Clinical trial NCT03901482
Conditions: Migraine Migraine With Aura Migraine Without Aura
Keywords: dihydroergotamine dihydroergotamine mesylate migraine
Sponsor: Satsuma Pharmaceuticals, Inc.
Start date: 2019-06-24; Completion date: 2020-08-13
Enrollment: 1201 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Study STS101-002 is a randomized, double-blind, parallel group, placebo-controlled, multicenter study to evaluate the efficacy, safety, and tolerability of single doses of STS101 (dihydroergotamine nasal powder) in the acute treatment of migraine

Detailed description:
The EMERGE trial is a multi-center, single-dose, randomized, double-blind, placebo-controlled, parallel group study in subjects with acute migraine (ages 18 to 65 years).

Arms: arm 1: STS101 (dihydroergotamine nasal powder), low dose arm 2: STS101 (dihydroergotamine nasal powder), high dose arm 3: STS101 Placebo
Interventions: intervention 1: Dihydroergotamine intervention 2: Placebos
Intervention descriptions: intervention 1: Dihydroergotamine is a semi-synthetic derivative of ergotamine tartrate. intervention 2: Placebo for STS101

Protocol documents:
Prot_SAP_000.pdf: 
STS101 (dihydroergotamine nasal powder) 
 
Satsuma Pharmaceuticals, Inc. 
Study STS101-002 Clinical Study Report 
 
Page 1 
 
16.1.1 
PROTOCOL AND PROTOCOL AMENDMENTS 
The study protocol is provided on the following pages. 


Confidentiality Statement 
The information contained in this document is the property of Satsuma Pharmaceuticals, Inc. and 
contains trade secrets and commercial information that are privileged or confidential and may not 
be disclosed unless such disclosure is required by law or regulations. In any event, persons to 
whom the information is disclosed must be informed that the information is privileged or 
confidential and may not be further disclosed by them. In the event of any actual or suspected 
breach of this obligation, Satsuma Pharmaceuticals, Inc. should be promptly notified. 
CLINICAL STUDY PROTOCOL 
Title: 
A Randomized, Double-Blind, Parallel Group, Placebo-Controlled, 
Multicenter Study to Evaluate the Efficacy, Safety, and Tolerability of 
Single Doses of STS101 (Dihydroergotamine Nasal Powder) in the 
Acute Treatment of Migraine 
Study Number: 
STS101-002 
Investigational Drug: STS101 (Dihydroergotamine Nasal Powder) 
IND Number: 
136585 
Sponsor: 
Satsuma Pharmaceuticals, Inc. 
400 Oyster Point Boulevard, Suite 221 
South San Francisco, CA 94080 
Tel. No.: 408-857-5248 
Medical Monitor: 
Detlef Albrecht, MD 
Tel. No.: 408-857-5248 
Version History: 
Original 
April 9, 2019 


STSlOl (Dihydroergotamine Nasal Powder) 
Clinical Trial Protocol: STSl0l-002, April 9, 2019 
Satsuma Pharmaceuticals, Inc. 
Page 2 of72 
SIGNATURE PAGE (SPONSOR) 
I have read and understand the contents of this protocol and agree to meet all obligations of 
Satsuma Pharmaceuticals, Inc. as detailed in all applicable regulations and guidelines. In addition, 
I will ensure that the Principal Investigator is informed of all relevant information that becomes 
available during the conduct of the study. 
Detlef Albrecht, MD 
Chief Medical Officer 
Satsuma Pharmaceuticals, Inc. 
Date 
( 
Confidential 


STS101 (Dihydroergotamine Nasal Powder) 
Satsuma Pharmaceuticals, Inc. 
Clinical Trial Protocol: STS101-002, April 9, 2019 
Page 3 of 72 
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PRINCIPAL INVESTIGATOR AGREEMENT 
I have carefully read this study protocol and agree that it contains all necessary information 
required to conduct this study. I agree to conduct the study according to this protocol (including 
any amendments) and in accordance with ICH Good Clinical Practices (GCP) and all other 
applicable regulations. I will inform all who assist me in the conduct of this study of their 
responsibilities and obligations. Furthermore, I understand that the Sponsor and the Institutional 
Review Board/Ethics Committee (IRB/EC) must approve any changes to the protocol in writing 
before implementation, unless a deviation is required to eliminate an immediate safety hazard to 
a subject. In such cases the Sponsor and the IRB/EC will be notified as soon as possible. 
 
Principal Investigator Signature 
 
Date 
 
Principal Investigator Name (print) 
 
Site Name 


STS101 (Dihydroergotamine Nasal Powder) 
Satsuma Pharmaceuticals, Inc. 
Clinical Trial Protocol: STS101-002, April 9, 2019 
Page 4 of 72 
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PROTOCOL SYNOPSIS 
Sponsor/Company Satsuma Pharmaceuticals, Inc. 
Investigational 
Product 
STS101 (Dihydroergotamine Nasal Powder) 
Active Ingredient 
Dihydroergotamine mesylate 
Protocol Number 
STS101-002 
Title of Study 
A Randomized, Double-Blind, Parallel Group, Placebo-Controlled, 
Multicenter Study to Evaluate the Efficacy, Safety, and Tolerability of 
Single Doses of STS101 (Dihydroergotamine Nasal Powder) in the Acute 
Treatment of Migraine 
Study center 
Approximately 100 in the United States 
Objectives 
Primary 
• To evaluate the efficacy of single doses of two strengths of STS101 to 
achieve freedom from pain at 2 hours after dosing in subjects with acute 
migraine attacks 
• To evaluate the efficacy of single doses of two strengths of STS101 to 
achieve freedom from most bothersome symptom at 2 hours after dosing 
in subjects with acute migraine attacks 
Secondary 
• To evaluate the efficacy of single doses of two strengths of STS101 to 
achieve 2 to 24 hour sustained pain free status in subjects with acute 
migraine attacks 
• To evaluate the efficacy of single doses of two strengths of STS101 to 
achieve 2 to 48 hour sustained pain free status in subjects with acute 
migraine attacks 
• To evaluate the efficacy of single dose of two strengths of STS101 to 
avoid the use of rescue medication within 24 hours after dosing in 
subjects with acute migraine attacks 
• To evaluate the efficacy of single dose of two strengths of STS101 to 
avoid the use of rescue medication within 48 hours after dosing in 
subjects with acute migraine attacks 
• To evaluate the efficacy of single doses of two strengths of STS101 to 
achieve pain relief at 2 hours after dosing in subjects with acute 
migraine attacks 
• To evaluate the efficacy of single doses of two strengths of STS101 to 
avoid headache pain relapse within 24 hours after dosing in subjects 
with acute migraine attacks 
• To evaluate the efficacy of single doses of two strengths of STS101 to 
avoid headache pain relapse within 48 hours after dosing in subjects 
with acute migraine attacks 
• To evaluate the effects of single doses of two strengths of STS101 on the 
Functional Impairment Scale (FIS) in subjects with acute migraine attacks 
• To evaluate the effects of single doses of two strengths of STS101 on 
the 24-hour Migraine Quality of Life Questionnaire (24-MQoLQ) in 
subjects with acute migraine attacks 


STS101 (Dihydroergotamine Nasal Powder) 
Satsuma Pharmaceuticals, Inc. 
Clinical Trial Protocol: STS101-002, April 9, 2019 
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• To evaluate the efficacy of single doses of two strengths of STS101 to 
achieve freedom from pain depending upon time elapsed from onset of 
migraine attack to time of dosing 
• To evaluate the efficacy of single doses of two strengths of STS101 to 
achieve freedom from pain by allodynia status at time of dosing in 
subjects with acute migraine attacks 
• To evaluate the efficacy of single doses of two strengths of STS101 to 
achieve freedom from pain and most bothersome symptom at 2 hours 
after dosing in subjects with severe acute migraine attacks 
• To evaluate the efficacy of single doses of two strengths of STS101 to 
achieve freedom from pain and most bothersome symptom at 2 hours 
after dosing in subjects who wake up with acute migraine attacks 
• To evaluate the efficacy of single doses of two strengths of STS101 to 
achieve freedom from pain and most bothersome symptom at 2 hours 
after dosing in subjects with acute menstrually related migraine attacks 
• To evaluate the efficacy of single doses of two strengths of STS101 to 
achieve pain relief at 2 hours after dosing in subjects with acute 
migraine attacks by allodynia status at time of treatment 
• To evaluate the efficacy of single doses of two strengths of STS101 to 
achieve freedom from pain at various timepoints after dosing 
• To evaluate the efficacy of single doses of two strengths of STS101 to 
achieve pain relief at various timepoints after dosing 
• To estimate the probability of a subject responding to treatment 
(freedom from pain) during the 24-hour post dose period 
• To estimate the probability of a subject requiring rescue medication 
during the 24-hour post dose period 
• To evaluate the efficacy of single doses of two strengths of STS101 to 
achieve freedom from photophobia at 2 hours after dosing 
• To evaluate the efficacy of single doses of two strengths of STS101 to 
achieve freedom from phonophobia at 2 hours after dosing 
• To evaluate the efficacy of single doses of two strengths of STS101 to 
achieve freedom from nausea at 2 hours after dosing 
• To evaluate the efficacy of single doses of two strengths of STS101 to 
achieve pain relief depending upon time elapsed from onset of migraine 
to time of dosing 
• To evaluate the efficacy of single doses of two strengths of STS101 to 
achieve freedom from pain and most bothersome symptom at 2 hours 
after dosing in subjects with acute migraine attacks 
• To evaluate the efficacy of single doses of two strengths of STS101 to 
achieve freedom from pain and most bothersome symptom at various 
timepoints after dosing in subjects with acute migraine attacks 
• To evaluate the study subject’s global impression of the study treatment  
• To assess the safety and tolerability of single doses of two strengths of 
STS101 in the treatment of acute migraine attacks 


STS101 (Dihydroergotamine Nasal Powder) 
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Clinical Trial Protocol: STS101-002, April 9, 2019 
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Methodology 
This is a multi-center, single-dose, randomized, double-blind, placebo-
controlled, parallel group study in approximately 1140 subjects with acute 
migraine (ages 18 to 65 years). 
After establishing initial eligibility, the study participants will document 
their headache attacks for 28 days in an electronic diary. Attack frequency, 
duration, pain severity, presence of symptoms (nausea; photophobia, 
phonophobia) and impact on functional status will be documented. Study 
participants must have 2 to 8 migraine attacks, and fewer than 15 headache 
days during the 28-day screening period to be eligible for randomization. 
After establishing full eligibility, the study participants will be trained in 
the use of the STS101 device and randomized (1:1:1) to receive one of 
three treatments: 
• 3.9 mg STS101 (equivalent to 4.5 mg of DHE mesylate USP) 
• 5.2 mg STS101 (equivalent to 6.0 mg of DHE mesylate USP) 
• Placebo (matching nasal powder) 
After randomization, the study participants will treat their next qualifying 
migraine attack of at least moderate pain severity with the allocated 
blinded study medication at home. The subjects will be instructed to treat 
a qualifying migraine attack within 8 hours of the onset of the attack. 
The study participants will document the pain severity of their treated 
migraine attack, presence of symptoms (photophobia, phonophobia, 
nausea), presence of allodynia and functionality status over the 48-hour 
period after study drug administration in an e-diary. Headache pain 
severity and symptom data will be collected at the onset of the migraine 
attack, immediately before drug administration (time 0), at 15, 30, 45 
minutes and 1, 1.5, 2, 3, 4, 6, 12, 24, and 48 hours after study drug 
administration. The subjects must select a most bothersome symptom 
among photophobia, phonophobia, and nausea immediately before study 
drug administration. Additionally, subjective nasal irritation assessments 
will be documented during the treatment period. 
If subjects require rescue medication, they will be encouraged to wait until 
the 2-hour post study drug administration data collection timepoint. The 
use of triptans or other DHE mesylate products as rescue medications 
should be avoided for 24 hours after study drug administration. The study 
participants will return to the study site within one week of the treated 
migraine attack. 
Adverse events, objective nasal evaluation data, safety laboratory data, 
vital sign data and ECGs will be recorded before and after treatment to 
evaluate the tolerability and safety of STS101. 
Number of 
subjects (planned) 
A total of approximately 1140 evaluable adult male and female subjects 
aged 18 to 65 years with acute migraine headaches. 


STS101 (Dihydroergotamine Nasal Powder) 
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Clinical Trial Protocol: STS101-002, April 9, 2019 
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Inclusion criteria 
1. Males or females, 18-65 years of age at the time of Screening Visit 
2. Signed Informed Consent Form 
3. Subject has at least 1-year history of migraines (with or without aura), 
according to the International Classification of Headache Disorder, 3rd 
Edition (ICHD3), including the following: 
a. Migraine onset before the age of 50 years 
b. Migraine headache frequency of 2 to 8 attacks of moderate or 
severe intensity in each of the 3 months prior to the Screening Visit 
and maintains this requirement during the Screening Period 
c. Fewer than 15 days with headache (migraine or non-migraine) per 
month in each of the 3 months prior to the Screening Visit and 
maintains this requirement during the Screening Period 
d. Individual migraine attacks separated by at least 2 days of no headache 
pain 
4. Subjects on preventive migraine medication are permitted to remain on 
therapy provided they have been on a stable dose for at least 3 months 
prior to study entry and have no plans to change the dose during the study 
5. Female subjects will be included if they are post-menopausal (at least 
1 year since last menses) or surgically sterilized; or if they are of 
childbearing potential, they are not breastfeeding, have a negative 
pregnancy test, have no intention of becoming pregnant during the 
course of the study, and are using adequate contraceptive drugs or 
devices during the course of this study. Medically acceptable methods 
of contraception that may be used by the subject and/or her partner are: 
a. Simultaneous use of male condom and intra-uterine contraceptive 
device placed at least 4 weeks prior to Screening Visit 
b. Simultaneous use of male condom with intravaginally applied 
spermicide and diaphragm 
c. Simultaneous use of male condom and hormonal contraceptives 
started at least 4 weeks prior to Screening Visit 
d. Surgical sterilization of their partner(s) at least 6 months prior to 
Screening Visit 
6. Intact nasal mucosa (no erythema, no inflammation, no ulceration, no 
swelling, no bleeding, no atrophy (severe local dryness and/or 
crusting), no septal perforation, and no other nasal conditions that may 
interfere with intranasal dosing 
7. Willing and able to comply with the requirements of the protocol and 
follow directions from the clinic staff 
8. Adequate compliance (≥80%) in the completion of the e-diary during 
the Screening Period 


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Clinical Trial Protocol: STS101-002, April 9, 2019 
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Exclusion criteria 1. Pregnant or breast-feeding women 
2. Women of child-bearing potential not using or not willing to use 
highly effective contraception 
3. Diagnosis of headache conditions other than migraine with or without 
aura, including diagnosis of basilar or hemiplegic migraines or cluster 
headache 
4. Abnormal physical findings of clinical significance at the screening or 
baseline examination which would interfere with the objectives of the 
study 
5. History of coronary artery disease, coronary artery vasospasm 
(including Printz-metals’ angina), clinically significant arrhythmia or, 
peripheral vascular disease, ischemic disease (e.g. Raynaud’s 
syndrome, ischemic bowel syndrome, angina pectoris, myocardial 
infarction, or documented silent ischemia); percutaneous coronary 
intervention, or cardiac surgery 
6. History of cerebrovascular disease, including but not limited to stroke, 
transient ischemic attack, cerebral hemorrhage, subarachnoid 
hemorrhage 
7. Presence of two or more of the following cardiovascular risk factors: 
a. Receiving antihypertensive medication for treatment of 
hypertension 
b. Hypercholesteremia (LDL >159 mg/dL) or receiving cholesterol 
lowering medication 
c. Obesity (BMI > 31) 
d. Diabetes mellitus 
e. Family history of premature coronary artery disease (in male first-
degree relatives < 55 years or female first-degree relatives < 65 
years)  
f. Females who are surgically or physiologically postmenopausal 
g. Males over age 45  
8. Clinically significant abnormal laboratory values (as determined by the 
Principal Investigator) at the Screening Visit 
9. Severely impaired hepatic function (liver function tests ALT or AST 
greater than 2 times upper limit of normal) or renal function (serum 
creatinine greater than 1.5 times the upper limit of normal) 
10. Screening 12-lead ECG showing any clinically significant abnormalities 
11. Systolic blood pressure lower than 90 or over 140 mmHg, diastolic 
blood pressure lower than 50 or over 90 mmHg, at the Screening Visit 
12. Diagnosis of major depression with current symptoms, psychosis, 
alcohol abuse or dependence, drug abuse or dependence, major 
psychiatric conditions (e.g. schizophrenia, psychosis or Bipolar 
disorder), or dementia. Other significant neurological or psychiatric 


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Clinical Trial Protocol: STS101-002, April 9, 2019 
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disorders (including other pain syndromes or risk of suicide) that in the 
opinion of the investigator might interfere with study participation and 
assessments or subject safety 
13. Any clinically significant symptoms or conditions, including but not 
limited to central nervous system (e.g., seizures), cardiac, pulmonary, 
metabolic, renal, hepatic or gastrointestinal conditions or history of 
such conditions that, in the opinion of the investigator might interfere 
with study assessments or subject safety 
14. Participation in another drug research study within 30 days of 
Screening Visit or within less than 5 half-lives of tested drug 
(whichever is longer) 
15. Concomitant use of potent CYP3A4 inhibiting medications, for 
example protease inhibitors (e.g. ritonavir, nelfinavir, indinavir, 
saquinavir, tipranavir, lopinavir, atazanavir, darunavir), macrolide 
antibiotics (e.g. erythromycin, clarithromycin, troleandomycin), or 
strong imidazole antifungals (e.g. ketoconazole, and itraconazole) 
16. Previously shown hypersensitivity to ergot alkaloids or the inactive 
ingredients of STS101 (microcrystalline cellulose, hydroxypropyl 
methylcellulose, mannitol) 
17. Concomitant use of more than one preventive migraine medication. 
18. Current use of opioids, barbiturates, or cannabis or cannabinoid 
containing products 
19. Concomitant use of peripheral and central vasoconstrictors including 
propranolol and nicotine (from smoking, vaping or smokeless products) 
Investigational 
product, dosage 
and mode of 
administration 
• 3.9 & 5.2 mg STS101 dose strengths (equivalent to 4.5 and 6.0 mg of 
DHE mesylate USP; nasal powder) 
• Placebo (matching nasal powder) 
For subject training 
• STS101 Empty Training Devices 
• STS101 Filled Training Devices 
Duration of study 
• Screening period: Up to 35 days 
• Treatment & follow up period: Up to 56 days 


STS101 (Dihydroergotamine Nasal Powder) 
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Clinical Trial Protocol: STS101-002, April 9, 2019 
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Criteria for 
evaluation 
Efficacy 
Primary Efficacy: 
• Proportion of subjects free from headache pain at 2 hours post dose 
(defined as moderate or severe headache pain [2 or 3 on a 4-point 
scale] at baseline [time 0] becoming none [0] on a 4-point scale) 
• Proportion of subjects free from most bothersome symptom (MBS) 
among photophobia, phonophobia and nausea at 2 hours post dose 
(defined as the MBS identified at baseline [time 0] being absent) 
Secondary Efficacy: 
• Proportion of subjects free from headache pain at 2 hours post dose and 
remaining headache free at 24 hours post dose with no use of rescue 
medication and no relapse of any headache pain (defined as score of 0 
on a 4-point scale from 2-24 hours) 
• Proportion of subjects free from headache pain at 2 hours post dose and 
remaining headache free at 48 hours post dose with no use of rescue 
medication and no relapse of any headache pain (defined as score of 0 
on a 4-point scale from 2-48 hours) 
• Proportion of subjects who use rescue medication within 24 hours 
post dose 
• Proportion of subjects who use rescue medication within 48 hours 
post dose 
• Proportion of subjects with relief from headache pain at 2 hours post 
dose (defined as reduction in headache pain from moderate or severe 
[2 or 3 on a 4-point scale] to mild or none [0 or 1 on a 4-point scale]) 
• Proportion of subjects free from headache pain at 2 hours post dose by 
allodynia status at baseline (allodynia status will be defined as 
“present” with at least 2 “yes” responses to the 6-question allodynia 
questionnaire [Ashkenazi 2007; Tepper 2011]) 
• Proportion of subjects with headache relapse within 24 hours post dose 
(defined as the return of headache of any severity within 24 hours post 
dosing of the investigational drug, when the subject was pain-free at 
2 hours after dosing) 
• Proportion of subjects with headache relapse within 48 hours post dose 
(defined as the return of headache of any severity within 48 hours post 
dosing of the investigational drug, when the subject was pain-free at 
2 hours after dosing) 
• Mean change in scores on Functional Impairment Scale (FIS) at 
various timepoints post dosing compared to baseline (time 0) 
• 24-hour Migraine Quality of Life Questionnaire summary scores at 
24 hours post dose 
• Proportion of subjects free from headache pain at 2 hours post dose 
depending upon time elapsed from onset of migraine attack to time of 
dosing (investigational drug dosing ≤2 hours, 2-4 hours or >4 hours 
after onset of migraine attack) 


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• Proportion of subjects free from headache pain and free from most 
bothersome symptom (MBS) at 2 hours post dose in subjects with 
severe headache 
• Proportion of subjects free from headache pain and free from most 
bothersome symptom (MBS) at 2 hours post dose in subjects who wake 
up with migraine headache 
• Proportion of subjects free from headache pain and free from most 
bothersome symptom (MBS) at 2 hours post dose in subjects with 
menstrually related migraine attack 
• Proportion of subjects with relief from headache pain at 2 hours post 
dose by allodynia status at baseline (time 0) (allodynia status will be 
defined as “present” with at least 2 “yes” responses to the 6-question 
allodynia questionnaire [Ashkenazi 2007; Tepper 2011]) 
• Proportion of subjects with headache relief at 2 hours post dose 
depending upon time elapsed from onset of migraine attack to time of 
dosing (investigational drug dosing ≤2 hours, 2-4 hours or >4 hours 
after onset of migraine attack) 
• Proportion of subjects free from headache pain at various time points 
after dosing 
• Proportion of subjects achieving headache relief at various time points 
after dosing 
• Proportion of subjects free from photophobia (defined as photophobia 
being absent at 2 hours post-dose if present at baseline [time 0]) 
• Proportion of subjects free from phonophobia (defined as phonophobia 
being absent at 2 hours post-dose if present at baseline [time 0]) 
• Proportion of subjects free from nausea (defined as nausea being 
absent at 2 hours post-dose if present at baseline [time 0]) 
• Proportion of subjects free from headache pain and free from most 
bothersome symptom (MBS) at 2 hours post-dose 
• Proportion of subjects free from headache pain and free from most 
bothersome symptom (MBS) at various time points post-dose 
• Patient Global Impression ratings 
Safety 
The following assessment and measurements will be conducted at 
screening, before randomization and at the final visit: 
• Physical examination 
• Vitals signs and body weight 
• Subjective nasal irritation assessment 
• Objective nasal irritation assessment 
• 12-lead ECG 
• Blood tests for hematology and biochemistry analysis (including liver 
function, renal function, thyroid function, electrolytes) 
• Urinalysis 
• Adverse events (AEs) 
• Documentation of concomitant medications 


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Clinical Trial Protocol: STS101-002, April 9, 2019 
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Statistical methods Sample Size Determination 
A total of approximately 1140 evaluable subjects is planned for the study. 
Given the 1:1:1 randomization ratio, approximately 380 subjects will be 
randomized to each treatment group. For the co-primary endpoint of pain 
freedom at 2 hours post dosing of investigational drug, a therapeutic gain 
of 15% is considered clinically meaningful and targeted. This is assuming 
a 30% responder rate for STS101 and 15% for the placebo. Based on these 
assumptions, 380 subjects per arm can provide 99% power to detect the 
target treatment difference. For the co-primary endpoint of MBS freedom 
at 2 hours post investigational drug, a therapeutic gain of 12.5%, assuming 
a 47.5% responder rate for STS101 and 35% for the placebo is targeted. 
Based on these assumptions, 380 subjects per arm can provide 95% power 
to detect the target treatment difference. The sample size calculation is 
based on a chi-square test with a significance level of 0.05 and a 2-sided 
test. 
The primary efficacy objective will be addressed by simultaneously testing 
the 2 co-primary endpoints of pain freedom and MBS freedom at 2 hours 
after drug administration at a significance level of 0.05. This sample size 
will provide an overall power of at least 94%. 
Efficacy 
A detailed Statistical Analysis Plan (SAP) including the final hierarchy of 
testing of primary and secondary endpoints will be created before data base 
lock and study unblinding. 
All study data will be summarized by treatment using descriptive statistics. 
Unless otherwise specified, for numeric data (e.g., age, weight), descriptive 
statistics will include the number of subjects with data to be summarized 
(n), mean, standard deviation (SD), median, minimum (min) and maximum 
(max). All categorical/qualitative data (e.g., gender, race) will be presented 
using absolute and relative frequency counts and percentage. 
Data from all investigational centers will be pooled for analysis. For the 
primary analysis of the co-primary endpoints, missing data will be imputed 
based on a single-imputation method. Subjects who do not have evaluable 
assessments at the 2-hour time point, or who received rescue medications 
prior to the 2-hour time point will be considered as non-responders. The 
impact of missing data will be further investigated in a number of 
sensitivity analyses with other single and multiple-imputation approaches.  
A study-wise Type I error of 0.05 will be used for the study. A multi-family 
gate-keeping strategy will be employed to control for the study-wise Type 
I error rate at alpha=0.05. There are 2 families of hypotheses tests. The 
first family is the primary endpoints family for the 2 dose groups. The 
second family includes the hypotheses tests with respect to a subset of 
secondary endpoints for which the control of Type I error is planned. 
For both co-primary endpoints, the Chi-square test will be used to 


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compare the active treatment groups and placebo. Chi-square test will also 
be used to test secondary endpoints consisting of proportion of responders. 
For analyses stratified by allodynia status, timing of treatment, the 
Cochran-Mantel-Haenszel test will be used. The Kaplan-Meier method 
will be used for time to use of rescue medications. Analysis of Covariance 
(ANCOVA) with treatment factor and baseline scores as a covariate, will 
be used for the analysis of FIS. The 24-hour Migraine Quality of Life 
Questionnaire assessments will be analyzed with the Analysis of Variance 
(ANOVA) models. The chi-square test will be used to analyze the Patient 
Global Impression ratings. 
Subgroup analyses of the key efficacy endpoints will be conducted to gain 
insight of the nature and consistency of the treatment effect. 
Safety 
Safety analyses will include all subjects who received at least one dose of 
study medication. 
All adverse events reported or observed will be listed, documenting 
severity, start and stop date and time, possible relationship to study 
medication, action taken, and outcome. Treatment emergent adverse 
events (TEAE) are defined as adverse events recorded after dosing of the 
investigational product. Verbatim terms will be classified to preferred 
terms (PT) and related system organ class (SOC) using the MedDRA 
dictionary. The preferred terms and system organ classes will be tabulated 
by treatment group. All reported adverse events will be summarized by the 
number of subjects reporting adverse events, system organ class, preferred 
term, severity and relationship to study drug. 
Safety labs including complete blood count (CBC), chemistry and 
urinalysis will be tabulated using descriptive statistics. A tabulation of 
by-subject abnormal/out-of-range findings and changes from pre-dose 
(baseline at Visit 2) to post-dose in all laboratory variables will be provided. 
Vital signs, objective and subjective evaluations of nasal irritation and 
standard 12-lead ECGs will be tabulated using descriptive statistics. A 
tabulation of by-subject abnormal/out-of-range findings and changes from 
pre-dose (baseline at Visit 2) to post-dose variables will be provided. 
 


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TABLE OF CONTENTS 
Signature Page (Sponsor) ................................................................................................................ 2 
Principal Investigator Agreement ................................................................................................... 3 
Protocol Synopsis............................................................................................................................ 4 
List of Tables ................................................................................................................................ 18 
List of Figures ............................................................................................................................... 18 
List of Appendices ........................................................................................................................ 18 
List of Abbreviations and Definitions of Terms ........................................................................... 19 
1. BACKGROUND INFORMATION .......................................................................................21 
1.1. Introduction .................................................................................................................. 21 
1.2. STS101 Description ..................................................................................................... 22 
1.2.1. STS101 Device ................................................................................................. 22 
1.2.2. STS101 Powder Formulation ........................................................................... 23 
1.2.2.1. DHE Mesylate Information ............................................................... 23 
1.2.3. DHE Mechanism of Action in the Treatment of Migraine .............................. 23 
1.2.4. STS101 DHE Pharmacokinetics ...................................................................... 23 
1.2.5. DHE Clinical Experience ................................................................................. 24 
1.2.6. DHE Mesylate Pregnancy Category................................................................. 25 
1.3. Summary of Nonclinical Data ...................................................................................... 25 
1.4. Rationale for the study ................................................................................................. 25 
2. STUDY OBJECTIVES AND PURPOSE ..............................................................................26 
3. STUDY DESIGN....................................................................................................................28 
3.1. Overall Study Design and Plan .................................................................................... 28 
3.2. Study Procedures Descriptions ..................................................................................... 29 
3.2.1. Informed Consent ............................................................................................. 29 
3.2.2. Assignment of Subject Identification Number ................................................. 29 
3.2.3. Inclusion and Exclusion Criteria Assessment .................................................. 29 
3.2.4. Medical History, Demographics, Concomitant and Prior Medications ........... 29 
3.2.5. Headache Impact Test (HIT-6TM) ..................................................................... 30 
3.2.6. Physical Examination ....................................................................................... 30 
3.2.7. Vital Signs ........................................................................................................ 30 


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3.2.8. Weight, Height and Body Mass Index (BMI) .................................................. 30 
3.2.9. Evaluations of Effects in the Nose ................................................................... 31 
3.2.9.1. Subjective Assessment of Nasal Irritation ........................................ 31 
3.2.9.2. Objective Assessment of Nasal Irritation .......................................... 31 
3.2.10. Clinical Laboratory Tests ................................................................................. 31 
3.2.11. Electrocardiogram ............................................................................................ 32 
3.2.12. Adverse Events Recording ............................................................................... 32 
3.2.13. Electronic Headache Diary ............................................................................... 32 
3.3. Schedule of Observations and Procedures ................................................................... 33 
3.3.1. Screening Procedures ....................................................................................... 33 
3.3.2. Screening Visit & Period (Day-35 to Day -1) .................................................. 33 
3.3.3. Randomization Visit (Visit 2) .......................................................................... 34 
3.3.4. Final Visit/Early Termination (Visit 3) ............................................................ 35 
4. SELECTION AND WITHDRAWAL OF SUBJECTS ..........................................................36 
4.1. Subject Inclusion Criteria ............................................................................................. 36 
4.2. Subject Exclusion Criteria ............................................................................................ 37 
4.3. Subject Withdrawal Criteria ......................................................................................... 38 
5. TREATMENT OF SUBJECTS ..............................................................................................39 
5.1. Description of Investigational Product and Packaging ................................................ 39 
5.2. Investigational Product Labeling.................................................................................. 39 
5.3. Investigational Product Storage.................................................................................... 40 
5.4. Investigational Product Administration & Training ..................................................... 40 
5.5. Investigational Product Accountability ........................................................................ 40 
5.6. Investigational Product Handling and Disposal ........................................................... 41 
5.7. Concomitant Medications............................................................................................. 41 
5.8. Treatment Compliance ................................................................................................. 41 
5.9. Randomization and Blinding ........................................................................................ 42 
5.9.1. Subject Randomization..................................................................................... 42 
5.9.2. Blinding ............................................................................................................ 42 
5.9.3. Unblinding Procedures ..................................................................................... 42 
6. ASSESSMENT OF EFFICACY ............................................................................................43 
6.1. Efficacy Evaluation Parameters ................................................................................... 43 


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6.1.1. Migraine Headache Pain Severity .................................................................... 43 
6.1.2. Most Bothersome Symptom ............................................................................. 43 
6.1.3. Evaluation of Allodynia ................................................................................... 43 
6.1.4. Use of Rescue Medication ................................................................................ 44 
6.1.5. Evaluation of Function ..................................................................................... 44 
6.1.5.1. Functional Impairment Scale ............................................................ 44 
6.1.5.2. 24-hour Migraine Quality of Life Questionnaire .............................. 44 
6.2. Patient Global Impression ............................................................................................ 44 
7. ASSESSMENT OF SAFETY .................................................................................................45 
7.1. Safety Parameters ......................................................................................................... 45 
7.1.1. Examinations .................................................................................................... 45 
7.1.1.1. Physical Examinations ...................................................................... 45 
7.1.1.2. Height, Weight, and BMI .................................................................. 45 
7.1.1.3. Vital Signs ......................................................................................... 45 
7.1.1.4. Nasal Mucosa Irritation Assessments ............................................... 45 
7.1.1.5. Electrocardiogram (ECG) ................................................................. 45 
7.1.2. Laboratory Assessments ................................................................................... 46 
7.1.2.1. Hematology ....................................................................................... 46 
7.1.2.2. Serum Chemistry ............................................................................... 46 
7.1.2.3. Urinalysis .......................................................................................... 46 
7.1.2.4. Urine Drug Screen ............................................................................. 46 
7.1.2.5. Serum Pregnancy Test ....................................................................... 46 
7.2. Adverse Events ............................................................................................................. 46 
7.2.1. AE Relationship to Study Drug ........................................................................ 47 
7.2.2. Assessment of Adverse Event Severity ............................................................ 48 
7.2.3. Serious Adverse Events (SAEs) Recording and Reporting.............................. 48 
8. STATISTICS ..........................................................................................................................50 
8.1. Sample Size Determination .......................................................................................... 50 
8.2. Subject Populations ...................................................................................................... 50 
8.2.1. Intent-to-Treat Population ................................................................................ 50 
8.2.2. Modified Intent-to-Treat Population ................................................................ 50 
8.2.3. Per-Protocol Population ................................................................................... 50 


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8.2.4. Safety Population ............................................................................................. 51 
8.3. Statistical Analysis ....................................................................................................... 51 
8.3.1. Demographic and Baseline Variables .............................................................. 51 
8.3.2. Efficacy Analysis ............................................................................................. 52 
8.3.2.1. Primary Efficacy Endpoints .............................................................. 52 
8.3.2.2. Secondary Efficacy Endpoints .......................................................... 52 
8.3.2.3. Hypotheses Testing and Significance Level ..................................... 53 
8.3.2.4. Handling of Missing Data ................................................................. 54 
8.3.2.5. Pooling of Centers ............................................................................. 54 
8.3.2.6. Analysis Methods for Efficacy Endpoints ........................................ 54 
8.3.2.7. Subgroup Analysis of Efficacy Endpoints ........................................ 55 
8.3.3. Safety Analysis ................................................................................................. 55 
8.3.3.1. Extent of Exposure ............................................................................ 55 
8.3.3.2. Adverse Events .................................................................................. 55 
8.3.3.3. Assessment of Nasal Irritation .......................................................... 56 
8.3.3.4. Laboratory Evaluations ..................................................................... 56 
8.3.3.5. Vital Signs ......................................................................................... 56 
8.3.3.6. ECG Evaluations ............................................................................... 57 
8.3.3.7. Concomitant Medications ................................................................. 57 
8.3.4. Interim analysis ................................................................................................ 57 
9. DATA HANDLING AND RECORDKEEPING ...................................................................58 
9.1. Case Report Forms (CRFs) .......................................................................................... 58 
9.2. Retention of Records .................................................................................................... 58 
10. QUALITY CONTROL AND QUALITY ASSURANCE ......................................................59 
10.1. Study Monitoring ......................................................................................................... 59 
10.2. Audits and Inspections ................................................................................................. 59 
11. ETHICS...................................................................................................................................60 
11.1. Ethics Review ............................................................................................................... 60 
11.2. Ethical Conduct of the Study........................................................................................ 60 
11.3. Written Informed Consent ............................................................................................ 60 
11.4. Disclosure of Data ........................................................................................................ 61 
12. REFERENCES .......................................................................................................................62 


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List of Tables 
Table 1. DHE PK Parameters, mean (±SD); STS101-001, Part 1 ............................................. 24 
Table 2. DHE PK Parameters, mean (±SD); STS101-001, Part 2 ............................................. 24 
Table 3. Laboratory Tests ........................................................................................................... 32 
Table 4. Adverse Event Relationship to Study Drug ................................................................. 47 
Table 5. Assessment of Adverse Event Severity ........................................................................ 48 
List of Figures 
Figure 1. STS101 Device ............................................................................................................. 22 
Figure 2. Dihydroergotamine mesylate chemical structure ......................................................... 23 
Figure 3. Study Schematic ........................................................................................................... 29 
List of Appendices 
Appendix A. Schedule of Assessments ...................................................................................... 64 
Appendix B. Subjective Assessment of Nasal Irritation ............................................................ 65 
Appendix C. Objective Assessment of Nasal Irritation ............................................................. 66 
Appendix D. STS101 Instructions for Use ................................................................................. 68 
Appendix E. 24-Hour Migraine Quality of Life Questionnaire ................................................. 70 
Appendix F. Headache Impact Test (HIT-6™) ......................................................................... 72 
 
 


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List of Abbreviations and Definitions of Terms 
Abbreviation or specialist term 
Explanation 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Concentration-Time Curve 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CGRP 
Calcitonin Gene-Related Peptide 
CI 
Confidence Interval 
CM 
Concomitant Medication 
Cmax 
Maximum Observed Plasma Concentration 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CV 
Coefficient of Variation 
DHE 
Dihydroergotamine 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
e-diary 
Electronic diary in handheld device 
ET 
Ergotamine Tartrate 
FIS 
Functional Impairment Scale 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GRAS 
Generally Recognized As Safe 
hCG 
Human Chorionic Gonadotropin 
HPMC 
Hydroxypropyl Methylcellulose 
ICF 
Informed Consent Form 
IM 
Intramuscular 
IN 
Intranasal 
IRB 
Institutional Review Board 
IV 
Intravenous 
kel 
Terminal Rate Constant 
MAO 
Monoamine Oxidase 
MedDRA 
Medical Dictionary for Regulatory Activities 
NDA 
New Drug Application 
OTC 
Over the Counter 
PE 
Physical Exam 
PK 
Pharmacokinetic 
PT 
Preferred Term (in MedDRA dictionary) 


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Abbreviation or specialist term 
Explanation 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SD 
Standard Deviation 
SOC 
System Organ Class (in MedDRA dictionary) 
SOP 
Standard Operating Procedure 
T1/2 
Terminal Elimination Half-Life 
TEAE 
Treatment Emergent Adverse Events 
TK 
Toxicokinetic 
Tmax 
Time to reach Cmax 
VAS 
Visual Analog Scale 


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1. 
BACKGROUND INFORMATION 
1.1. Introduction 
Satsuma Pharmaceuticals, Inc. (Satsuma) is developing STS101 (dihydroergotamine nasal 
powder), a drug-device combination of a dihydroergotamine (DHE) mesylate dry powder 
formulation prefilled in a single use delivery device for nasal administration. DHE mesylate is 
currently indicated for the acute treatment of migraine headaches with or without aura and the 
acute treatment of cluster headache episodes. DHE mesylate is available as a solution for 
subcutaneous (SC), intramuscular (IM), or intravenous (IV) administration and as a nasal spray 
(IN) (DHE 45® Prescribing Information 2017; Migranal® Prescribing Information 2017). 
DHE mesylate is a semi-synthetic derivative of ergotamine tartrate that has been used effectively 
to treat migraine since 1945 (Silberstein 2003) and was first approved in U.S. in 1946. The 
antimigraine activity of DHE mesylate is likely related to the agonist activity at 5-HT1B, 5-HT1D, 
and 5-HT1F receptors (Dahlöf 2012). Additionally, DHE mesylate can cause vasoconstriction via 
CGRP release by stimulating adrenergic α2A/2c and 5-HT2A receptors and may inhibit neurogenic 
inflammation in peripheral meningeal tissues and nociceptive neuronal transmission centrally in 
the trigeminal nucleus caudalis (Hoskin 1996; Burstein 2004; Silberstein 2003; Dahlöf 2012; 
González-Hernández 2018). The DHE mesylate-related side effects of nausea and vomiting are 
likely related to activation of central 5-HTlA receptors and dopamine D2 receptors 
(Silberstein 2003). 
DHE mesylate is listed as first-line treatment in migraine treatment guidelines from the American 
Academy of Neurology (Marmura 2015). The effectiveness of DHE mesylate via intravenous, 
intramuscular, subcutaneous, intranasal and orally inhaled administration routes has been 
demonstrated (Raskin 1986; Winner 1996; Gallagher 1996; Carleton 1998; Edwards 2001; 
Aurora 2011). In these studies, treatment with DHE mesylate has consistently resulted in 
headache relief in 50 to 70% of the treated patients at 2 hours after administration. 
However, patient acceptance of DHE mesylate has been limited due to these shortcomings: 
• D.H.E.45® (Injectable DHE mesylate solution) 
o Inconvenience and side effects of administration by injection (IV, IM, SC) 
o DHE mesylate-related side effects, especially nausea, which is likely related to rate of 
administration (IV) and Cmax and has been reported to occur less frequently when 
plasma concentrations remain below 6-10 ng/mL (Cook 2009) 
• Migranal® (DHE mesylate intranasal spray) 
o Inconvenient multi-step procedure of vial opening, spray device-to-vial assembly, and 
priming (Migranal® Administration Instructions 2017) 
o Inconvenient administration procedure requiring four 0.125 mL sprays (two in each 
nostril, repeated after 15 minutes) (Migranal® Prescribing Information 2017) and 
Migranal® Administration Instructions 2017) 


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o Low and variable bioavailability (Tfelt-Hansen 2013; 
Migranal® Prescribing Information 2017) 
o Slow onset of action (Tfelt-Hansen 2013) 
o Drug run off into the pharynx and out of the nose (Djupesland 2013) 
o Side effect of bad or altered sense of taste (Migranal® Prescribing Information 2017; 
van der Kuy 1999). 
STS101 (DHE nasal powder) is designed and being developed to address the shortcomings of the 
injectable and intranasal DHE mesylate formulations: 
• STS101 is designed to be easy and convenient for patients to quickly self-administer 
during a migraine attack. 
• STS101 is rapidly and consistently absorbed with Tmax, Cmax and AUC values falling 
within ranges that have previously been established to be effective for DHE mesylate. 
• Consistent with DHE mesylate effectiveness data reported in multiple studies, STS101 
treatment is expected to be effective in early and late treatment of migraines, in attacks 
with and without allodynia, and to result in high 24-hour pain-free and low 24-hour 
recurrence rates. 
1.2. STS101 Description 
STS101 is a drug-device combination product consisting of a powder formulation of DHE 
mesylate prefilled in a single use delivery device for intranasal (IN) administration. 
1.2.1. 
STS101 Device 
STS101 will be delivered by a pre-filled single use device, which is a manually operated and air 
driven device specifically designed for IN drug delivery (Figure 1). 
Figure 1. STS101 Device 
 


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1.2.2. 
STS101 Powder Formulation 
STS101 is a white to off-white powder formulation containing DHE mesylate, microcrystalline 
cellulose (MCC), hypromellose (hydroxypropyl methylcellulose, HPMC), and mannitol.  
1.2.2.1. 
DHE Mesylate Information 
DHE mesylate is a semi-synthetic derivative of ergotamine tartrate and is known chemically as 
ergotaman-3´,6´,18-trione,9,10-dihydro-12´-hydroxy-2´-methyl-5´-(phenylmethyl)-,(5´α)-
,monomethanesulfonate. Its molecular weight is 679.80 and its empirical formula is 
C34H41N5O8S. The chemical structure is shown in Figure 2. 
Figure 2. Dihydroergotamine mesylate chemical structure 
1.2.3. 
DHE Mechanism of Action in the Treatment of Migraine 
The antimigraine activity of DHE is likely related to the agonist activity at 5-HT1B, 5-HT1D, 
and 5-HT1F receptors (Dahlöf 2012). Additionally, DHE can cause vasoconstriction via CGRP 
release by stimulating adrenergic α2A/2c and 5-HT2A receptors and may inhibit neurogenic 
inflammation in peripheral meningeal tissues and nociceptive neuronal transmission centrally in 
the trigeminal nucleus caudalis (Hoskin 1996; Burstein 2004; Silberstein 2003; Dahlöf 2012; 
González-Hernández 2018). The DHE mesylate-related side effects of nausea and vomiting are 
likely related to activation of central 5-HTlA receptors and dopamine D2 receptors (Silberstein, 
2003). Because of slow diffusion from the receptor biophase, the effects of DHE mesylate last 
far longer than can be expected from plasma concentrations (Dahlöf 2012; Tfelt-Hansen 2013). 
1.2.4. 
STS101 DHE Pharmacokinetics 
In a 2-part, three period, cross-over Phase 1 study, 15 healthy subjects were dosed with 
ascending doses of 1.3, 2.6 and 5.2 mg STS101 (equivalent to 1.5, 3.0, and 6.0 mg DHE 
mesylate USP). STS101 demonstrated dose dependent plasma concentrations. Table 1 shows 
selected PK parameters of Part 1 of the study. 
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Table 1. DHE PK Parameters, mean (±SD); STS101-001, Part 1 
Parameter 
STS101 (1.3 mg) 
STS101 (2.6 mg) 
STS101 (5.2 mg) 
Cmax (pg/mL) 
645 (418) 
1243 (576) 
1870 (823) 
Tmax (h) 
0.7 (0.28) 
0.7 (0.47) 
0.4 (0.12) 
AUC0-30min (h*pg/mL) 
188 (137) 
362 (225) 
606 (295) 
AUC0-2hr (h*pg/mL) 
956 (591) 
1683 (719) 
2549 (1132) 
AUC0-inf (h*pg/mL) 
4172 (1860) 
7022 (2557) 
10150 (3814) 
T1/2 (h) 
12.9 (2.1) 
12.6 (1.3) 
12 (1.6) 
Source: STS101-001 Data Tables, February 2019 
 
In Part 2 of the study, 27 healthy subjects were dosed with 5.2 mg STS101 (equivalent to 6.0 mg 
DHE mesylate USP), 1.0 mg IM DHE mesylate, and 2.0 mg intranasal DHE mesylate spray in a 
randomized order. Table 2 shows selected PK parameters. 
Table 2. DHE PK Parameters, mean (±SD); STS101-001, Part 2 
Parameter 
IM DHE Mesylate 
(1.0 mg) 
Migranal 
(IN DHE Mesylate Spray 
2.0 mg) 
STS101 
(DHE Nasal Powder 5.2 mg 
(Equivalent to 6.0 mg 
DHE Mesylate USP) 
Cmax (pg/mL) 
3368 (840) 
961 (727) 
2175 (884) 
Tmax (h) 
0.37 (0.3) 
1.04 (0.4) 
0.6 (0.4) 
AUC0-30min (h*pg/mL)* 
1357 (389) 
152 (131) 
686 (326) 
AUC0-2hr (h*pg/mL)* 
4791 (908) 
1316 (990) 
2979 (1147) 
AUC0-inf (h*pg/mL) 
13650 (2143) 
6498 (3551) 
12030 (4716) 
T1/2 (h) 
11.2 (1.93) 
12.7 (2) 
11.8 (2.2) 
Source: STS101-001 Data Tables, February 2019 
 
Adverse events reported with STS101 use were all mild and mostly local nasal events such as 
discomfort, burning, or rhinorrhea, and taste sensations such as bitter or sour taste. 
Additional information including detailed adverse event data may be found in the STS101 
Investigator’s Brochure. 
1.2.5. 
DHE Clinical Experience 
Migranal® (DHE mesylate intranasal liquid) and D.H.E. 45® (DHE mesylate injectable solution), 
approved in the United States in 1998 and 1946, respectively, have been prescribed to a large 
number of patients with migraine headaches. A detailed summary of human experience with 


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marketed DHE mesylate formulations and other data regarding Migranal and DHE mesylate 
Injectable solution can be found in the STS101 Investigator’s Brochure. 
1.2.6. 
DHE Mesylate Pregnancy Category 
DHE mesylate may cause fetal harm when administered to a pregnant woman. There are no 
adequate studies of DHE mesylate in human pregnancy, but developmental toxicity has been 
demonstrated in experimental animals. DHE mesylate possesses oxytocic properties and, 
therefore, should not be administered during pregnancy. If this drug is used during pregnancy, or 
if the patient becomes pregnant while taking this drug, the patient should be apprised of the 
potential hazard to the fetus. DHE mesylate is designated Pregnancy Category X in the U.S 
(DHE 45® Prescribing Information 2017; Migranal® Prescribing Information 2017). 
1.3. Summary of Nonclinical Data 
The nonclinical toxicology program for STS101 was designed to supplement the known 
nonclinical studies in support of the general safe use of DHE mesylate. In a GLP 14-day 
intranasal toxicology study with a 14-day recovery period conducted in dog, the presumed No 
Observed Adverse Effect Level (NOAEL) of DHE mesylate dose given to dogs (the most 
sensitive species) was approximately 49-fold more than the planned highest clinical dose of 
STS101 on a dose/weight (mg/kg) basis and 5-fold more based on a normalized nasal cavity 
surface area comparison. The results of the dog 14-day study support the presumption that the 
STS101 DHE mesylate formulation yields no new or unexpected significant toxicity at the 
highest feasible concentrations possible. The large safety multiples based on the NOAEL provide 
reassurance that the proposed human clinical dosing is reasonable and safe. The study is 
summarized in detail in the STS101 Investigator’s Brochure. 
1.4. Rationale for the study 
In the Phase 1 Study STS101-001, STS101 showed DHE plasma concentrations and PK 
parameters comparable to those previously reported for other DHE mesylate formulations and 
routes of administration (Schran 1994; Humbert 1996; Shrewsbury 2008). Based on the reported 
clinical efficacy data for these other DHE mesylate formulations and routes of administration, 
the PK profile of STS101 is assumed to be predictive of at least comparable clinical efficacy 
(Gallagher 1996; Winner 1996, Aurora 2011). 
This study follows the FDA Guidance1 and the Guidelines of International Headache Society for 
acute migraine studies (Diener 2019) and is being conducted as part of the clinical development 
program for STS101 to demonstrate the efficacy, safety and tolerability of STS101 in the 
treatment of acute migraine attacks with or without aura. 
                                                 
1 FDA Guidance for Industry. Migraine: Developing Drugs for Acute Treatment. February 2018. 


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2. 
STUDY OBJECTIVES AND PURPOSE 
The objectives of this study are: 
Primary 
• To evaluate the efficacy of single doses of two strengths of STS101 to achieve freedom from 
pain at 2 hours after dosing in subjects with acute migraine attacks 
• To evaluate the efficacy of single doses of two strengths of STS101 to achieve freedom from 
most bothersome symptom at 2 hours after dosing in subjects with acute migraine attacks 
Secondary 
• To evaluate the efficacy of single doses of two strengths of STS101 to achieve 2 to 24 hour 
sustained pain free status in subjects with acute migraine attacks 
• To evaluate the efficacy of single doses of two strengths of STS101 to achieve 2 to 48 hour 
sustained pain free status in subjects with acute migraine attacks 
• To evaluate the efficacy of single dose of two strengths of STS101 to avoid the use of rescue 
medication within 24 hours after dosing in subjects with acute migraine attacks 
• To evaluate the efficacy of single dose of two strengths of STS101 to avoid the use of rescue 
medication within 48 hours after dosing in subjects with acute migraine attacks 
• To evaluate the efficacy of single doses of two strengths of STS101 to achieve pain relief at 
2 hours after dosing in subjects with acute migraine attacks 
• To evaluate the efficacy of single doses of two strengths of STS101 to avoid headache pain 
relapse within 24 hours after dosing in subjects with acute migraine attacks 
• To evaluate the efficacy of single doses of two strengths of STS101 to avoid headache pain 
relapse within 48 hours after dosing in subjects with acute migraine attacks 
• To evaluate the effects of single doses of two strengths of STS101 on the Functional 
Impairment Scale (FIS) in subjects with acute migraine attacks 
• To evaluate the effects of single doses of two strengths of STS101 on the 24-hour Migraine 
Quality of Life Questionnaire (24-MQoLQ) in subjects with acute migraine attacks 
• To evaluate the efficacy of single doses of two strengths of STS101 to achieve freedom from 
pain depending upon time elapsed from onset of migraine attack to time of dosing 
• To evaluate the efficacy of single doses of two strengths of STS101 to achieve freedom from 
pain by allodynia status at time of dosing in subjects with acute migraine attacks 
• To evaluate the efficacy of single doses of two strengths of STS101 to achieve freedom from 
pain and most bothersome symptom at 2 hours after dosing in subjects with severe acute 
migraine attacks 


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• To evaluate the efficacy of single doses of two strengths of STS101 to achieve freedom from 
pain and most bothersome symptom at 2 hours after dosing in subjects who wake up with 
acute migraine attacks 
• To evaluate the efficacy of single doses of two strengths of STS101 to achieve freedom from 
pain and most bothersome symptom at 2 hours after dosing in subjects with acute 
menstrually related migraine attacks 
• To evaluate the efficacy of single doses of two strengths of STS101 to achieve pain relief at 
2 hours after dosing in subjects with acute migraine attacks by allodynia status at time of 
treatment 
• To evaluate the efficacy of single doses of two strengths of STS101 to achieve freedom from 
pain at various timepoints after dosing 
• To evaluate the efficacy of single doses of two strengths of STS101 to achieve pain relief at 
various timepoints after dosing 
• To estimate the probability of a subject responding to treatment (freedom from pain) during 
the 24-hour post dose period 
• To estimate the probability of a subject requiring rescue medication during the 24-hour post 
dose period 
• To evaluate the efficacy of single doses of two strengths of STS101 to achieve freedom from 
photophobia at 2 hours after dosing 
• To evaluate the efficacy of single doses of two strengths of STS101 to achieve freedom from 
phonophobia at 2 hours after dosing 
• To evaluate the efficacy of single doses of two strengths of STS101 to achieve freedom from 
nausea at 2 hours after dosing 
• To evaluate the efficacy of single doses of two strengths of STS101 to achieve pain relief 
depending upon time elapsed from onset of migraine to time of dosing 
• To evaluate the efficacy of single doses of two strengths of STS101 to achieve freedom from 
pain and most bothersome symptom at 2 hours after dosing in subjects with acute migraine 
attacks 
• To evaluate the efficacy of single doses of two strengths of STS101 to achieve freedom from 
pain and most bothersome symptom over various timepoints after dosing in subjects with 
acute migraine attacks 
• To evaluate the study subject’s global impression of the study treatment 
• To assess the safety and tolerability of single doses of two strengths of STS101 in the 
treatment of acute migraine attacks 


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3. 
STUDY DESIGN 
3.1. Overall Study Design and Plan 
This is a multi-center, single-dose, randomized, double-blind, placebo-controlled, parallel group 
study in approximately 1140 subjects with acute migraine (ages 18 to 65 years). 
After establishing initial eligibility, the study participants will document their headache attacks 
for 28 days in an electronic diary. Attack frequency, duration, pain severity, presence of 
symptoms (nausea; photophobia, phonophobia) and impact on functional status will be 
documented. Study participants must have 2 to 8 migraine attacks, and fewer than 15 headache 
days during the 28-day screening period to be eligible for randomization. 
After establishing full eligibility, the study participants will be trained in the use of the STS101 
device and randomized (1:1:1) to receive one of three treatments: 
• 3.9 mg STS101 (equivalent to 4.5 mg of DHE mesylate USP) 
• 5.2 mg STS101 (equivalent to 6.0 mg of DHE mesylate USP) 
• Placebo (matching nasal powder) 
After randomization, the study participants will treat their next qualifying migraine attack of at 
least moderate pain severity with the allocated blinded study medication at home. The subjects 
will be instructed to treat a qualifying migraine attack within 8 hours of the onset of the attack. 
The study participants will document the pain severity of their treated migraine attack, presence 
of symptoms (photophobia, phonophobia, nausea) presence of allodynia and functional status over 
the 48-hour period after study drug administration in an e-diary. Headache pain severity and 
symptom data will be collected at the onset of the migraine attack, immediately before drug 
administration (time 0), at 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 6, 12, 24, and 48 hours after 
study drug administration. The subjects must select a most bothersome symptom among 
photophobia, phonophobia, and nausea immediately before study drug administration. 
Additionally, subjective nasal irritation assessments will be documented during the treatment 
period. 
If subjects require rescue medication, they will be encouraged to wait until the 2-hour post study 
drug administration data collection timepoint. The use of triptans or other ergot-containing 
products (including DHE mesylate and ergotamine) as rescue medications should be avoided for 
24 hours after study drug administration. The study participants will return to the study site 
within one week of the treated migraine attack. 
Adverse events, objective nasal evaluation data, safety laboratory data, vital sign data and ECGs 
will be recorded before and after treatment to evaluate the tolerability and safety of STS101. 
Sufficient numbers of subjects will be screened to enroll approximately 1140 subjects in the 
study. The dropout rate is estimated to be less than 20%. Subjects who withdraw or are withdrawn 
from the study after dosing will not be replaced. However, in the event that the number of drop-


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outs or number of subjects with missing data exceeds initial expectations, subjects who withdraw 
or are withdrawn might be replaced. 
Figure 3 displays the study schematic design: 
Figure 3. Study Schematic 
 
3.2. Study Procedures Descriptions 
The following list is a description of the procedures to be completed at screening and during the 
study: 
3.2.1. 
Informed Consent 
An Ethics Committee (EC)/Investigational Review Board (IRB)-approved informed consent 
form (ICF) must be signed and dated by each study subject prior to any study procedures being 
performed and a copy must be given to the subject. 
3.2.2. 
Assignment of Subject Identification Number 
Each subject will be assigned an individual subject identification number. The first three digits 
will identify the study site (ranging from 001 to 999) and last three digits will identify the subject 
as a running number starting with 001. As an example, the first subject entering screening at site 
001 would receive the subject identification number 001-001, the second subject 001-002 etc.  
3.2.3. 
Inclusion and Exclusion Criteria Assessment 
All subjects must qualify for the study based on the inclusion and exclusion criteria specified in 
Section 4.1 and Section 4.2, respectively. 
3.2.4. 
Medical History, Demographics, Concomitant and Prior Medications 
A complete medical history will be obtained including a review of all major organ systems, and 
a history of alcohol, tobacco and caffeine use. Demographics will include gender, date of birth 
RANDOMIZE 
STS101 
3.9 mg 
STS101 
5.2 mg 
Placebo 
28-day e-diary 
screening period 


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race and ethnicity. Prior medications will include all medications taken for 1 month (28 days) 
prior to Screening. The medical history, demographics and a list of concomitant and prior 
medications will be documented at the screening visit. 
In female subjects who menstruate the following additional information will be documented for 
the three months prior to the Screening Visit: 
• Timing and duration of menstruation in each month 
• Occurrence of migraine headaches on day 1 (± 2 days) of menstruation in each month 
Previous or current triptan use will be documented. Subjects who have or are currently using 
triptans will be asked to estimate how often they experience(d) pain relief (moderate or severe 
pain becoming mild to no pain) with triptan use: 
• >75% of the time; >50 to 75% of the time; >25 to 50% of the time; <25% of the time 
3.2.5. 
Headache Impact Test (HIT-6TM) 
At the Randomization Visit (Visit 2), subjects will complete the 6-question Headache Impact 
Test (Appendix F), a tool for assessing the impact of headache on daily life in subjects with 
migraine (Yang 2010). 
3.2.6. 
Physical Examination 
A physical examination will be performed at Screening (Visit 1), Randomization (Visit 2) and at 
the Follow-up/early termination visit. The examination will include all major body systems with 
the exception of genitourinary. Site Personnel performing the physical exams must be qualified 
by training and licensure. 
3.2.7. 
Vital Signs 
Vital signs will be obtained at Screening (Visit 1), Randomization (Visit 2), and at the Follow-
up/early termination visit. Vital signs will include oral temperature, sitting blood pressure (to be 
taken after 5 minutes of sitting), pulse rate, and respiration rate. 
3.2.8. 
 Weight, Height and Body Mass Index (BMI) 
Subjects will be weighed in street clothes after removing shoes, coat or jacket. Weight will be 
measured at Screening, Randomization, and at the follow-up/early termination visit. Subject 
height will only be measured at screening, without shoes. Subjects will have their BMI calculated 
at the Screening visit (Visit 1) using the following formula: BMI = weight (kg)/height (m2). 


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3.2.9. 
Evaluations of Effects in the Nose 
3.2.9.1. 
Subjective Assessment of Nasal Irritation 
This is an 8-item questionnaire to be completed by the study subject with each item having to do 
with various aspects of nasally related signs and symptoms (e.g., nasal burning, itching, and pain). 
The subject will check the severity of each item on a visual analog scale (VAS; range 0-100 mm) 
in the electronic diary. The questionnaire and completion instructions are shown in Appendix B. 
The subjective assessment of nasal irritation will be performed at the following times: Screening 
(Visit 1), Randomization (Visit 2), immediately before and 15 and 60 minutes and 24 hours after 
study drug administration and at the Follow-up/early termination Visit (Visit 3). 
All VAS assessments will be converted to a numerical value in millimeters (range 0-100). 
3.2.9.2. 
Objective Assessment of Nasal Irritation 
This is a 5-item assessment to be completed by a qualified physician or physician assistant. 
Using categorical scales ranging from “none” to “severe”, the physician will rate various aspects 
of the findings on physical examination of the nasal cavity. The questionnaire and detailed 
instructions for completion are shown in Appendix C. 
The objective assessment of nasal irritation will be performed during Screening (Visit 1), 
Randomization (Visit 2), and at the Follow-up/early termination Visit (Visit 3). Assessment 
sheets must be retained for all subjects. The person performing the assessments should be the 
same at all visits. 
3.2.10. Clinical Laboratory Tests 
A designated central laboratory will perform the hematology, biochemistry, urinalysis and 
diagnostic tests as specified in Table 3. 
Samples for clinical laboratory tests will be taken at Screening (Visit 1), Randomization (Visit 2) 
and at the Follow-up/early termination visit (Visit 3). All samples will be collected in accordance 
with the Study Laboratory Manual and shipped to the designed central laboratory.  
Laboratory reports will be reviewed by the investigator and out of range values will be identified 
and may be repeated at the Investigator's discretion. The Investigator will determine if any out of 
range values are clinically-significant and require recording as adverse events (AEs) in the 
electronic Case Report Form (eCRF). All clinically-significant out of range laboratory values 
obtained at the Randomization Visit or Follow-up visit will be followed until they return to 
normal or become medically stable. 


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Table 3. Laboratory Tests 
Hematology 
Serum Chemistry 
Urinalysis 
Hematocrit 
Hemoglobin 
MCV 
Red Blood Cell Count 
Platelet Count 
White Blood Cell Count (with Differential) 
Albumin 
Alkaline Phosphatase 
Alanine Transaminase (ALT) 
Aspartate Transaminase (AST) 
Blood Urea Nitrogen (BUN) 
Calcium 
Chloride 
Cholesterol profile 
Creatine phosphokinase 
Creatinine 
Gamma Glutamyl Transferase 
Glucose  
Lactate Dehydrogenase 
Potassium 
Sodium 
Direct and Total Bilirubin 
Total Protein 
Thyroid function tests (TSH, 
total T3 & T4) 
Serum pregnancy test 
Appearance 
Color 
pH 
Specific Gravity 
Protein  
Glucose  
Ketones 
Occult Blood 
Nitrites 
Urobilinogen 
Leukocytes 
Bilirubin 
Urine microscopy, if necessary 
Diagnostic Screening 
Urine 
Alcohol & Drug Panel: Amphetamines, Barbiturates, Benzodiazepines, Cannabinoids, Cocaine, Opiates, PCP and 
Methadone  
 
3.2.11. Electrocardiogram 
A 12-lead ECG will be performed at Screening (Visit 1), Randomization (Visit 2), and at the 
Follow-up/early termination Visit (Visit 3). At the Screening and Randomization Visits the 
investigator or a qualified delegate will review the ECG to assure subject eligibility. All ECGs 
will be done in triplicate. 
3.2.12. Adverse Events Recording 
Adverse events will be recorded and assessed as specified in Section 7. 
3.2.13. Electronic Headache Diary 
Study participants will receive a handheld device for collection of electronic diary data. At the 
Screening and Randomization Visits, study participants will receive training in the use of the 
device. During the Screening Period the study participants will document their headaches for 
28 days. Headache frequency, and migraine attacks (including information on pain severity and 
symptoms identifying a migraine headache) will be documented. Study participants must have at 


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least 2 attacks but no more than 8 attacks of migraine and less than 15 headache days during the 
28-day period to be eligible for randomization. 
During the treatment period, the study participants will document sign and symptom symptoms 
identifying a migraine headache, the pain severity of their treated migraine attack, presence and 
severity of symptoms (photophobia, phonophobia, nausea, allodynia) and functional status over 
the 48-hour period after study drug administration in the e-diary. Additionally, subjective nasal 
irritation assessments will be documented during the treatment period. 
The complete content and the training procedures for the electronic diary device will be 
described in separate documents. 
3.3. Schedule of Observations and Procedures 
Appendix A shows the procedure for the study. The following assessments should be completed 
at the designated time period(s). 
3.3.1. 
Screening Procedures 
Initial screening will be performed at Study Entry, and it will determine whether subjects will 
qualify for the study. 
3.3.2. 
Screening Visit & Period (Day-35 to Day -1) 
Subject screening procedures and study entry procedures include: 
a. Signing of informed consent 
b. Review of inclusion/exclusion criteria 
c. Recording of demographic data 
d. Medical history, including concomitant medications 
e. Physical examination 
f. Vital signs (including pulse rate, respiration rate, sitting blood pressure and oral 
temperature) 
g. Body weight, height and BMI calculation 
h. Objective assessment of nasal irritation 
i. Subjective assessment of nasal irritation 
j. STS101 device training  
k. Electronic headache diary use training 
l. Clinical laboratory tests 
m. Urinalysis 


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n. Serum pregnancy test (females only) 
o. Urine drug and alcohol screen 
p. 12-lead ECG (in triplicate) 
q. Completion of Headache Diary by subject (28 days) 
3.3.3. 
Randomization Visit (Visit 2)  
Eligible subjects will be randomized to treatment on study Day 1 
a. Review of 28-day migraine headache diary data 
b. Review of eligibility criteria 
c. Vital signs (including pulse rate, respiration rate, sitting blood pressure and oral 
temperature) 
d. Physical examination 
e. Weight 
f. Concomitant medication review 
g. Clinical laboratory tests and urinalysis 
h. Serum pregnancy test (females only) 
i. Urine drug and alcohol screen 
j. 12-lead ECG (in triplicate) 
k. Objective assessment of nasal irritation 
l. Subjective assessment of nasal irritation 
m. Completion of HIT-6 instrument 
Any subject that no longer qualifies for study participation based on findings in any of the 
procedures will be withdrawn from the study as a screen failure and the reasons recorded on the 
screen failure log. 
If the subject still meets all eligibility criteria for study participation, the following procedures 
will be done: 
a. Randomization 
b. STS101 device and administration training 
c. Dispense Investigational Product 
d. Electronic headache diary use training and dispensation of electronic diary 


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3.3.4. 
Final Visit/Early Termination (Visit 3) 
Subjects will undergo final safety assessment procedures within one week (7 days ± 3days) after 
migraine treatment. The follow-up visit/early termination procedures will comprise the 
following: 
a. Physical examination 
b. Vital signs (including pulse rate, respiration rate, sitting blood pressure and oral 
temperature) 
c. Weight 
d. Concomitant medication review 
e. Serum pregnancy test (females only) 
f. Clinical laboratory tests  
g. Urinalysis 
h. 12-lead ECG (in triplicate) 
i. Objective assessment of nasal irritation 
j. Subjective assessment of nasal irritation 
k. Patient Global Impression Question 
l. Adverse events 
m. Collect used Investigational Product (STS101 device) 
n. Collect electronic diary device 
 


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4. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
A total of approximately 1140 adult male and female subjects aged 18 to 65 years with acute 
migraine headaches will be enrolled into the study. 
4.1. Subject Inclusion Criteria 
A subject will be eligible for inclusion in this study only if all of the following criteria applied: 
1. Males or females, 18-65 years of age at the time of Screening Visit 
2. Signed Informed Consent Form 
3. Subject has at least 1-year history of migraines (with or without aura), according to the 
International Classification of Headache Disorder, 3rd Edition (ICHD3), including the following: 
a. Migraine onset before the age of 50 years 
b. Migraine headache frequency of 2 to 8 attacks of moderate or severe intensity in each of 
the 3 months prior to the Screening Visit and maintains this requirement during the 
Screening Period 
c. Fewer than 15 days with headache (migraine or non-migraine) per month in each of the 
3 months prior to the Screening Visit and maintains this requirement during the Screening 
Period 
d. Individual migraine attacks separated by at least 2 days of no headache pain 
4. Subjects on preventive migraine medication are permitted to remain on therapy provided they 
have been on a stable dose for at least 3 months prior to study entry and have no plans to 
change the dose during the study 
5. Female subjects will be included if they are post-menopausal (at least 1 year since last 
menses) or surgically sterilized; or if they are of childbearing potential, they are not 
breastfeeding, have a negative pregnancy test, have no intention of becoming pregnant during 
the course of the study, and are using adequate contraceptive drugs or devices during the 
course of this study. Medically acceptable methods of contraception that may be used by the 
subject and/or her partner are: 
a. Simultaneous use of male condom and intra-uterine contraceptive device placed at least 
4 weeks prior to Screening Visit 
b. Simultaneous use of male condom with intravaginally applied spermicide and diaphragm 
c. Simultaneous use of male condom and hormonal contraceptives started at least 4 weeks 
prior to Screening Visit 
d. Surgical sterilization of their partner(s) at least 6 months prior to Screening Visit 
6. Intact nasal mucosa (no erythema, no inflammation, no ulceration, no swelling, no bleeding, 
no atrophy (severe local dryness and/or crusting), no septal perforation, and no other nasal 
conditions that may interfere with intranasal dosing 
7. Willing and able to comply with the requirements of the protocol and follow directions from 
the clinic staff 
8. Adequate compliance (≥80%) in the completion of the e-diary during the Screening Period 


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4.2. Subject Exclusion Criteria 
1. Pregnant or breast-feeding women 
2. Women of child-bearing potential not using or not willing to use highly effective contraception 
3. Diagnosis of headache conditions other than migraine with or without aura, including 
diagnosis of basilar or hemiplegic migraines or cluster headache 
4. Abnormal physical findings of clinical significance at the screening or baseline examination 
which would interfere with the objectives of the study 
5. History of coronary artery disease, coronary artery vasospasm (including Printz-metals’ 
angina), clinically significant arrhythmia or, peripheral vascular disease, ischemic disease 
(e.g. Raynaud’s syndrome, ischemic bowel syndrome, angina pectoris, myocardial infarction, 
or documented silent ischemia); percutaneous coronary intervention, or cardiac surgery 
6. History of cerebrovascular disease, including but not limited to stroke, transient ischemic 
attack, cerebral hemorrhage, subarachnoid hemorrhage 
7. Presence of two or more of the following cardiovascular risk factors: 
a. Receiving antihypertensive medication for treatment of hypertension 
b. Hypercholesteremia (LDL >159 mg/dL) or receiving cholesterol lowering medication 
c. Obesity (BMI > 31) 
d. Diabetes mellitus 
e. Family history of premature coronary artery disease (in male first-degree relatives 
< 55 years or female first-degree relatives < 65 years) 
f. Females who are surgically or physiologically postmenopausal 
g. Males over age 45 
8. Clinically significant abnormal laboratory values (as determined by the Principal 
Investigator) at the Screening Visit 
9. Severely impaired hepatic function (liver function tests ALT or AST greater than 2 times 
upper limit of normal) or renal function (serum creatinine greater than 1.5 times the upper 
limit of normal) 
10. Screening 12-lead ECG showing any clinically significant abnormalities 
11. Systolic blood pressure lower than 90 or over 140 mmHg, diastolic blood pressure lower than 
50 or over 90 mmHg, at the Screening Visit 
12. Diagnosis of major depression with current symptoms, psychosis, alcohol abuse or 
dependence, drug abuse or dependence, major psychiatric conditions (e.g. schizophrenia, 
psychosis or Bipolar disorder), or dementia. Other significant neurological or psychiatric 
disorders (including other pain syndromes or risk of suicide) that in the opinion of the 
investigator might interfere with study participation and assessments or subject safety 
13. Any clinically significant symptoms or conditions, including but not limited to central 
nervous system (e.g., seizures), cardiac, pulmonary, metabolic, renal, hepatic or 
gastrointestinal conditions or history of such conditions that, in the opinion of the 
investigator might interfere with study assessments or subject safety 


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14. Participation in another drug research study within 30 days of Screening Visit or within less 
than 5 half-lives of tested drug (whichever is longer) 
15. Concomitant use of potent CYP3A4 inhibiting medications, for example protease inhibitors 
(e.g. ritonavir, nelfinavir, indinavir, saquinavir, tipranavir, lopinavir, atazanavir, darunavir), 
macrolide antibiotics (e.g. erythromycin, clarithromycin, troleandomycin), or strong 
imidazole antifungals (e.g. ketoconazole, and itraconazole) 
16. Previously shown hypersensitivity to ergot alkaloids or the inactive ingredients of STS101 
(microcrystalline cellulose, hydroxypropyl methylcellulose, mannitol) 
17. Concomitant use of more than one preventive migraine medication 
18. Current use of opioids, barbiturates, or cannabis or cannabinoid containing products. 
19. Concomitant use of peripheral and central vasoconstrictors including propranolol and 
nicotine (from smoking, vaping or smokeless products) 
4.3. Subject Withdrawal Criteria 
Subjects will be informed that they are free to withdraw from the study at any time. The Investigator 
or the Medical Monitor may exercise his/her medical judgment to terminate a subject’s participation 
in the study due to compliance, medical or behavioural reasons. All data normally collected at 
completion of the study (Visit 3) must be collected as soon as possible once a subject is withdrawn. 
The primary reason for discontinuation of treatment should be noted in the CRF and source data 
using the following categories: 
a. Adverse Event: The subject has experienced an AE that, in the opinion of the Investigator, 
requires early termination. If a subject is discontinued from the study due to an AE, the 
Investigator is required to follow the subject until the AE is resolved, or declared 
medically stable or the subject is lost to follow up. 
b. Non-compliance: The subject did not adhere to protocol requirements in a fashion that 
would impair the data integrity or subject safety. 
c. Withdrawal of Consent: The subject wishes to withdraw from the study. 
d. Death. The event causing the death will be an SAE and will be documented. 
e. Investigator Discretion: In the Investigator’s judgment, continued participation in the 
study would not be in the best interest of the subject or the study. 
f. Study Termination: The Sponsor, or IRB terminates the study. 
g. Lost to follow up. Every effort should be expended to contact the subject and have them 
return for follow up assessments and return of Investigational Product (used or unused) 
and the electronic diary device. 
h. Other: If subject is discontinued from the study for any reason not applicable to the 
reasons stated above, this category should be used. The specific reason should then 
be indicated in the subject’s source documents and the appropriate CRF. 


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5. 
TREATMENT OF SUBJECTS 
5.1. Description of Investigational Product and Packaging 
STS101 is a drug-device combination product consisting of a powder formulation of DHE 
mesylate prefilled in a single use delivery device for IN administration. The STS101 drug 
constituent contains a formulation of DHE mesylate, microcrystalline cellulose, mannitol and 
hydroxypropyl methylcellulose (HPMC). 
DHE mesylate is a white or almost white to faintly red powder or colourless crystals. DHE 
mesylate is known chemically as ergotaman-3´,6´,18-trione,9,10-dihydro-12´-hydroxy-2´-
methyl-5´-(phenylmethyl)-,(5´α)-,monomethanesulfonate. Its molecular weight is 679.80 and its 
empirical formula is C34H41N5O8S. Further information can be found in the Investigator’s Brochure. 
The investigational product will be made available as: 
• 3.9 and 5.2 mg STS101 dose strengths (equivalent to 4.5 and 6.0 mg DHE mesylate USP) 
as unit dose in a labeled foil wrap. 
• Matching placebo as unit dose in a labeled foil wrap. 
The non-investigational product will be made available for training during the Screening and 
Randomization Visits: 
• STS101 Empty Training Devices (empty STS101 Device) in a foil wrap. 
• STS101 Filled Training Devices (STS101 Device containing microcrystalline cellulose) 
in a foil wrap. 
5.2. Investigational Product Labeling 
The foil wrap will be labeled with a label designating: 
• STS101 dose strength (3.9 mg, 5.2 mg, or placebo) 
• Protocol number 
• Lot number 
• Kit Number 
• Name and address of study sponsor 
• Recommended storage conditions 
• Investigational use only 
• Directions: Use as directed following the Instructions for Use  
• Warning: For nasal use only 
• Blank spaces for: Date dispensed & Subject Number (to be completed by site personnel 
at time of dispensing) 


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5.3. Investigational Product Storage 
Investigational Product supplies are to be stored under secure conditions in a dry, locked, limited 
access cabinet, at controlled room temperature. All Investigational Product must be stored at 
room temperature (15-25oC or 59°F-77°F). 
The study site pharmacist or designee will maintain an inventory and acknowledge receipt of all 
shipments of the Investigational Product. Accurate storage and dispensation records must be kept 
for drug accountability. Supplies of the investigational products will be checked and accountability 
records will be reviewed at each monitoring visit. A copy of all completed drug accountability 
forms will be collected by the monitor. 
5.4. Investigational Product Administration & Training 
STS101 will be self-administered by the subjects using the delivery device according to the 
Instructions for Use. 
At Screening (Visit 1) and Randomization (Visit 2), study personnel will train the subject in the 
study drug preparation and administration. Instructions for Use (Appendix D), an instructional 
video, STS101 Empty Training Devices and STS101 Filled Training Devices will be used for 
training of the study subject at both visits. 
For the treatment at home, the study subject will record the following information in the 
electronic diary: 
• Time of dosing (defined as time of last intranasal delivery device actuation). 
• The nostril (right or left) into which study drug was administered. 
• Whether or not there was any sneezing and/or nose blowing, within 30 minutes after dosing. 
Subjects will be instructed to: 
• Place clear Cap, Nozzle’s Tab and Nasal Device into the plastic bag provided. 
• Place the plastic bag and Foil wrap into the carton. 
• Return the carton to the clinical site. 
5.5. Investigational Product Accountability 
The Investigational Product will be prescribed by a licensed medical doctor. 
The Investigator must maintain accurate records accounting for the receipt and dispensing of the 
investigational materials. This should consist of a dispensing record including the identification 
of the person to whom the drug is dispensed, the quantity and the date of dispensing, and the 
return of study drug/devices. 
All Investigational Products dispensed to and taken by subjects must be accurately recorded on 
an appropriate drug accountability record maintained at the site and reviewed by the study monitor. 


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All Investigational Products designated for this clinical study must not be administered to any 
subjects other than those enrolled in this study and may not be utilized for any laboratory or 
animal research. 
5.6. Investigational Product Handling and Disposal 
Site study staff will retain used and unused Investigational Product at the study site. At the end of 
the study, all used and unused Investigational Product will be reconciled by the Sponsor’s 
designee. At the end of the study, all used and unused STS101 devices will be returned to the 
Sponsor or if requested by sponsor, destroyed at the study site in compliance with the rules and 
regulations set forth by the institution conducting the study, and in observance with the rules and 
regulations of federal agencies concerning prescription only drug products. 
5.7. Concomitant Medications 
Use of any concomitant medications will be documented and reported. 
Triptans and ergot alkaloids are not allowed within 48 hours before and for 24 hours after study 
drug administration.  
No other medication intended for treatment of the acute migraine attack should be taken within 
24 hours before and for 2 hours after study drug administration. 
Allowed rescue medication include NSAIDs, neuroleptics, corticosteroids, antiemetics, muscle 
relaxants, sleep medications, gabapentin. 
The concomitant use of potent CYP3A4 inhibiting medications, for example protease inhibitors 
(e.g. ritonavir, nelfinavir, indinavir, saquinavir, tipranavir, lopinavir, atazanavir, darunavir), 
macrolide antibiotics (e.g. erythromycin, clarithromycin, troleandomycin), or strong imidazole 
antifungals (e.g. ketoconazole, and itraconazole) is not allowed. 
The concomitant use of more than one prevention medication for migraine is not allowed. 
The concomitant use of a peripheral and central vasoconstrictive medication is not allowed. 
The concomitant use of opioids, barbiturates, or cannabis or cannabinoid containing products is 
not allowed. 
5.8. Treatment Compliance 
All used or unused Investigational Product will be returned to the site at Visit 3 at which time the 
dispensed Investigational Product will be reconciled in the drug accountability log. 


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5.9. Randomization and Blinding 
5.9.1. 
Subject Randomization 
After evaluation of the subject eligibility (including review of screening laboratories, 28-day 
headache diary data) and confirmation that subject meets the Inclusion and Exclusion criteria at 
the Randomization Visit, a study subject will be randomized in the IWRS system according to 
the pre-programmed randomization schedule. The randomization will be stratified for the use of 
migraine prevention medication. The randomization process will be described in a separate 
document. 
5.9.2. 
Blinding 
The study is a double-blind study of STS101 and matching placebo. No personnel directly 
involved with the conduct of the study will have knowledge of a subject’s treatment assignment. 
This includes all personnel at the study site, at the sponsor and any CRO involved in the conduct 
and monitoring of the study. A randomization code will be generated by a statistician independent 
of the study and not be available to the analysis team until the clinical and data collection, entry, 
and cleaning processes are complete and database is locked for unblinded analysis. 
5.9.3. 
Unblinding Procedures 
Unblinding procedures will be described in a separate document. 


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6. 
ASSESSMENT OF EFFICACY 
6.1. Efficacy Evaluation Parameters 
The following efficacy evaluation parameters will be programmed in an electronic handheld 
device (e-Diary) that the study subjects will use to provide their information. 
6.1.1. 
Migraine Headache Pain Severity 
The study participants will be prompted to document the pain severity of the treated migraine 
attack by this request: “Please rate the pain severity of your current migraine headache.” 
The subject’s rating will be documented on a four-point scale from no pain (= 0), mild pain (= 1), 
moderate pain (= 2) to severe pain (= 3). 
Headache pain severity ratings will be collected at the onset of the migraine attack, immediately 
before drug administration (time 0), at 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 6, 12, 24, and 48 hours 
after study drug administration. 
6.1.2. 
Most Bothersome Symptom 
The study participants will be prompted to document the presence of three symptoms, photophobia, 
phonophobia and nausea during the treated migraine attack by these requests: 
For photophobia: 
“Do you have sensitivity to light?” 
For phonophobia: 
“Do you have sensitivity to sound?” 
For nausea: 
“Do you have nausea?” 
For each of the three symptoms, the subject will respond with “Yes” (if symptom present) or 
“No” (if symptom absent). 
Immediately before study drug administration (time 0), the study subjects will be prompted to 
declare the most bothersome symptom among the symptoms present by this request: “Please 
indicate which of the symptoms that you have at (sensitivity to light, sensitivity to sound or 
nausea) bothers you the most at this time.” 
The presence of the three symptoms will be recorded at the onset of the migraine attack, 
immediately before drug administration (time 0), at 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 6, 12, 
24, and 48 hours after study drug administration. 
6.1.3. 
Evaluation of Allodynia 
The presence of allodynia (painful cutaneous sensations) will be assessed by prompting the study 
subjects to respond to these questions (Ashkenazi 2007; Tepper 2011): 
1. Is your scalp tender to touch? 
2. Does combing your hair bother you? 
3. Does wearing your glasses or sunglasses bother you? 


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4. Does washing your face bother you? 
5. Are your teeth and gums tender to touch? 
6. Is your skin over the face tender to touch? 
For each question, the possible responses are “Yes”, “No” and for questions 2 and 3 also “Not 
applicable (NA)”. 
Study subjects answering “Yes” to at least 2 questions will be considered to have allodynia. The 
presence of allodynia will be assessed immediately before drug administration (time 0), at 2 and 
4 hours after study drug administration. 
6.1.4. 
Use of Rescue Medication 
Rescue medication is defined as any medication taken to treat the migraine headache after study 
drug administration. 
Any use of medications to treat the migraine headache will be recorded for 48 hours after study 
drug administration. Study subjects will be encouraged to avoid use of any rescue medication 
until the 2-hour post study drug administration data collection timepoint. 
6.1.5. 
Evaluation of Function 
6.1.5.1. 
Functional Impairment Scale 
The study subjects will be prompted to record their functional status using the Functional 
Impairment Scale (FIS): “Please rate how much your current migraine headache impacts your 
ability to function right now.” 
The subject’s rating will be documented on a four-point scale from no impairment (=0; able to 
function normal)), mild impairment (= 1; able to perform all activities of daily living but with some 
difficulty), moderate impairment (= 2; unable to perform certain activities of daily living) to severe 
impairment (= 3; unable to perform most to all activities of daily living or requiring bed rest). 
The FIS will be recorded at the onset of the migraine attack, immediately before drug 
administration (time 0), at 1, 2, 4, 24, and 48 hours after study drug administration. 
6.1.5.2. 
24-hour Migraine Quality of Life Questionnaire 
The study subjects will be prompted to complete the 24-hour Migraine Quality of Life 
Questionnaire (24-MQoL) (Appendix E) at 24 hours after drug administration. 
6.2. Patient Global Impression 
The study subjects will be asked to rate the global impression of the study treatment at Visit 3 
with this question: “What is your global impression of the study treatment? 
The subject’s rating will be documented on a five-point verbal Likert scale with these response 
options: very poor, poor, no opinion, good, very good. 


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7. 
ASSESSMENT OF SAFETY 
7.1. Safety Parameters 
The following evaluations and assessments will be conducted during the course of the study 
(Refer to the Schedule of Assessments in Appendix A). 
7.1.1. 
Examinations 
7.1.1.1. 
Physical Examinations 
A physical examination will include the following body systems: HEENT, Lymphatic, 
Cardiovascular, Respiratory, Gastrointestinal, Dermatologic, Musculoskeletal, Neurologic and Other. 
New physical examination observations that meet the definition of an AE will be recorded on the 
AE form. 
7.1.1.2. 
Height, Weight, and BMI 
Subjects will be weighed in street clothes after removing coat or jacket and shoes at the 
Screening Visit, Randomization visit, and follow-up or early termination visit. At the Screening 
Visit, subject height will be measured without shoes. Subjects will have their BMI calculated 
using the following formula: BMI = weight (kg)/height (m2).  
7.1.1.3. 
Vital Signs 
Vital signs consist of the subject’s resting sitting blood pressure, pulse rate, respiration rate and 
oral temperature. 
The subject should rest for at least 5 minutes prior to recording the vital signs. The Investigator 
will review the vital signs and comment on all clinically-significant abnormalities. 
7.1.1.4. 
Nasal Mucosa Irritation Assessments 
An assessment of subjective (subject questionnaire) and objective (investigator) nasal irritation 
assessment will be performed at the Screening, Randomization and follow-up visits.  
7.1.1.5. 
Electrocardiogram (ECG) 
Standard 12-lead ECG will be performed in triplicate. All ECGs will be reviewed by a competent 
physician who will comment on any abnormal findings. Clinically significant findings if found at 
screening or randomization may be a reason to exclude the subject.  


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7.1.2. 
Laboratory Assessments 
Central laboratory tests results will be reviewed for any clinically significant abnormalities by a 
qualified physician or physician assistant. If any clinically significant findings are present at 
screening, the subject will be considered a screen failure and ineligible for study participation. 
7.1.2.1. 
Hematology 
Complete blood count (CBC) with differential including: white blood cell count with differential, 
red blood cell count, hemoglobin, hematocrit, MCV, and platelet count. 
7.1.2.2. 
Serum Chemistry 
Serum chemistry including: albumin, alkaline phosphatase, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), bilirubin (direct and total), blood urea nitrogen (BUN), calcium, 
chloride, cholesterol profile, creatine phosphokinase, creatinine, gamma glutamyl transferase, 
glucose, lactate dehydrogenase, potassium, sodium, thyroid function tests (TSH, total T3 & T4), 
and total protein. 
7.1.2.3. 
Urinalysis 
Urinalysis examination including: Appearance, color, pH, specific gravity, protein, glucose, 
ketones, occult blood, nitrites, urobilinogen, leukocytes, bilirubin and if necessary, urine microscopy. 
7.1.2.4. 
Urine Drug Screen 
Alcohol & Drug Panel: Amphetamines, Barbiturates Benzodiazepines, Cannabinoids, Cocaine, 
Opiates, PCP and Methadone. 
7.1.2.5. 
Serum Pregnancy Test 
A serum hCG pregnancy test will be performed at Screening (Visit 1), Randomization (Visit 2) 
and the Follow-up/early termination visit in all female subjects. 
7.2. Adverse Events 
An adverse event (AE) is defined as: “Any untoward medical occurrence in a subject or clinical 
investigation subject administered a pharmaceutical product that does not necessarily have to 
have a causal relationship with this treatment.” An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an investigational product, whether or not related to the investigational 
product. Treatment emergent adverse events (TEAE) are defined as adverse events recorded after 
dosing of the investigational product. 


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AEs will be recorded as volunteered by the subject or solicited through indirect questioning. 
AE collection will begin after the Randomization Visit (Visit 2) and continue until the follow-
up/early termination visit. 
AEs will be solicited at the times indicated in the schedule of assessments by asking a question 
such as: “Since you were last seen, have you felt unwell or different from usual in any way?” 
AEs may also be reported spontaneously. 
Each AE should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values) or symptoms should NOT be recorded as additional AEs. If a 
diagnosis is unknown, sign(s) or symptom(s) should be recorded as an AE(s). Changes in 
laboratory values are only considered to be AEs if they are judged to be clinically significant 
(i.e., if some action or intervention is required or if the Investigator judges the change to be 
beyond the range of normal physiological fluctuation). If abnormal laboratory values are the 
result of pathology for which there is an overall diagnosis (e.g., increased liver enzymes in 
hepatitis), the diagnosis only should be reported as an AE. 
Any adverse events, signs, and symptoms will be fully recorded on the AE form including date 
of onset, date of resolution, frequency, severity, seriousness, relationship to the drug, treatments 
administered and outcome. AEs may also be reported spontaneously at any time. 
All AEs must be recorded in the source data and the CRF. Any AE will be followed, whenever 
possible, until it returns to the baseline condition, is declared medically stable with no further 
change expected or the subject is lost to follow up. 
7.2.1. 
AE Relationship to Study Drug 
An AE will be considered ‘related” or “not related” to the use of the investigational product 
based on the criteria listed in Table 4. Assessment of the causal relationship between any Serious 
Adverse Event (SAE) and study drug administration will be performed by both the Investigator 
and the Sponsor. If at least one of the parties assesses the event as related, it will be reported 
expeditiously as required to the appropriate authorities. 
Table 4. Adverse Event Relationship to Study Drug 
 Related: 
There is “a reasonable possibility” that the event may have been caused by the product under 
investigation (i.e., there are facts, evidence, or arguments to suggest possible causality). 
Individual AE reports will be considered “related” to the use of the product if the “not related” 
criteria are not met. 
Not 
Related: 
There is an unreasonable temporal relationship between administration of the product and the onset 
of the AE (i.e., the event occurred either before, or too long after administration of the product for it 
to be considered product-related); 
The causal relationship between the product, and the AE is biologically implausible (i.e., death of a 
passenger in an automobile accident); 
There is a clearly more likely alternative explanation for the AE (i.e., typical adverse reaction to a 
concomitant drug and/or typical disease-related event). 
 


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7.2.2. 
Assessment of Adverse Event Severity 
Table 5 shows the guidelines for rating severity of AEs may be used: 
Table 5. Assessment of Adverse Event Severity 
Mild: 
Awareness of signs or symptoms, but easily tolerated; are of minor irritant type; no loss of time from 
normal activities; symptoms would not require medication or a medical evaluation; signs and 
symptoms may be transient, disappearing during continued treatment with study medication. 
Moderate: 
Discomfort enough to cause interference with or modification of usual activities. 
Severe: 
Incapacitating, with inability or notable impairment in work or usual activities; signs and symptoms 
may be of systemic nature or require medical evaluation; the study drug may be stopped, and 
treatment for the event may be required. 
 
7.2.3. 
Serious Adverse Events (SAEs) Recording and Reporting 
The Investigator must decide whether each AE meets the definition of an SAE. An SAE is any 
untoward medical occurrence that at any dose: 
1. Results in death. 
2. Is life-threatening. 
3. Requires inpatient hospitalization or prolongation of existing hospitalization. 
4. Results in persistent or significant disability/incapacity. 
5. Is a congenital anomaly/birth defect. 
6. Is considered medically significant by the Investigator or requires intervention to prevent 
any one of the outcomes above. 
For fatal events, the cause of death is reported whenever known. If an autopsy was performed, an 
autopsy report should be provided. Death should be reported as the outcome of a specific SAE. 
Life-threatening, in the definition of serious, refers to an event in which the subject was at risk of 
death at the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe.  
Reports for hospitalization of elective procedures do not need to be reported as SAEs if there are 
no precipitating signs/symptoms or worsening of the pre-existing condition that necessitated the 
procedure. However, SAEs must be reported for any medical complications that prolonged the 
hospitalization. 
Medically significant events are those events considered important in the Investigator’s opinion 
that may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the subject or may require intervention to prevent one of the other outcomes listed in 
the definition above. These will also usually be considered serious. 


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Any SAE will be reported within 24 hours of knowledge by the Investigator. Investigator should 
not delay reporting while waiting for clarification or supporting medical information. 
The Investigator must complete the required information fields for SAE documentation and 
reporting in the electronic CRF (AE eCRF and SAE eCRF) and provide any supportive documents 
available (hospital summaries, diagnostic test results, laboratory test results, etc.). Any subject 
identifying information must be redacted prior to uploading. The investigator should not wait for 
these supporting documents in order to notify the medical monitor if doing so would place the 
notification outside the 24-hour window. All SAEs will also be reported on the AE eCRF and 
SAE eCRF and concomitant medications (CM) administered in association with the serious AE 
will be documented on the CM eCRF. 
For any information not available at the time of the first report that becomes available later, 
the Investigator should add this information to both the source documentation and the initial 
SAE section of the eCRFs, and provide any additional written documentation to the Safety 
Group immediately or within 1 working day of receipt. 
The Sponsor or designee is responsible for notifying regulatory agencies of SAEs that require 
reporting as per the governing regulations. 
It is the responsibility of the Investigator to report to the relevant IRB/EC in accordance with the 
IRB/EC’s reporting specific reporting requirements for SAEs.  
All SAEs must be followed up until the event is resolved, returns to the baseline condition, or is 
declared medically stable with no further change expected or the subject is lost to follow up. 
SAEs Occurring after the Follow-Up Visit: If an SAE comes to the attention of the 
Investigator after study termination within 30 days of the last dose of study drug(s), and it is 
considered related to study drug, it must be recorded and followed up in the same way as the 
SAEs occurring during the study. 
Any report of pregnancy identified for any female subject or for a female partner of a male 
subject should be reported immediately (within 24 hours of being informed) to the medical 
monitor. Pregnancies will be considered ‘events of special interest’ and will not be captured as 
serious adverse events (SAEs). The Pregnancy Report Form will be utilized to obtain follow-up 
information. Pregnancies will be followed to termination or eight weeks post- delivery for 
determination of resolution to the event. Subjects who become pregnant during treatment must 
immediately be withdrawn from the study (classified as ET). 


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8. 
STATISTICS 
8.1. Sample Size Determination 
A total of approximately 1140 evaluable subjects is planned for the study. Given the 1:1:1 
randomization ratio, approximately 380 subjects will be randomized to each treatment group. 
For the co-primary endpoint of pain freedom at 2 hours after drug administration, a therapeutic 
gain of 15% is considered clinically meaningful and is targeted. This is assuming a 30% 
responder rate for STS101 and 15% for the placebo. Based on these assumptions, 380 subjects 
per arm can provide 99% power to detect the target treatment difference. For the co-primary 
endpoint of MBS freedom at 2 hours after drug administration, a therapeutic gain of 12.5%, 
assuming a 47.5% responder rate for STS101 and 35% for the placebo is targeted. Based on 
these assumptions, 380 subjects per arm can provide 95% power to detect the target treatment 
difference. The sample size calculation is based on a chi-square test with a significance level of 
0.05 and a 2-sided test. 
The primary efficacy objective will be addressed by simultaneously testing the 2 co-primary 
endpoints of pain freedom and MBS freedom at 2 hours after drug administration at a 
significance level of 0.05. This sample size will provide an overall power of at least 94%. 
8.2. Subject Populations 
The analysis populations to be used in the study are defined below. 
8.2.1. 
Intent-to-Treat Population 
The intent-to-treat (ITT) population will include all randomized subjects who reported a qualifying 
migraine attack, received the study drug, and reported any post-treatment efficacy evaluation. 
Data will be analyzed according to the treatment group each subject is randomized to. 
8.2.2. 
Modified Intent-to-Treat Population 
For the purposes of efficacy data analysis, the modified intent-to-treat (mITT) population will be 
the primary analysis population. This population will include all randomized subjects who 
reported a qualifying migraine attack, received the study drug, and reported a post-treatment 
efficacy evaluation for at least 1 time point at or before the 2-hour time point. Data will be 
analyzed according to the treatment group each subject is randomized to. 
8.2.3. 
Per-Protocol Population 
The per protocol (PP) population will consist of all mITT subjects who do not have protocol 
deviations that could significantly affect the interpretation of the results for the primary 
endpoints. Subjects’ inclusion/exclusion from the PP population will be determined and 
documented prior to the database lock and unblinding. 


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8.2.4. 
Safety Population 
The safety population will include all subjects who are randomized and have received the study 
drug. Data will be analyzed according to the treatment each subject actually received. 
8.3. Statistical Analysis 
All study data will be summarized by treatment using descriptive statistics. Unless otherwise 
specified, for numeric data (e.g., age, weight), descriptive statistics will include the number of 
subjects with data to be summarized (n), mean, standard deviation (SD), median, minimum (min) 
and maximum (max). All categorical/qualitative data (e.g., gender, race) will be presented using 
absolute and relative frequency counts and percentage. 
All summaries, statistical analyses, and individual subject data listings described below will be 
completed using Version 9.3 or later of the SAS software (SAS Institute, Inc. Cary, NC). 
A detailed Statistical Analysis Plan (SAP) will be provided in a separate document. The SAP 
will include the final hierarchy for testing of the primary and secondary efficacy endpoints and 
will be finalized prior to database lock and unblinding of the study. 
8.3.1. 
Demographic and Baseline Variables 
Demographics and baseline characteristics (including HIT-6 and triptan response information) 
will be summarized descriptively by treatment group for the mITT Population, the ITT Population, 
the Per-Protocol Population, and the Safety Population. Exploratory hypotheses testing may be 
performed to assess the comparability of demographics and baseline characteristics among the 
treatment groups. No multiplicity adjustment will be applied to these tests. 


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8.3.2. 
Efficacy Analysis 
8.3.2.1. 
Primary Efficacy Endpoints 
• Proportion of subjects free from headache pain at 2 hours post dose (defined as moderate or 
severe headache pain [2 or 3 on a 4-point scale] at baseline [time 0] becoming none [0] on a 
4-point scale) 
• Proportion of subjects free from most bothersome symptom (MBS) among photophobia, 
phonophobia and nausea at 2 hours post dose (defined as the MBS identified at baseline 
[time 0] being absent) 
8.3.2.2. 
Secondary Efficacy Endpoints 
• Proportion of subjects free from headache pain at 2 hours post dose and remaining headache 
free at 24 hours post dose with no use of rescue medication and no relapse of any headache 
pain (defined as score of 0 on a 4-point scale from 2-24 hours) 
• Proportion of subjects free from headache pain at 2 hours post dose and remaining headache 
free at 48 hours post dose with no use of rescue medication and no relapse of any headache 
pain (defined as score of 0 on a 4-point scale from 2-48 hours) 
• Proportion of subjects who use rescue medication within 24 hours post dose 
• Proportion of subjects who use rescue medication within 48 hours post dose 
• Proportion of subjects with relief from headache pain at 2 hours post dose (defined as 
reduction in headache pain from moderate or severe [2 or 3 on a 4-point scale] to mild or 
none [0 or 1 on a 4-point scale]) 
• Proportion of subjects free from headache pain at 2 hours post dose by allodynia status at 
baseline (time 0) (allodynia status will be defined as “present” with at least 2 “yes” responses 
to the 6-question allodynia questionnaire [Ashkenazi 2007; Tepper 2011]) 
• Proportion of subjects with headache relapse within 24 hours post dose (defined as the return 
of headache of any severity within 24 hours post dosing of the investigational drug, when the 
subject was pain-free at 2 hours after dosing) 
• Proportion of subjects with headache relapse within 48 hours post dose (defined as the return 
of headache of any severity within 48 hours post dosing of the investigational drug, when the 
subject was pain-free at 2 hours after dosing) 
• Mean change in scores on Functional Impairment Scale (FIS) at various timepoints post 
dosing compared to baseline (time 0) 
• 24-hour Migraine Quality of Life Questionnaire summary scores at 24 hours post dose 
• Proportion of subjects free from headache pain at 2 hours post dose depending upon time 
elapsed from onset of migraine attack to time of dosing (investigational drug dosing ≤2 hours, 
2-4 hours or >4 hours after onset of migraine attack) 
• Proportion of subjects free from headache pain and free from most bothersome symptom 


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(MBS) at 2 hours post dose in subjects with severe headache 
• Proportion of subjects free from headache pain and free from most bothersome symptom 
(MBS) at 2 hours post dose in subjects who wake up with migraine headache 
• Proportion of subjects free from headache pain and free from most bothersome symptom 
(MBS) at 2 hours post dose in subjects with menstrually related migraine attack 
• Proportion of subjects with relief from headache pain at 2 hours post dose by allodynia status 
at baseline (time 0) (allodynia status will be defined as “present” with at least 2 “yes” 
responses to the 6-question allodynia questionnaire [Ashkenazi 2007; Tepper 2011]) 
• Proportion of subjects with headache relief at 2 hours post dose depending upon time elapsed 
from onset of migraine attack to time of dosing (investigational drug dosing ≤2 hours, 
2-4 hours or >4 hours after onset of migraine attack) 
• Proportion of subjects free from headache pain at various time points after dosing 
• Proportion of subjects achieving headache relief at various time points after dosing 
• Proportion of subjects free from photophobia (defined as photophobia being absent at 
2 hours post-dose if present at baseline [time 0]) 
• Proportion of subjects free from phonophobia (defined as phonophobia being absent at  hours 
post-dose if present at baseline [time 0]) 
• Proportion of subjects free from nausea (defined as nausea being absent at 2 hours post-dose 
if present at baseline [time 0]) 
• Proportion of subjects free from headache pain and free from most bothersome symptom 
(MBS) at 2 hours post-dose 
• Proportion of subjects free from headache pain and free from most bothersome symptom 
(MBS) at various time points post-dose 
• Patient Global Impression ratings 
8.3.2.3. 
Hypotheses Testing and Significance Level 
A study-wise Type I error of 0.05 will be used for the study. The multiplicity strategy will be 
taken into account when interpreting the nominal 2-sided p-values. 
A multi-family gate-keeping strategy will be employed to control for the study-wise Type I error 
rate at alpha=0.05. There are 2 families of hypotheses tests. The first family is the primary 
endpoints family for the 2 dose groups. The second family includes the hypotheses tests with 
respect to a subset of secondary endpoints for which Type I error protection is planned. 
To adjust for the multiplicity of having 2 dose groups in the primary endpoints family, the 
truncated Hochberg Step-up Procedure will be used. If both co-primary endpoints for both dose 
groups are significant at 0.05 level, the secondary endpoints family of hypotheses will be tested 
according to a pre-specified hierarchy at the 0.05 significance level. If both co-primary endpoints 
are significant for only one of the two dose groups, the secondary endpoints family of hypotheses 
will be tested according to a pre-specified hierarchy at the 0.025 significance level. 


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To adjust for the multiplicity for the endpoints in the secondary endpoints family, a fixed-sequence 
hierarchical testing procedure will be used. The secondary endpoints will be tested in a pre-
defined order at the unused significance level passed on from the testing of the primary endpoints 
family. The multiplicity adjustment and the order of the secondary endpoints to be tested will be 
described in detail in the SAP. 
8.3.2.4. 
Handling of Missing Data 
For the primary analysis of the co-primary endpoints, missing data will be imputed based on a 
single-imputation method. Subjects who do not have evaluable assessments at the 2-hour time 
point, or who received rescue medications prior to the 2-hour time point will be considered as 
non-responders. The impact of missing data will be further investigated in a number of 
sensitivity analyses with other single and multiple-imputation approaches. The details of the 
sensitivity analyses will be described in the SAP. 
8.3.2.5. 
Pooling of Centers 
Data from all investigational centers will be pooled for analysis. The analyses will not be 
performed by center and will not include adjustment for centers. 
8.3.2.6. 
Analysis Methods for Efficacy Endpoints 
For both co-primary endpoints, the Chi-square test will be used to compare the active treatment 
groups and placebo. Chi-square test will also be used to test secondary endpoints consist of 
proportion of responders. For analyses stratified by allodynia status, timing of treatment, the 
Cochran-Mantel-Haenszel test will be used. The Kaplan-Meier method will be used for time to 
use of rescue medications. Analysis of Covariance (ANCOVA) with treatment factor and 
baseline scores as a covariate, will be used for the analysis of FIS. The 24-hour Migraine Quality 
of Life Questionnaire assessments will be analyzed with the Analysis of Variance (ANOVA) 
models. The chi-square test will be used to analyze the Patient Global Impression ratings. 
To fully describe the treatment benefit of STS101, the proportion of subjects achieving “no 
headache pain” at various time points following treatment will be tested between the active 
treatment groups and placebo. The results will also be displayed graphically to show the time 
course of effect. To address the onset of efficacy, treatment difference vs. placebo will be 
examined from the 2 hour-timepoint towards the baseline in a sequential manner (i.e. 2 hours, 
1.5 hours, 1 hour, 45 minutes, 30 minutes, 15 minutes). A significance level of 0.05 will be used 
for this analysis. 


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8.3.2.7. 
Subgroup Analysis of Efficacy Endpoints 
Subgroup analyses of the key efficacy endpoints will be conducted to gain insight of the nature 
and consistency of the treatment effect. Subgroups prospectively identified include: 
1. age group 
2. gender 
3. race 
4. baseline severity of attack (time 0) 
5. allodynia status 
6. menstrually related migraine attacks  
7. in subjects who wake up with migraine headache 
Among these subgroup analyses, # 4, 5, 6, 7 are also included in the secondary endpoints. Analysis 
by additional subgroups may be considered. They will be specified in the SAP before the study is 
unblinded for analysis. 
Because of the smaller sample sizes for each subgroup, the objective of the analysis is to evaluate 
the consistency of efficacy results across these factors. Statistical tests will be performed. 
However, the interpretation of the p-values will take into account sample size and multiplicity 
issues. Forest plots with estimates and 95% confidence intervals of the treatment effect across 
different subgroups will be presented. 
8.3.3. 
Safety Analysis 
Safety analyses will be conducted for the safety population, which will include all subjects who 
received at least one dose of study medication. All clinical safety and tolerability data will be 
summarized by treatment group and listed by treatment group and by subject. All reported 
adverse events will be coded using MedDRA and listed by System Organ Class, Preferred Term, 
and verbatim term. No inferential statistics will be performed; only summary statistics will be 
provided unless otherwise noted. Missing safety data will not be imputed. 
8.3.3.1. 
Extent of Exposure 
The number of subjects exposed to each treatment group will be summarized. Because this is a 
single-dose study, each subject is expected to receive one dose only. 
8.3.3.2. 
Adverse Events 
A TEAE is defined as an AE that begins after the dosing of study drug. 
An overview of adverse events will be presented by treatment group, which will include the number 
and percent of subjects who had at least one AE, TEAE, Serious TEAE, TEAE related/Suspected 
to study drug, TEAE related/Suspected to study procedure, maximum severity of TEAE. 


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Multiple occurrences of an AE are counted only once per subject per SOC and PT for summary 
tables. 
The following TEAEs will be summarized by SOC, PT and treatment group: 
• Incidence of all TEAEs 
• Nasal TEAEs 
• Incidence of all TEAEs by maximum severity (severe, moderate and mild) specified by 
investigators 
• Incidence of TEAEs related to the study drug as determined by the investigators 
• Incidence of serious TEAEs 
• Incidence of TEAEs leading to early discontinuation withdrawn from study 
All data collected in the AE case report form (CRF) will be listed in by-subject listings. 
8.3.3.3. 
Assessment of Nasal Irritation 
The data from the Subjective and Objective Assessment of Nasal Irritation will be summarized 
by treatment group. Exploratory hypothesis testing may be performed to compare treatment 
group by question. No multiplicity adjustment will be applied to these tests. 
8.3.3.4. 
Laboratory Evaluations 
The observed data at each time point and change from baseline (Visit 2) at each post-baseline 
time point in hematology, serum chemistry and quantitative urinalysis test results will be 
summarized by treatment group. 
For hematology and serum chemistry including calculated creatinine clearance, normal ranges 
for each parameter will be used to categorize the test result as low (value lower than the lower 
limit), normal (value within the normal range), or high (value higher than the upper limit). For 
urinalysis, test results will be categorized as normal and abnormal. Frequency counts and 
percentages will be presented over time by treatment groups for these categorical data. In 
addition, shifts from baseline (shift to maximum value, shift to minimum value) to each post-
baseline time point and to any post-baseline time point for each parameter will be summarized 
by treatment group. 
If a continuous laboratory value is reported as either below or above the limits of quantification, 
the qualifiers should be dropped and the numeric value used in the analysis (e.g., “< 1” should be 
“1” and “> 100” should be “100”). 
8.3.3.5. 
Vital Signs 
Observed data at each time point and the change from baseline (Visit 2) at each post-baseline 
time point for vital signs will be summarized by treatment group. 


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Normal ranges for each vital sign parameter will be used to categorize the results as low (lower 
than the lower limit), normal (within the normal range), or high (higher than the upper limit). 
Frequency counts and percentages will be presented over time by treatment group for these 
categorical data. 
8.3.3.6. 
ECG Evaluations 
Observed data at each time point and the change from baseline (Visit 2) at each post-baseline 
time point in ECG parameters, heart rate (HR), RR, PR, QRS, and QT corrected with the 
Fridericia’s formula (QTcF), will be summarized by treatment groups. 
The number and percentage of subjects with other clinically significant ECG findings will also 
be summarized at each post baseline time point by treatment group. 
8.3.3.7. 
Concomitant Medications 
Concomitant medication usage will be summarized by the number and proportion of subjects in 
each treatment group. The World Health Organization Drug Dictionary (WHO Drug) will be 
used to classify prior and concomitant medications by therapeutic class and generic name based 
on ATC code level 3. Subjects will only be counted one time in each unique ATC Class and 
generic name if multiple drugs are used by a subject. 
8.3.4. 
Interim analysis 
No interim analysis is planned for this study. 


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9. 
DATA HANDLING AND RECORDKEEPING 
9.1. Case Report Forms (CRFs) 
All clinical study data will be collected by the clinical investigator and staff, recorded on source 
documents and captured electronically in the electronic CRF. 
The populated electronic CRFs will be monitored against source documents by the Sponsor’s 
representative and any subsequent data discrepancies identified will be recorded and 
communicated to the investigative site for resolution. 
Completion of the electronic CRF should occur within 24 hours of a subject’s visit. 
9.2. Retention of Records 
The Investigator must maintain adequate records for the study including all source 
documentation, completed CRFs, logs, medical records, laboratory reports, signed ICFs, 
investigational product disposition records, adverse event reports, information regarding subjects 
who discontinued, all correspondence with the EC and the Sponsor (or designee) and other 
pertinent data.  
The study site will maintain adequate study records for at least 2 years after product approval for 
marketing or until instructed by the Sponsor in writing. After that period, the Sponsor may be 
contacted to determine whether the study records will be forwarded to the Sponsor, destroyed or 
kept at another facility for a longer period of time at the Sponsor's expense. 
To avoid any possible errors, the Investigator must contact Satsuma (or designee) prior to the 
destruction of any study records. The Investigator will also notify Satsuma (or designee) in the 
event of accidental loss or destruction of any study records. 


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10. QUALITY CONTROL AND QUALITY ASSURANCE 
10.1. Study Monitoring 
The study will be monitored by the Sponsor's representatives at all stages of study conduct from 
inception to completion in accordance with current Good Clinical Practice (GCP) guidelines. 
This monitoring will be in the form of site visits and other communication and will include review 
of original source documents and CRFs. The Sponsor's monitor or representative will notify the 
Principal Investigator prior to conducting any investigational site visit. The frequency of these 
visits will depend upon the progress of the study, and will include monitoring to assess facilities 
and equipment, recruiting, record-keeping, protocol adherence, data collection, investigational 
product accountability, AE reporting and other factors. 
10.2. Audits and Inspections 
The clinical site will be subject to audit and inspection by the Sponsor or representative during 
and/or at the end of the study as appropriate. 
The Investigator will permit representatives of Satsuma or representative or FDA auditors to 
inspect facilities and records relevant to this study, including the subject’s original medical 
records for verification of study-related procedures and data. 


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11. ETHICS 
11.1. Ethics Review 
The Ethics Committee/Institutional Review Board will review and approve the study protocol, 
the ICF and other relevant substantive information or documents before the study is initiated. If 
an Investigator chooses to advertise for subjects for this study, whether in professional or 
consumer publications, radio, or television or any digital media, all advertising copy and 
language must be approved by Satsuma and the EC/IRBs prior to initiation. 
A copy of the EC/IRB approval letter for the protocol and the consent form/subject information 
sheet, which specifically identifies the protocol name and the Satsuma protocol number, must be 
sent to Satsuma (or designee) prior to initiating the study. Subsequently, the Investigator is 
responsible for keeping the EC/IRB advised of the progress of the study as deemed appropriate 
but, in any case, at least once a year during the course of the study and for keeping the EC/IRB 
informed of any significant study change or adverse reactions per EC/IRB specific guidelines. 
11.2. Ethical Conduct of the Study 
This study will be conducted in strict compliance with the Declaration of Helsinki, ICH, GCP, 
EC/IRB and other relevant regulatory requirements and laws. 
The Investigator must ensure that each subject’s anonymity is maintained as described within 
this protocol. On the CRFs or other documents submitted to Satsuma, or its designee, subjects 
must be identified only by their initials and a subject number. Documents that are not for 
submission to Satsuma, and/or its designee, (i.e., signed ICFs) should be kept in strict confidence 
by the Investigator, in compliance with Federal regulations and ICH and GCP Guidelines. The 
Investigator is obligated to inform the subject in the ICF that his/her study-related records will be 
reviewed by the above-named study sponsor and representatives. 
11.3. Written Informed Consent 
Prior to any study procedures being performed, each study participant will be required to read, 
sign and date an EC/IRB -approved ICF, explaining the nature, purpose, possible risks and 
benefits, and the duration of the study. 
The ICF must be written in English or Spanish, and all subjects must be fluent in English or 
Spanish (speaking, writing, and reading). The Investigator or designee shall give the subject, 
adequate time to read the ICF and consider study participation and have all questions answered. 
They should also express understanding of the information presented regarding the trial before it 
is signed and dated. 
The ICF must contain the subject’s dated signature confirming the consent. In addition, a witness 
must also sign and date the ICF. The person who conducted the informed consent discussion will 


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also be sign and date the consent form. Each participant will be given a copy of the fully 
executed ICF. 
Each subject’s signed ICF must be kept on file by the Investigator and be available for possible 
inspection by regulatory authorities, and/or the study Sponsor or designee, or the EC/IRB. 
Documentation of the informed consent and subject information discussion must appear in the 
subject’s medical record and/or the subject’s study file and be available for verification by 
monitors at any time. 
11.4. Disclosure of Data 
Individual subject medical information obtained as a result of this study is considered confidential, 
and disclosure to third parties other than those noted below is prohibited. 
However, at the request of the subject such medical information may be given to the subject’s 
personal physician, or to other appropriate medical personnel responsible for the subject’s welfare. 
In addition, data generated during this study are to be available for inspection upon request by 
FDA auditors, the Sponsor’s monitors or by the EC/IRB. Therefore, absolute confidentiality 
cannot be guaranteed. 
The sponsor is planning a publication of the complete study data. No publication of an individual 
site’s data may occur before that publication and no publications may occur without the 
sponsor’s written approval. 


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12. REFERENCES 
Ashkenazi A, Sholtzow M, Shaw JW, Burstein R, Young WB. Identifying cutaneous allodynia in 
chronic migraine using a practical clinical method. Cephalalgia. 2007;27(2):111-7. 
doi: 10.1111/j.1468-2982.2006.01255.x. 
Aurora SK, Silberstein SD, Kori SH, Tepper SJ, Borland SW, Wang M, Dodick DW. MAP0004, 
orally inhaled DHE: a randomized, controlled study in the acute treatment of migraine. 
Headache. 2011;51(4):507-17. doi: 10.1111/j.1526-4610.2011.01869.x. 
Burstein R, Collins B, Jakubowski M. Defeating migraine pain with triptans: a race against the 
development of cutaneous allodynia. Ann Neurol. 2004;55(1):19-26. doi: 10.1002/ana.10786. 
Carleton SC, Shesser RF, Pietrzak MP, Chudnofsky CR, Starkman S, Morris DL, Johnson G, 
Rhee KJ, Barton CW, Chelly JE, Rosenberg J, Van Valen MK. Double-blind, multicenter trial to 
compare the efficacy of intramuscular dihydroergotamine plus hydroxyzine versus intramuscular 
meperidine plus hydroxyzine for the emergency department treatment of acute migraine 
headache. Ann Emerg Med. 1998;32(2):129-38. 
Cook RO, Shrewsbury SB, Ramadan NM. Reduced adverse event profile of orally inhaled DHE 
(MAP0004) vs IV DHE: potential mechanism. Headache. 2009;49(10):1423-34. 
doi: 10.1111/j.1526-4610.2009.01510.x. 
DHE 45® Prescribing Information. Valeant Pharmaceuticals; 2017. 
Dahlöf C, Maassen Van Den Brink A. Dihydroergotamine, ergotamine, methysergide and 
sumatriptan - basic science in relation to migraine treatment. Headache. 2012;52(4):707-14. 
doi: 10.1111/j.1526-4610.2012.02124.x. 
Diener HC, Tassorelli C, Dodick DW, Silberstein SD, Lipton RB, Ashina M, Becker WJ, Ferrari 
MD, Goadsby PJ, Pozo-Rosich P, Wang SJ, Mandrekar J, International Headache Society 
Clinical Trials Standing C. Guidelines of the International Headache Society for controlled trials 
of acute treatment of migraine attacks in adults: Fourth edition. Cephalalgia. 
2019:333102419828967. doi: 10.1177/0333102419828967. 
Djupesland PG, Messina JC, Mahmoud RA. Breath powered nasal delivery: a new route to rapid 
headache relief. Headache. 2013;53 Suppl 2:72-84. doi: 10.1111/head.12186. 
Edwards KR, Norton J, Behnke M. Comparison of intravenous valproate versus intramuscular 
dihydroergotamine and metoclopramide for acute treatment of migraine headache. Headache. 
2001;41(10):976-80. 
Gallagher RM. Acute treatment of migraine with dihydroergotamine nasal spray. 
Dihydroergotamine Working Group. Arch Neurol. 1996;53(12):1285-91. 
González-Hernández A, Lozano-Cuenca J, Marichal-Cancino BA, MaassenVanDenBrink A, 
Villalón CM. Dihydroergotamine inhibits the vasodepressor sensory CGRPergic outflow by 
prejunctional activation of α2-adrenoceptors and 5-HT1 receptors. The Journal of Headache and 
Pain. 2018;19(1):40. doi: 10.1186/s10194-018-0869-8. 


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Hartmaier SL, Santanello NC, Epstein RS, Silberstein SD. Development of a brief 24-hour 
migraine-specific quality of life questionnaire. Headache. 1995;35(6):320-9. 
Hoskin KL, Kaube H, Goadsby PJ. Central activation of the trigeminovascular pathway in the 
cat is inhibited by dihydroergotamine. A c-Fos and electrophysiological study. Brain. 1996;119 
(Pt 1):249-56. 
Humbert H, Cabiac MD, Dubray C, Lavene D. Human pharmacokinetics of dihydroergotamine 
administered by nasal spray. Clin Pharmacol Ther. 1996;60(3):265-75. doi: 10.1016/s0009-
9236(96)90053-3. 
Marmura MJ, Silberstein SD, Schwedt TJ. The acute treatment of migraine in adults: the 
american headache society evidence assessment of migraine pharmacotherapies. Headache. 
2015;55(1):3-20. doi: 10.1111/head.12499. 
Migranal® Administration Instructions. Valeant Pharmaceuticals; 2017. 
Migranal® Prescribing Information. Valeant Pharmaceuticals; 2017. 
Raskin NH. Repetitive intravenous dihydroergotamine as therapy for intractable migraine. 
Neurology. 1986;36(7):995-7. 
Schran HF, Tse FLS, Chang C-T, Hunt TL, Saxe MA, Ventura DF, Diserio FJ, Hendler J. 
Bioequivalence and safety of subcutaneously and intramuscularly administrred 
dihydroergotamine in healthy volunteers. Current Therapeutic Research. 1994;55(12):1501-8. 
doi: https://doi.org/10.1016/S0011-393X(05)80758-1. 
Silberstein SD, McCrory DC. Ergotamine and dihydroergotamine: history, pharmacology, and 
efficacy. Headache. 2003;43(2):144-66. 
Tepper SJ, Kori SH, Goadsby PJ, Winner PK, Wang MH, Silberstein SD, Cutrer FM. MAP0004, 
orally inhaled dihydroergotamine for acute treatment of migraine: efficacy of early and late 
treatments. Mayo Clin Proc. 2011;86(10):948-55. doi: 10.4065/mcp.2011.0093. 
Tfelt-Hansen PC. Relatively slow and long-lasting antimigraine effect of dihydroergotamine is 
most likely due to basic pharmacological attributes of the drug: a review. Cephalalgia. 
2013;33(13):1122-31. doi: 10.1177/0333102413483372. 
van der Kuy PH, Lohman JJ, Hooymans PM, Ter Berg JW, Merkus FW. Bioavailability of 
intranasal formulations of dihydroergotamine. Eur J Clin Pharmacol. 1999;55(9):677-80. 
Winner P, Ricalde O, Le Force B, Saper J, Margul B. A double-blind study of subcutaneous 
dihydroergotamine vs subcutaneous sumatriptan in the treatment of acute migraine. Arch Neurol. 
1996;53(2):180-4. 
Yang M, Rendas-Baum R, Varon SF, Kosinski M. Validation of the Headache Impact Test (HIT-
6) across episodic and chronic migraine. Cephalalgia. 2010;31(3):357-67. doi: 
10.1177/0333102410379890. 
 


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Appendix A. Schedule of Assessments 
 
Visit 1 
Visit 2 
Visit 3 
Screening 
Randomization 
Follow-up / Early Termination 
Timing of Visit 
Day -35 to -1 
Day 1 
Day 1-56 (±3) days, 
but within one week of treatment 
Informed consent 
X 
 
 
Demographic data / Medical history 
X 
 
 
Physical examination 
X 
X 
X 
Vital signs 
X 
X 
X 
Body weight and height 
X 
Xa 
Xa 
BMI Calculation 
X 
 
 
Hematology, clinical chemistry, urinalysis 
X 
X 
X 
Serum pregnancy screen (females only) 
X 
X 
X 
Urine Drug and Alcohol Screen 
X 
X 
 
12-lead ECG (in triplicate) 
X 
X 
X 
Determine / review eligibility 
X 
X 
 
HIT-6 Instrument 
 
X 
 
Headache Diary use training & review 
X 
X 
Xe 
Headache Diary event recording 
Xb 
Xc 
 
Subjective Nasal Irritation Assessment 
X 
X 
X 
Objective Nasal Irritation Assessment 
X 
X 
X 
Patient Global Impression Rating 
 
 
X 
Randomization 
 
X 
 
Concomitant medications 
X 
X 
X 
STS101 Instructions for use training 
X 
X 
 
Investigational Product supply 
 
X 
Xf 
Adverse events recording 
 
Xd 
X 
a Weight only; b Recording of headaches for 28 days; c Recording of headache severity & symptoms of treated attack, d Starting after randomization visit; e Collect e-diary device; 
f Collect STS101 device 
 


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Appendix B. 
Subjective Assessment of Nasal Irritation 
 
1. Please rate your overall nasal discomfort. 
none  
 
 
 
 
 
 
 
 
 
worst imaginable 
 
 
 
 
 
 
 
 
 
 
2. Please rate your nasal burning. 
none  
 
 
 
 
 
 
 
 
 
worst imaginable 
 
 
 
 
 
 
 
 
 
 
3. Please rate your nasal itching. 
none  
 
 
 
 
 
 
 
 
 
worst imaginable 
 
 
 
 
 
 
 
 
 
 
4. Please rate your nasal pain.  
none  
 
 
 
 
 
 
 
 
 
worst imaginable 
 
 
 
 
 
 
 
 
 
 
5. Please rate your nasal blockage or obstruction. 
none  
 
 
 
 
 
 
 
 
 
worst imaginable 
 
 
 
 
 
 
 
 
 
 
6. Please rate how much abnormal taste you experience. 
none  
 
 
 
 
 
 
 
 
 
worst imaginable 
 
 
 
 
 
 
 
 
 
 
7. Please rate how much runny nose you experience. 
none  
 
 
 
 
 
 
 
 
 
worst imaginable 
 
 
 
 
 
 
 
 
 
 
8. Please rate how much sneezing you experience. 
none  
 
 
 
 
 
 
 
 
 
worst imaginable 
 
 
 
 
 
 
 
 
 
 
Check marks on the VAS will be converted to numerical values in millimeters (0-100 mm) 
within the database. 
 
 
On the rating scale below, identify how much you are bothered by the BOLD symptom by 
placing a vertical line ( | ) on the line from “none” (left edge) to “worst imaginable” (right edge).  


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Appendix C. Objective Assessment of Nasal Irritation 
 
 
1. Nasal Erythema (please circle) 
0 
(none) 
1 
(mild) 
2 
(moderate) 
3 
(severe) 
Mild 
= redness limited to < 20 % of visible nasal mucosa 
Moderate = redness 20-50 % of visible nasal mucosa 
Severe 
= redness > 50 % of visible nasal mucosa 
 
2. Nasal Edema (please circle) 
0 
(none) 
1 
(mild) 
2 
(moderate) 
3 
(severe) 
Mild 
= localized swelling < 20 % of visible nasal mucosa 
Moderate = area of swelling 20-50 % of visible nasal mucosa 
Severe 
= swelling affects > 50 % of visible nasal mucosa 
 
3. Rhinorrhea (please circle)* 
0 
(none) 
1 
(mild) 
2 
(moderate) 
3 
(severe) 
Mild 
= blows nose < 3 times in 1 hour 
Moderate = blows nose 4-7 times in 1 hour 
Severe 
= blows nose 8 or greater number of times in 1 hour 
* Assessment for this question will be based on the subject record of the number 
of nose blows as recorded in worksheet 
 
(continued on next page) 
A total of 5 questions are listed in this assessment sheet. On the numerical rating scale below, 
identify the degree of the presence of the BOLD physical finding by choosing a number from 
0: none, 1: mild, 2: moderate, 3: severe. This sheet will be completed by the qualified physician 
or physician assistant or nurse practitioner who performs the examination. 


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4. Nasal Bleeding (please circle) 
0 
(none) 
1 
(mild) 
2 
(moderate) 
3 
(severe) 
Mild 
= blood streaking on tissue 
Moderate = less than 5 mL (1 teaspoon) estimated bleeding 
Severe 
= greater than or equal to 5 mL (1 teaspoon) estimated bleeding 
 
5. Nasal Ulceration (please circle) 
0 
(none) 
1 
(mild) 
2 
(moderate) 
3 
(severe) 
Mild 
= mucosal erosion < 2 mm in diameter 
Moderate = mucosal erosion 3-5 mm in diameter 
Severe 
= mucosal erosion/ulceration 6 mm or greater in diameter 
 
 
 
Signature of Investigator 
 
Date (dd/mm/yyyy) 


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Appendix D. STS101 Instructions for Use 
 
 
 


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Appendix E. 
24-Hour Migraine Quality of Life Questionnaire  
 
 
 
 
 
 


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Reference: Hartmaier 1995 


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Appendix F. 
Headache Impact Test (HIT-6™) 
HIT-6TM 
HEADACHE IMPACT TEST 
 
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 check one box for each question. 
 
 
1. When you have headaches, how often is the pain severe? 
 
 
 Never 
 Rarely 
 Sometimes 
 Very Often 
 Always 
 
 
2. 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 
 
 
3. When you have a headache, how often do you wish you could lie down? 
 
 
 Never 
 Rarely 
 Sometimes 
 Very Often 
 Always 
 
 
4. 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 
 
 
5. In the past 4 weeks, how often have you felt fed up or irritated because of your headaches? 
 
 
 Never 
 Rarely 
 Sometimes 
 Very Often 
 Always 
 
 
6. 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 
 
 
 
 
 
 
 
 
 
 
 
Headache Impact Test™ (HIT-6™) © 2001, 2015 QualityMetric Incorporated and the GlaxoSmithKline Group of Companies. All rights reserved.  
HIT-6™ United States (English) Version 
 
 


 
 
400 Oyster Point Boulevard, Suite 221, South San Francisco, CA  94080 
 
 
August 12, 2019 
 
TO:  ADVARRA IRB 
 
FR:  Detlef Albrecht, MD 
         Satsuma Chief Medical Officer 
 
 
Re.:  STS101-002; Administrative Change #1 to Study Protocol dated 9 April 2019 
          
 
A Randomized, Double-Blind, Parallel Group, Placebo-Controlled, Multicenter Study to 
Evaluate the Efficacy, Safety, and Tolerability of Single Doses of STS101 
(Dihydroergotamine Nasal Powder) in the Acute Treatment of Migraine 
 
 
Protocol Page 60  Written Informed Consent 
 
11.3 Written Informed Consent 
 
In the third paragraph of this section the protocol states: 
 
witness must also sign and date the ICF.  
 
 
Revision to Page 60  Subject Preference Question 
 
Since neither the IRB nor the ICH guidelines or GCP process require the signature of a witness, 
the ICF does not contain a signature line for a witness and a witness signature will not be 
required. 
 
 
 
 
  
Detlef Albrecht 


 
400 Oyster Point Boulevard, Suite 221, South San Francisco, CA  94080 
October 10, 2019
TO:  EMERGE Study Investigators
FR:  Detlef Albrecht, MD
Satsuma Chief Medical Officer
Re.:  STS101-002: Clarifications for Study protocol
A Randomized, Double-Blind, Parallel Group, Placebo-Controlled, Multicenter Study to 
Evaluate the Efficacy, Safety, and Tolerability of Single Doses of STS101 (Dihydroergotamine 
Nasal Powder) in the Acute Treatment of Migraine
 
 
1. Evaluation of intact nasal mucosa (Visits 1 and 2): 
 
1.1 Study Protocol Inclusion Criterion # 6:
“Intact nasal mucosa (no erythema, no inflammation, no ulceration, no swelling, no bleeding, no 
atrophy (severe local dryness and/or crusting), no septal perforation, and no other nasal 
conditions that may interfere with intranasal dosing” 
Interpretation and documentation 
To meet Inclusion Criterion # 6, the nasal examinations at Visits 1 and 2 must be negative and 
the criteria “nasal erythema, nasal edema, nasal bleeding, nasal ulceration” in the Objective 
Assessment of Nasal Irritation (Appendix C) must be checked with “none” = 0. For “rhinorrhea”, 
responses of “none” = 0 and “mild” = 1 in the Objective Assessment of Nasal Irritation are 
acceptable. 
 
 
1.2 Objective Assessment of Nasal Irritation (Appendix C)
 
All five nasal symptoms should be evaluated based on visual inspection of the nose. Please note 
that the information marked with an asterisk under 3. Rhinorrhea (“Assessment for this 
question will be based on the subject record of the number of nose blows as recorded in 
worksheet”) does not apply in this study. The number of nose blows should be based on the 
information provided by the subject.


- 2 - 
2. Contraception
 
Study Protocol Inclusion Criterion # 5: 
 
“Female subjects will be included if they are post-menopausal (at least 1 year since last menses) 
or surgically sterilized; or if they are of childbearing potential, they are not breastfeeding, have a 
negative pregnancy test, have no intention of becoming pregnant during the course of the 
study, and are using adequate contraceptive drugs or devices during the course of this study. 
Medically acceptable methods of contraception that may be used by the subject and/or her 
partner are:
a. Simultaneous use of male condom and intra-uterine contraceptive device placed at least 4 
weeks prior to Screening Visit  
b. Simultaneous use of male condom with intravaginally applied spermicide and diaphragm 
c. Simultaneous use of male condom and hormonal contraceptives started at least 4 weeks prior 
to Screening Visit  
d. Surgical sterilization of their partner(s) at least 6 months prior to Screening Visit” 
 
 
Interpretation and documentation 
 
1) Hysterectomy or bilateral tubal ligation fulfil the criteria “surgically sterilized” 
2) All subjects of child bearing potential must agree to use one of the options listed, even if 
they practiced abstinence before the study, have a same sex partner or no sexual partner. 
The spirit of this criterion is that a medically acceptable method of contraception is 
practiced when the potential of pregnancy exists.  
3. Cardiovascular Risk Factors 
Study Protocol Exclusion Criteria # 7
“Presence of two or more of the following cardiovascular risk factors: 
a. Receiving antihypertensive medication for treatment of hypertension  
b. Hypercholesteremia (LDL >159 mg/dL) or receiving cholesterol lowering medication 
c. Obesity (BMI > 31) 
d. Diabetes mellitus  


- 3 - 
e. Family history of premature coronary artery disease (in male first-degree relatives < 55 years 
or female first-degree relatives < 65 years) 
f. Females who are surgically or physiologically postmenopausal  
g. Males over age 45”  
 
Interpretation
Criterion 7b, is considered present if:
a) a subject is taking any kind of cholesterol lowering medications
b) a subject has an LDL >159 mg/dL in the screening or randomization visit labs
c) a subject has the diagnosis of hypercholesteremia in the medical history, regardless if the 
subject is currently taking drug or other cholesterol lowering treatments, or has no LDL 
>159 mg/dL. The presence of the diagnosis constitutes the risk factor. 
4. Nicotine Use & Beta-blockers
Study Protocol Exclusion Criteria # 19
“Concomitant use of peripheral and central vasoconstrictors including propranolol and nicotine 
(from smoking, vaping or smokeless products)” 
Interpretation
If subjects have been using nicotine products in the past, they must have discontinued those for 
at least one year before screening to be enrolled in the study. The rationale is resumption of 
nicotine is common and a long enough period of abstinence must be achieved before the 
subject can be allowed into the study. 
Additional note: beta-blockers other than propranolol such as metoprolol are allowed.
5. Serum HCG tests
a) All females are required to have serum HCG tests at Visits 1, 2, and 3 regardless of results.
b) Females who are surgically sterile (bilateral tubal ligation, hysterectomy, or total 
hysterectomy) and who have serum HCG results of “Inconclusive” at Visit 1, DO NOT need 
to repeat the test; however, serum HCG tests at Visits 2 and 3 must still be done.  


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c) All other “Inconclusive” HCG test results except as noted in “b” need to be repeated at least 
one week after the first HCG test and the results need to be sent to the Medical Monitor for 
confirmation.
d) Surgical sterilization must be documented in medical records/medical history/source 
documents and eCRFs.  
Detlef Albrecht 


 
400 Oyster Point Boulevard, Suite 221, South San Francisco, CA  94080 
20 Feb 2020
To:    
EMERGE Study Investigators 
From:   
Detlef Albrecht, MD 
  
Satsuma Chief Medical Officer 
 
Reg.:   
STS101-002 – Administrative Change Letter #3 (20 Feb 2020) 
           
Protocol Section 5.1 – PBO Filled Devices 
         
 
A Randomized, Double-Blind, Parallel Group, Placebo-Controlled, Multicenter 
Study to Evaluate the Efficacy, Safety, and Tolerability of Single Doses of STS101 
(Dihydroergotamine Nasal Powder) in the Acute Treatment of Migraine 
 
Protocol Section 5.1.1 – Description of Investigational Product and 
Packaging (P. 39) 
The non-investigational product used for subject training during the Screening and 
Randomization Visits currently are STS1010 devices filled with microcrystalline cellulose (MCC).
Clarification 
In addition to the MCC filled STS101 Training Devices, Satsuma will utilize Placebo filled STS101 
Training Devices.  Additional information regarding this change:
1. In the Study STS101-002 currently devices filled with microcrystalline cellulose (MCC) are 
used for training and demonstration of the study drug administration.
2. Due to a shortage of MCC filled devices, Satsuma needs to use placebo filled devices for 
training and demonstration.  These placebo-filled devices contain mannitol and 
hydroxypropyl methylcellulose (HPMC) in addition to the MCC.
3. Please note that these training devices are used for demonstration only and no 
administration of powder into the nose occurs during training with the subject.
Detlef Albrecht