank spaces should not be present unless otherwise 
directed. 
The data entered into the eCRF will be subject to data validation checks for consistency 
and completeness by the data management group. Data queries will then be generated and 
sent to the investigational site for response. The investigator will ensure prompt 
resolution of data queries before the database is locked and released for statistical 
analysis. 

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12 STATISTICAL ANALYSES 
A detailed SAP will be prepared for approval by the study Sponsor, will be shared with 
the FDA, and any changes will be incorporated prior to database lock. 
There will be two safety analysis time points in this study:  
1) A Primary Safety Analysis will be conducted once all 300 to 340 enrolled subjects 
have completed (or withdrawn early from) the 24-Week Treatment Period. This will 
include the 26-Week visit for those subjects exiting the study after the 24-Week 
Treatment Period (who do not continue on into the 52-Week Treatment Period).  
2) A Secondary Safety Analysis will be conducted once the subset of 80 subjects 
continuing into the 52-Week Treatment Period have completed (or withdrawn early from) 
the study through the 54-Week follow-up visit.  
12.1 Sample size calculation 
Since this is an open-label safety study, the sample size calculation is not based on 
statistical inference (Type I error or power considerations). Approximately 300 to 340 
subjects will be enrolled in the study with the goal of having at least 150 subjects 
complete 24 weeks of treatment; where each individual subject within these 150 subjects 
has an average of 2 or more migraines per 28-day period. Additionally, at least 80 
subjects will be enrolled into an additional 28 weeks of treatment with the goal of having 
at least 60 subjects complete a total of 52 weeks of treatment, with each individual 
subject having an average of 2 or more migraines per 28 days period. At least 30 subjects 
of each sex will be enrolled in the initial 300 to 340 subjects. 
12.2 Subjects to analyze 
Analysis sets will include: 
A 24-Week Enrolled Set which includes all subjects who sign the informed consent form 
and are provided IP. 
A 52-Week Enrolled Set which includes all subjects who sign an extension informed 
consent at 24 weeks and are provided IP.  
Full Safety Sets (for each of the 24-Week and 52-Week treatment periods) which will 
include all subjects who are enrolled and receive at least 1 dose of INP104. 
Primary Safety Sets (for each of the 24-Week and 52-Week treatment periods) which will 
include all subjects with an average of 2 or more migraines and/or headaches treated with 
INP104 on average per 28 day period during the identified study periods. 

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12.3 Study endpoints 
Please refer to sections 3.2, 3.3 and 3.4 for information on the primary, secondary and 
exploratory endpoints, respectively. 
12.4 Exploratory efficacy analysis 
All efficacy analyses are exploratory in nature with no testing and will be performed for 
the 24-week treatment period and 52-week treatment period on the Full and Primary 
Safety Set for each identified study period.  
Descriptive statistics (n, mean, standard deviation, standard error, median, minimum, 
maximum) will be presented. For percentages, severity of symptom, MIDAS and HIT-6 
scores, the 95% confidence intervals of average and change from baseline will be 
provided. 
The components of the migraine diary (i.e., pain, nausea, photophobia, and phonophobia) 
are measured as ordinal variables that vary from 0 to 3 (0 being none present). During 
screening, the MBS of the migraine will be determined at the subject level. Type of 
rescue medication (e.g., ergots other than IP, triptans, acetaminophen) will also be 
collected in the migraine diary. 
All migraine diary related efficacy endpoints will be summarized by monthly measures 
(i.e., per 4-week interval of baseline, week 1-4, week 5-8, etc.). 
For analysis by monthly migraine measures, for each 4-week interval, number of 
headache and treated headache for those migraine(s) and non-migraine(s) will be 
summarized. Subject level percentage of symptom-free migraine and severity of each 
symptom at each 4-week interval are calculated as the average of all IP treated migraines 
within each 4-week interval. Subject level maximum severity of a symptom at each 4-
week interval will be identified among all timepoints through the course of all IP treated 
migraine events during each 4-week interval.  
Number and percentage of migraines with a need for rescue medication, number of 
calendar days of triptan usage and percentage of migraine for which triptan is ever used 
will be summarized for each 4-week interval. 
Descriptive statistics (including 95% confidence interval) will be presented for the 
MIDAS and HIT-6 total score at baseline, each scheduled visit and EOT. These statistics 
will be presented based upon the observed values as well as the change from baseline. 
MIDAS and HIT-6 total score will also be summarized by category at the same visit as 
above.  
12.5 Safety analysis 
No formal inferential statistics will be performed on safety assessments and will be 
evaluated via descriptive statistics and point estimates. Safety analyses will be performed 
for the 24-week treatment period and for the 52-week treatment period on the Full and 

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Primary Safety Set for each identified study period. Summaries of the overall study 
period will also be provided. Safety and tolerability will be analyzed based upon the 
reporting of AEs, SAEs, nasal endoscopy, change in sense of smell (UPSIT), vital sign 
assessments, laboratory findings, and electrocardiogram parameters. Continuous safety 
data will be summarized with descriptive statistics (n, mean, standard deviation, median, 
minimum, and maximum). Categorical safety data will be summarized with frequency 
counts and percentages.  
Adverse events will be coded using the most current Medical Dictionary for Regulatory 
Affairs (MedDRA®) version available. A by-subject SAE and AE data listing, including 
verbatim term, preferred term, system organ class, treatment, severity, and relationship to 
IP drug, IP device and IP procedure, leading to treatment and/or study discontinuation, 
and leading to death will be provided. The number of subjects experiencing SAEs and/or 
AEs and number of SAEs/AEs will be summarized by system organ class and preferred 
term using frequency counts. Adverse events will also be summarized by severity, 
relationship to IP drug, IP device, IP procedure, leading to treatment discontinuation, 
study discontinuation, and death. Adverse events of olfactory test abnormal or a 
significant change in quantitative scoring scale of evaluation of the nasal mucosa will 
also be summarized. In addition, each SAE will include a narrative. 
Individual nasal endoscopy evaluation results will be listed for each subject. Summaries 
of nasal assessments will include observed values and changes from baseline for each 
parameter, with any other cause noted (e.g., recurrent allergic rhinitis, etc.). 
Individual sense of smell (UPSIT) results will be listed for each subject. Summaries of 
sense of smell will include observed values and changes from baseline for total UPSIT 
result. 
Individual vital signs assessments will be listed for each subject. Summaries of vital signs 
will include descriptive statistics of observed values at each scheduled timepoint and 
changes from baseline for each parameter. 
Changes in physical examinations will be listed for each subject and described in the text 
of the final report where appropriate. Number and percentage of subjects who shift from 
normal to abnormal/abnormal clinically significant at any post-baseline time point will be 
summarized. 
Individual ECG results will be listed for each subject. Summaries of ECGs will include 
descriptive statistics of observed values and changes from baseline for each parameter. A 
frequency summary of ECG overall interpretation (normal, abnormal not clinically 
significant, and abnormal clinically significant) will be summarized at each scheduled 
time point. 
Individual clinical laboratory results will be listed for each subject. Summaries of clinical 
laboratory results will include descriptive statistics at each timepoint evaluated, changes 
from baseline, as well as a shift table of counts of the number of values out of normal 
range at each scheduled time point.  

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Individual clinical laboratory results will be listed for each subject. Summaries of clinical 
laboratory results will include descriptive statistics at each timepoint evaluated, changes 
from baseline, as well as a shift table of counts of the number of values out of normal 
range at each scheduled time point. Individual time course profiles will be presented for 
subjects with clinical laboratory results deemed clinically significant. 
Prior and concomitant medications or/and procedures collected from CRFs will be listed 
by subject and coded using the most current WHO drug dictionary. The number of 
subjects who use any prior or concomitant medication will be summarized by ATC2 level 
and standardized medication name using frequency counts.  
12.6 Exploratory analysis 
Product Acceptability Questionnaire will be summarized for the frequency of response 
for each question (strongly agree, agree, neutral, disagree, strongly disagree) and will be 
summarized at the scheduled time point. A listing for Product Acceptability 
Questionnaire will also be provided.  
Healthcare utilization will be summarized for the overall study period by exposure 
adjusted event rate at baseline and post-baseline for each of the events (i.e., 
hospitalization, emergency room visit, urgent care visit, unplanned clinic/physician office 
visit, new or changed prescription for acute migraine, prescription for preventive 
migraine, and preventive procedures for migraines).  

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13 REGULATORY REQUIREMENTS 
13.1 Regulatory approvals 
This study will be conducted in the United States under an Investigational New Drug 
application. It will be the first study conducted with INP104 in the United States and, as 
such, the protocol will be submitted to and reviewed by the FDA prior to conducting the 
study. Comments from the FDA as part of preliminary reviews have been incorporated. It 
is anticipated that the data from this study will be significant and relevant to a subsequent 
New Drug Application for INP104. 
13.2 Ethics committees 
The investigator must obtain IRB approval to conduct the study. Prior to initiation of the 
study, the Sponsor must receive a copy of the communication from the IRB to the 
investigator indicating approval of the protocol and consent form. All changes to the 
protocol must be reviewed and approved by the IRB prior to implementation, except for 
administrative changes to correct errors or to update study personnel or contact 
information or where necessary to eliminate apparent immediate hazards to subjects. 
13.3 Subject informed consent 
The Principal Investigator (or delegated study site staff) is responsible for obtaining and 
documenting informed consent per GCP. Once a subject is referred for consideration in 
the study, the subject’s history and status will be completely evaluated, and study 
treatment will be discussed thoroughly with the subject and the risks and hazards of the 
IP explained. The investigator shall seek consent only under circumstances that provide 
the subject sufficient opportunity to consider whether or not to participate. The 
information that is given to the subject shall be in language understandable to the subject. 
No informed consent may include any language through which the subject is made to 
waive or appear to waive any of their legal rights, or releases or appears to release the 
investigator, the Sponsor, the institution, or its agents from liability for negligence.  
The subject must be able to comprehend and sign the informed consent form prior to 
enrollment. The subject will then receive a signed copy of the consent form. 
13.4 Data protection 
Subjects will be informed that data will be held on file at the investigational site and the 
otolaryngology site and may be viewed by study/site staff, Sponsor staff, Data 
Management/CRO staff, including the Study Monitor, and by auditors and/or monitors on 
behalf of the Sponsor and appropriate regulatory authorities. Subjects will also be 
informed that a study report will be prepared and may be submitted to regulatory 
authorities and for publication; however, subjects will be anonymous in such reports, 
only being identified by subject identification number, gender, and age. All subject data 
will be held in strict confidence. 

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14 ADMINISTRATIVE PROCEDURES 
14.1 Liability/indemnity/insurance 
The Sponsor will ensure sufficient insurance is available to enable it to indemnify and 
hold the Investigator(s) and relevant staff, as well as any hospital, institution, IRB or the 
like, harmless from any claims for damages for unexpected injuries, including death, that 
may be caused by the IP but only to the extent that the claim is not caused by the fault or 
negligence of the subject or Investigator(s). 
14.2 Recording of data and retention of records 
All source data, clinical records and laboratory data relating to the study will be archived 
after the completion of the study in accordance with applicable regulatory requirements. 
All data will be available for retrospective review or audit. 
Source documents are original documents, data, and records from which the subjects’ 
eCRF data are obtained. These include, but are not limited to: hospital records, clinical 
and office charts, laboratory and pharmacy records, paper diaries, eDiaries, microfiches, 
radiographs, angiograms, study medication accountability logs, and correspondence. 
Electronic CRF entries may be considered source data if the eCRF is the repository of the 
original recording (i.e., there is no other written or electronic record of data). In this case, 
a Source Document Agreement should indicate which eCRFs are considered source 
documents for the study. 
The Investigator and study staff are responsible for maintaining a comprehensive filing 
system of all study-related (essential) documentation. These include, but are not limited 
to: IRB correspondence, study medication accountability logs, and curricula vitae of all 
personnel participating in the study. These files must be available for inspection at any 
time by the Sponsor, monitor, and/or applicable regulatory authorities. All essential 
documentation will be retained by the institution in accordance with applicable regulatory 
requirements. 
No study document should be destroyed without prior written agreement between the 
Sponsor and the Investigator. If the Investigator wishes to assign the study records to 
another party or move them to another location, he/she must notify the Sponsor in writing 
of the new responsible person and/or the new location. 
14.3 Publication of results 
Publication and reporting of results and outcomes of this trial will be accurate and honest, 
undertaken with integrity and transparency and in accordance with the Sponsor’s 
Publication Policy. 
Publication of results will be subjected to fair peer-review. Authorship will be discussed 
between researchers prior to study commencement (or as soon as possible thereafter) and 
reviewed whenever there are changes in participation. 

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All conflicts arising through disputes about authorship will be reviewed by the Sponsor. 
Acknowledgment will be given to collaborating institutions and hospitals and other 
individuals and organizations providing finance or facilities. Subject confidentiality will 
be maintained by referring to individual subjects by their subject identification number 
used in the trial. In the case of no publication, information will only be released to the 
public and media in accordance with the Sponsor’s policies. 
The study protocol and results summary will be posted to https://clinicaltrials.gov/. 
14.4 Disclosure and confidentiality 
By signing this protocol, the Investigator agrees to keep all information provided by the 
Sponsor in strict confidence and to request similar confidentiality from his/her staff and 
the IRB. Study documents provided by the Sponsor (protocol, IB, eCRFs, etc.) will be 
stored appropriately to ensure their confidentiality. The information provided by the 
Sponsor to the Investigator may not be disclosed to others without direct written 
authorization from the Sponsor, except to the extent necessary to obtain informed consent 
from subjects who wish to participate in the study. 
The Investigator must ensure that the subject’s anonymity is also maintained. Subjects 
should only be identified by their initials and a subject identification number on the 
eCRFs and other source documents. Other study-related documents (e.g., signed 
informed consent forms) should be kept in strict confidence by the Investigator. 

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15 QUALITY CONTROL AND QUALITY ASSURANCE 
15.1 Compliance with Good Clinical Practice 
The study will be carried out in accordance with the current version of the Declaration of 
Helsinki, concerning medical research in humans (recommendations guiding physicians 
in biomedical research involving human subjects), ICH Integrated Addendum to 
ICH E6(R1): Guideline for GCP E6(R2) (2015), and applicable local regulations. 
15.2 Archiving and regulatory inspection 
All study-related documents and records are to be retained according to applicable 
regulatory authority requirements after trial completion. Written agreement from the 
Sponsor must precede destruction of the same. 
In accordance with ICH GCP, this study may be selected for audit. Inspection of site 
facilities (e.g., pharmacy, medication storage areas, laboratories) and review of study-
related records may occur by the Sponsor, Sponsor’s representative, or regulatory 
authority to evaluate the study conduct and compliance with the protocol, ICH GCP, and 
applicable regulatory requirements. The Investigator, by signing this protocol, agrees to 
fully cooperate with any such inspection. 

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16 CLINICAL STUDY REPORT 
A clinical study report (CSR) will be prepared with reference to ICH Guidance E3 (1995) 
to include: 
• Details of where the study was carried out 
• A description of the study methods used 
• Dates of the start and completion of each period of the study 
• Details of the study medication and a statement of production 
• A statement confirming that the applicable IRB gave written approval for the 
study in accordance with local regulations 
• A demographic listing for all subjects 
• A list of all adverse events 
• Details of any occurrences which may be of significance to the study outcome 
• Details of all operations, calculations, and transformations performed on the 
reported data 
• A SAP 
• All data from any withdrawn subject not included in the statistical analysis, not 
including screen failures 
• A scientific interpretation of the results. 
The CSR will focus on the Primary Safety Analysis (see Section 12). The Secondary 
Safety Analysis will either be included in the primary CSR or may be presented in a 
supplementary or separate CSR as defined in the SAP.  
The report(s) will be issued under the study Sponsor’s responsibility. 
Where required by the applicable regulatory requirements, an Investigator’s signature 
will be required for the approval of the CSRs. The Investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review complete study results. The Sponsor will also provide the 
Investigator with the full summary of study results. 

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17 SPONSOR AND INVESTIGATOR OBLIGATIONS 
17.1 Protocol amendments 
Neither the Investigator nor the Sponsor will modify or alter this protocol without the 
agreement of the other. All agreed protocol amendments will be clearly recorded on a 
protocol amendment form and will be signed and dated by the original protocol 
approving signatories. All protocol amendments will be submitted to the relevant 
institutional IRB for approval before implementation, as required by local regulations. 
The only exception will be when the amendment is necessary to eliminate an immediate 
hazard to the trial subjects. In this case, the necessary action will be taken first, with the 
relevant protocol amendment following shortly thereafter. 
17.2 Protocol deviations 
A protocol deviation is any unplanned excursion from, or noncompliance with, the 
protocol. 
All protocol deviations should be reported to the Study Monitor as soon as is reasonably 
practical. Important deviations that potentially affect the safety of a subject and the 
reason for their occurrence must be documented and reported to the relevant IRB (as per 
the IRB’s requirements). Important protocol deviations will be summarized and listed in 
the clinical study report. 

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18 REFERENCES 
D.H.E. 45® (dihydroergotamine mesylate, USP) Injection. Approved Labeling, Valeant 
Pharmaceuticals North America (2009) 
Doty RL, Shaman, P, Kimmelman, CP, Dann, MS. University of Pennsylvania Smell 
Identification Test: A rapid quantitative olfactory function test for the clinic. 1984; 
94:176-178 
Hansen JM, Goadsby PJ, Charles AC. Variability of clinical features in attacks of 
migraine with aura. Cephalalgia. 2016; 36(3):216-24 
Headache Classification Committee of the International Headache Society (IHS). The 
International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018; 
38(1):1-211 
Lipton RB, Buse DC, Serrano D, Holland S, Reed ML. Examination of unmet treatment 
needs among persons with episodic migraine: results of the American Migraine 
Prevalence and Prevention (AMPP) Study. Headache. 2013; 53(8):1300-11 
Manzoni GC, Stovner LJ. Epidemiology of headache. Handb Clin Neurol. 2010; 97:3-22. 
 Migranal® (dihydroergotamine mesylate, USP) Nasal Spray. In Prescribing Information. 
Valeant Pharmaceuticals North America (2017) 
Silberstein SD, Kori SH. Dihydroergotamine: a review of formulation approaches for the 
acute treatment of migraine. CNS Drugs. 2013; 27(5):385-94 
Stewart WF, Lipton RB, Kolodner K, Liberman J, Sawyer J. Reliability of the Migraine 
Disability assessment score in a population-based sample of headache sufferers. 
Cephalalgia 1999; 19(2):107-114 
Yang M, Rendas-Baum R, Varon S, Kosinski M. Validation of the Headache Impact Test 
(HIT-6TM) across episodic and chronic migraine. Cephalalgia. 2011; 31(3):357-67 

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19 APPENDICES 
19.1 Appendix 1 – List of Permitted Migraine Medications 
Permitted concomitant medications include: 
• Acetaminophen, when necessary (PRN) 
• Aspirin – regular low dose or full dose PRN 
• Ibuprofen PRN (or other NSAIDs PRN) 
• Regular migraine preventative treatment (if the dose is stable and subjects have 
been receiving for at least 30 days before screening and still meet all entry 
criteria) may be continued at stable dose throughout the study. 
• If headache pain does not resolve within 2 hours after treatment with IP (or if IP 
cannot be used due to dose limitation) then a rescue medication such as 
acetaminophen, an NSAID (e.g., ibuprofen), an opioid or a barbiturate containing 
medication may be administered (per the Investigator’s instruction and normal 
practice). 
• Other prescribed medications may be continued throughout the study at the 
discretion of the Investigator (unless they are excluded or prohibited – 
Sections 4.3 and 4.4, respectively). All such medication use should be 
documented. 
Subjects should record their use of ALL rescue medications during every migraine they 
treat while on study. 
If subjects attend an emergency room or other healthcare provider, they MUST disclose 
that they have taken study medication. 

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19.2 Appendix 2 – Examples of CYP3A4 Inhibitors 
 
Strong inhibitors: 
• Atazanavir 
• Nefazodone 
• Clarithromycin 
• Nelfinavir 
• Darunavir 
• Ritonavir 
• Indinavir 
• Saquinavir 
• Itraconazole 
• Telithromycin 
• Ketoconazole 
• Tipranavir 
• Lopinavir 
 
 
Moderate Inhibitors: 
• Amiodarone 
• Erythromycin 
• Amprenavir 
• Fluconazole 
• Conivaptan 
• Fosamprenavir 
• Delavirdine 
• Miconazole 
• Diltiazem 
• Verapamil 

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19.3 Appendix 3 – Nasal Examination Manual 
Refer to attached INP104-301 Nasal Examination Manual 

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19.4 Appendix 4 – Migraine Disability Assessment Test (MIDAS) 
 

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19.5 Appendix 5 – Headache Impact Test (HIT-6TM) 
The HIT-6™ will be licensed for use in this study from Optum Inc. Below is an example 
of the questions. 
HIT is a tool used to measure the impact headaches have on your ability to function on the job, at 
school, at home and in social situations. Your score shows you the effect that headaches have on 
normal daily life and your ability to function. HIT was developed by an international team of 
headache experts from neurology and primary care medicine in collaboration with the 
psychometricians who developed the SF-36® health assessment tool. This questionnaire was 
designed to help you describe and communicate the way you feel and what you cannot do 
because of headaches. 
To complete, please circle one answer for each question. 
When you have headaches, how often is the pain severe? 
never 
rarely 
sometimes 
very often 
always 
How often do headaches limit your ability to do usual daily activities including household work, 
work, school, or social activities? 
never 
rarely 
sometimes 
very often 
always 
When you have a headache, how often do you wish you could lie down? 
never 
rarely 
sometimes 
very often 
always 
In the past 4 weeks, how often have you felt too tired to do work or daily activities because of 
your headaches? 
never 
rarely 
sometimes 
very often 
always 
In the past 4 weeks, how often have you felt fed up or irritated because of your headaches? 
never 
rarely 
sometimes 
very often 
always 
In the past 4 weeks, how often did headaches limit your ability to concentrate on work or daily 
activities? 
never 
rarely 
sometimes 
very often 
always 
 
Column 1 
6 points each 
Column 2 
8 points each 
Column 3 
10 points each 
Column 4 
11 points each 
Column 5 
13 points each 
To score, add points for answers in each column. 
If your HIT-6 is 50 or higher: 
TOTAL SCORE:______________ 
You should share your results with your doctor. Headaches that stop you from enjoying the 
important things in life, like family, work, school or social activities could be migraine. 

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19.6 Appendix 6 – Product Acceptability Questionnaire 
The following is an example of the Questions. 
Check the box that most closely matches your experience with the investigational product: 
1. The study drug is easy to use. 
• 
Strongly Agree 
• 
Agree 
• 
Neutral 
• 
Disagree 
• 
Strongly Disagree 
2. The investigational product works faster compared to my previous prescription 
migraine medication(s). 
• 
Strongly Agree 
• 
Agree 
• 
Neutral 
• 
Disagree 
• 
Strongly Disagree 
3. The investigational product keeps my migraine from coming back for a longer time 
than previous prescription migraine medications I’ve used. 
• 
Strongly Agree 
• 
Agree 
• 
Neutral 
• 
Disagree 
• 
Strongly Disagree 
4. With the investigational product I can return to normal activities faster 
(school/work/leisure activities) compared to my previous prescription migraine 
medication(s). 
• 
Strongly Agree 
• 
Agree 
• 
Neutral 
• 
Disagree 
• 
Strongly Disagree 

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5. Compared to previous migraine prescription medications, the investigational product 
more consistently relieves each one of my migraine headaches. 
• 
Strongly Agree 
• 
Agree 
• 
Neutral 
• 
Disagree 
• 
Strongly Disagree 
6. The investigational product was very convenient to carry with me and use outside of 
my home. 
• 
Strongly Agree 
• 
Agree 
• 
Neutral 
• 
Disagree 
• 
Strongly Disagree 
• 
I never used it outside my home 
7. Insertion of this device into my nose caused discomfort or hurt compared to other nasal 
migraine medications I’ve used. 
• 
Strongly Agree 
• 
Agree 
• 
Neutral 
• 
Disagree 
• 
Strongly Disagree 
• 
I have never used a nasal migraine medication before this study 
8. The investigational product produced a bad taste compared to other nasal migraine 
medications. 
• 
Strongly Agree 
• 
Agree 
• 
Neutral 
• 
Disagree 
• 
Strongly Disagree 
• 
I have never used a nasal migraine medication before this study 

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9. If the INP104 Product were commercially available, I would request a prescription for 
it from my physician. 
• 
Strongly Agree 
• 
Agree 
• 
Neutral 
• 
Disagree 
• 
Strongly Disagree 
 
Add any additional comments on your experience with the investigational product: