Clinical trial NCT04406649
Conditions: Migraine Migraine With Aura Migraine Without Aura
Keywords: dihydroergotamine dihydroergotamine mesylate migraine
Sponsor: Satsuma Pharmaceuticals, Inc.
Start date: 2020-09-14; Completion date: 2023-01-16
Enrollment: 482 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Study STS101-003 is a multi-center, multiple dose (PRN), open-label, 12-month study to evaluate the safety and tolerability of STS101 (dihydroergotamine nasal powder) in the acute treatment of migraine.

Detailed description:
The ASCEND trial is a multi-center, multiple dose (PRN), open-label, 12-month study to evaluate the safety and tolerability of STS101 (dihydroergotamine nasal powder) in the acute treatment of migraine.

Arms: arm 1: STS101 (dihydroergotamine nasal powder)
Interventions: intervention 1: Dihydroergotamine
Intervention descriptions: intervention 1: Dihydroergotamine is a semi-synthetic derivative of ergotamine tartrate.

Protocol documents:
Prot_000.pdf: 
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: 
An Open-Label, 12-Month Study to Evaluate the Safety and Tolerability 
of STS101 (Dihydroergotamine Nasal Powder) in the Acute Treatment 
of Migraine 
Study Number: 
STS101-003 
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: 
Version 6 
Version 5 
Version 4 
Version 3 
Version 2 
Version 1 
November 24, 2021 
 
June 30, 2021 
 
November 6, 2020 
 
September 25, 2020 
 
May 11, 2020 
 
March 31, 2020 


STS101 (Dihydroergotamine Nasal Powder) 
Satsuma Pharmaceuticals, Inc. 
Clinical Trial Protocol: STS101-003, November 24, 2021 (Version 6)
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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 
2


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Satsuma Pharmaceuticals, Inc. 
Clinical Trial Protocol: STS101-003, November 24, 2021 (Version 6) 
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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 
 


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Clinical Trial Protocol: STS101-003, November 24, 2021 (Version 6) 
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PROTOCOL SYNOPSIS 
Sponsor/Company 
Satsuma Pharmaceuticals, Inc. 
Investigational Product STS101 (Dihydroergotamine nasal powder) 
Active Ingredient 
Dihydroergotamine mesylate 
Protocol Number 
STS101-003 
Title of Study 
An Open-Label, 12-Month Study to Evaluate the Safety and 
Tolerability of STS101 (Dihydroergotamine Nasal Powder) in the 
Acute Treatment of Migraine 
Study center(s) 
Approximately 50 US sites 
Objectives 
Primary 
• To assess the safety and tolerability of STS101 in the acute 
treatment of migraine attacks over 12 months. 
Secondary 
• To describe the efficacy of STS101 in the acute treatment of 
migraine attacks over 12 months. 
Methodology 
This study will be a multi-center, multiple dose (PRN), open-label, 
12-month study in approximately 480 subjects with migraine (ages 
18 to 65 years). After establishing eligibility, the study participants 
will use STS101 (DHE nasal powder) on a PRN basis to treat migraine 
attacks for 12 months. Study participants will be able to use up to 
2 doses of STS101 to treat a single migraine attack within 24 hours 
and can use up to 12 doses of STS101 per month for 12 months. 
Subjects of the original cohort (enrolled before June 30, 2021) will 
be offered to continue use of study medication for another 6 months 
after the completion of the original 12-month period. Only safety 
data will be collected during this addtioanal period. 
The study participants will document the pain severity of their 
migraine attacks, presence and severity of symptoms (photophobia, 
phonophobia, nausea) and functionality status over the 48-hour period 
after study drug administration. Specifically, headache pain severity 
data and symptom presence will be collected at the onset of the 
migraine attack, immediately before drug administration (time 0), 30 
and 60 minutes, 2, 4, 24, and 48 hours after study drug administration. 
Migraine attacks not treated with study medication will also be 
documented. Use of rescue medication is allowed, but triptans or 
other DHE products as rescue medications should be avoided for 
24 hours after study drug administration (24 hours after the second 
dose if a repeat dose of STS101 is administered). 
Adverse events, nasal and physical examination data, safety 
laboratory data, vital sign data and ECGs will be recorded to describe 
the tolerability and safety of STS101. Additionally, subjective and 
objective nasal symptom assessments and the Smell Identification 


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Test (SIT) will be documented during the treatment period. 
Number of subjects 
(planned) 
A total of approximately 480 adult male and female subjects (18 to 
65 years of age) with migraine. At least 150 and 50 subjects are 
planned to complete at least 6 and 12 months, respectively. 
Approximately 20 subjects are expected to complete 18 months. 
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. History of 4 - 12 migraine attacks per month in each of the 
3 months prior to Screening Visit 
c. History <15 headache days per month in each of the 
3 months prior to Screening Visit 
4. Female subjects will be included if they are post-menopausal 
(at least 1 year since last menses with an FSH >40 IU/mL) 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 one of the following medically acceptable 
contraceptive methods during the course of this study: 
a. Simultaneous use of male condom and intra-uterine 
contraceptive device placed at least 4 weeks prior to 
screening (Visit 1) 
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 1) 
d. Surgical sterilization of their partner(s) at least 6 months 
prior to screening (Visit 1) 
5. Intact nasal mucosa (Appendix C), Objective Assessment of 
Nasal Symptoms: no ulceration; no bleeding; no or mild 
erythema, no or mild swelling and no or mild rhinorrhea) at 
baseline (Visit 2) 
6. Willing and able to comply with the requirements of the 
protocol and follow directions from the clinic staff 


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Clinical Trial Protocol: STS101-003, November 24, 2021 (Version 6) 
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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 but not limited to diagnosis of basilar 
migraine (aka migraine with brainstem aura) or hemiplegic 
migraines, medication overuse headache or cluster headache 
4. Clinically significant abnormal physical findings 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 for 
complications from ischemic heart disease 
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. Diagnosis of hypertension or receiving antihypertensive 
medication for treatment of hypertension 
b. Diagnosis of hypercholesteremia, or 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 screening (Visit 1) or Baseline 
(Visit 2). 
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) 
at screening (Visit 1) or Baseline (Visit 2). 


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10. Screening 12-lead ECG showing any clinically significant 
abnormalities at screening (Visit 1) or Baseline (Visit 2). 
11. Systolic blood pressure lower than 90 or over 140 mmHg, 
diastolic blood pressure lower than 50 or over 90 mmHg, at 
screening (Visit 1) or Baseline (Visit 2). 
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 
14. Participation in another drug research study within 30 days of 
screening (Visit 1) or within less than 5 half-lives of tested drug 
(whichever is longer). Note: Subjects who have participated in 
study STS101-002 are exempt from this. 
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 two preventive migraine 
medications 
18. Concomitant daily use of peripheral and central vasoconstrictors 
including but not limited to amphetamines, phenylephrine, 
pseudoephedrine, propranolol and nicotine (from smoking, 
vaping or smokeless products)  
19. Score of  >0 on any of the questions 1-14 of the Sheehan 
Suicidality Tracking Scale 
Investigational product, 
dosage and mode of 
administration 
STS101 (DHE nasal powder) as 5.2 mg STS101 


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Duration of study 
• Screening period: Up to 30 days 
• Treatment & follow up period: Up to 12 months; Subjects of the 
original cohort (enrolled before June 30, 2021) will be offered to 
continue use of study medication for another 6 months after the 
completion of the original 12-month period for a total of up to 
18 months. 
Criteria for evaluation 
Efficacy Endpoints 
 
• Proportion of subjects free from headache pain (defined as 
moderate or severe headache pain becoming none on a 4-point 
scale) at 30 and 60 minutes, 2, 4, 24 and 48 hours post dose 
• Proportion of subjects free from most bothersome symptom 
(MBS) (defined as the MBS identified prior to dosing being 
absent) at 30 and 60 minutes, 2, 4, 24 and 48 hours post dose 
• Proportion of subjects with relief from headache pain at 30 and 
60 minutes, 2, 4, 24 and 48 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 30 and 60 
minutes, 2, 4, 24 and 48 hours post dose by study month 
• Proportion of subjects free from most bothersome symptom (MBS) 
(defined as the MBS identified prior to dosing being absent) at 30 
and 60 minutes, 2, 4, 24 and 48 hours post dose by study month 
• Proportion of subjects with headache relief at 2 hours post dose 
by study month 
• Proportion of subjects free from headache pain at 2 hours post 
dose and remain headache free at 24 hours post dose by study 
month 
• Frequency of migraine headaches treated with STS101 by study 
month 
• Frequency of migraine headaches by study month 
• Proportion of subjects with headache relapse within 48 hours 
post dose (defined as the return of headache of any severity 
within 48 hours after administration of the investigational drug, 
when the patient was pain-free at 2 hours after investigational 
drug administration) 
• Mean change in scores on Functional Impairment Scale (FIS) by 
study month. 
• Mean change in scores on 24-hour Migraine Quality of Life 
Questionnaire by study month. 
• Satisfaction with treatment questions 
• Mean change from baseline in HIT-6 


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Safety Endpoints 
The following endpoints will be analyzed: 
• Physical examination 
• Vitals signs and body weight 
• 12-lead ECG 
• Subjective nasal symptom assessment 
• Objective nasal symptom evaluation 
• Smell Identification Test 
• Blood tests for hematology and biochemistry analysis (including 
liver function, renal function, thyroid function, electrolytes) 
• Urinalysis 
• Adverse events (AEs) 
• Documentation of concomitant medications 
Statistical methods 
Efficacy 
Efficacy data will be summarized using descriptive statistics. Unless 
otherwise specified, for numeric data, 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., proportion of 
responders) will be presented using absolute and relative frequency 
counts and percentage. 
No formal hypotheses testing is planned for this study. When 
appropriate, exploratory hypotheses testing may be conducted at the 
significance level of 0.05. No adjustment for multiplicity will be 
employed. Data from all investigator center will be pooled. Missing 
data will not be imputed. 
For categorical efficacy endpoints (#1 - #10, and #13 as numbered 
in Section 8.3.2.1), frequencies and percentages of each category 
will be tabulated. For endpoints #1 - #7, and #10, the analysis will 
be a responder analysis with the responder defined by meeting the 
criteria for respective endpoints. For responder analysis, the 
proportions of responders and their 95% confidence intervals will be 
presented. For continuous efficacy endpoints #11, #12, and #14, the 
change from baseline will be summarized descriptively. Exploratory 
hypothesis testing of the mean change from baseline may be 
conducted using the paired t-test. 


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Safety 
All adverse events and serious adverse events will be collected 
starting with the signining of the Informed Consent Form at Visit 1. 
All adverse events reported or observed will be listed, documenting 
course, severity, start and stop date, possible relationship to study 
medication, action taken, and outcome. Verbatim terms will be 
classified to preferred terms and related system organ class using the 
MedDRA dictionary. All reported adverse events will be 
summarized by the number and percentage of subjects reporting 
adverse events, system organ class, preferred term, severity and 
relationship to study drug. 
Descriptive statistics will be used to summarize safety labs including 
complete blood count (CBC), chemistry and urinalysis, physical and 
nasal exams, vital signs and 12-lead ECG, subjective nasal symptom 
assessment and the Smell Identification Test. Tabulations of out-of-
range findings and changes from pre-dose to post-dose will be 
provided. 


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TABLE OF CONTENTS 
Signature Page (Sponsor) ............................................................................................................2 
Principal Investigator Agreement ................................................................................................3 
Protocol Synopsis ........................................................................................................................4 
List of Tables ............................................................................................................................ 16 
List of Figures ........................................................................................................................... 16 
List of Appendices .................................................................................................................... 16 
List of Abbreviations and Definitions of Terms ......................................................................... 17 
Study Protocol Revision History ............................................................................................... 19 
1. 
BACKGROUND INFORMATION .................................................................................... 24 
1.1. Introduction............................................................................................................... 24 
1.2. STS101 Description .................................................................................................. 25 
1.2.1. STS101 Device .............................................................................................. 25 
1.2.2. STS101 Powder Formulation ......................................................................... 26 
1.2.2.1. DHE Mesylate Information ............................................................. 26 
1.2.3. DHE Mechanism of Action in the Treatment of Migraine .............................. 26 
1.2.4. STS101 DHE Pharmacokinetics .................................................................... 26 
1.2.5. DHE Clinical Experience ............................................................................... 27 
1.2.6. DHE Mesylate Pregnancy Category ............................................................... 28 
1.3. Summary of Nonclinical Data ................................................................................... 28 
1.4. Rationale for the Study .............................................................................................. 28 
1.5. Rationale for Dosing Frequency ................................................................................ 28 
2. 
STUDY OBJECTIVES AND PURPOSE ........................................................................... 31 
3. 
STUDY DESIGN ............................................................................................................... 32 
3.1. Overall Study Design and Plan .................................................................................. 32 
3.2. Study Procedures Descriptions .................................................................................. 32 
3.2.1. Informed Consent .......................................................................................... 32 
3.2.2. Assignment of Subject Identification Number ................................................ 32 
3.2.3. Inclusion and Exclusion Criteria Assessment ................................................. 33 
3.2.4. Medical History, Demographics, Concomitant and Prior Medications ............ 33 
3.2.5. Headache Impact Test (HIT-6TM) ................................................................... 33 
3.2.6. Physical Examination .................................................................................... 33 


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3.2.7. Vital Signs ..................................................................................................... 33 
3.2.8. Weight, Height and Body Mass Index (BMI) ................................................. 34 
3.2.9. Evaluations of Effects in the Nose ................................................................. 34 
3.2.9.1. Subjective Assessment of Nasal Symptoms ..................................... 34 
3.2.9.2. Objective Assessment of Symptoms ................................................ 34 
3.2.10. Smell Identification Test™ ............................................................................ 34 
3.2.11. Clinical Laboratory Tests ............................................................................... 35 
3.2.12. Electrocardiogram ......................................................................................... 36 
3.2.13. Adverse Events Recording ............................................................................. 36 
3.2.14. Electronic Headache Diary ............................................................................ 36 
3.2.15. Sheehan Suicidality Tracking Scale (S-STS) .................................................. 36 
3.3. Schedule of Observations and Procedures ................................................................. 36 
3.3.1. Screening Visit (Visit 1; Day-30 to Day -1) ................................................... 36 
3.3.2. Baseline Visit (Visit 2; Day 0) ....................................................................... 37 
3.3.3. Visits 3 & 4 (Month 1 and 2) ......................................................................... 38 
3.3.4. Visit 5 (Month 3) ........................................................................................... 38 
3.3.5. Visits 6 & 7 (Month 4 & 5) ............................................................................ 39 
3.3.6. Visit 8 (Month 6) ........................................................................................... 39 
3.3.7. Visits 9 & 10 (Month 8 & 10) ........................................................................ 40 
3.3.8. 12-Month Visit/Early Termination (Visit 11; Month 12) ................................ 40 
3.3.9. Visits 12 & 13 (Month 14 & 16) .................................................................... 41 
3.3.10. Final Visit/Early Termination (Visit 14; Month 18) ....................................... 41 
4. 
SELECTION AND WITHDRAWAL OF SUBJECTS ....................................................... 43 
4.1. Subject Inclusion Criteria .......................................................................................... 43 
4.2. Subject Exclusion Criteria ......................................................................................... 43 
4.3. Subject Withdrawal Criteria ...................................................................................... 45 
5. 
TREATMENT OF SUBJECTS .......................................................................................... 46 
5.1. Description of Investigational Product and Packaging ............................................... 46 
5.2. Investigational Product Labeling ............................................................................... 46 
5.3. Investigational Product Storage ................................................................................. 47 
5.4. Investigational Product Administration & Training ................................................... 47 
5.5. Investigational Product Accountability ...................................................................... 47 


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5.6. Investigational Product Handling and Disposal.......................................................... 48 
5.7. Concomitant Medications .......................................................................................... 48 
5.8. Treatment Compliance .............................................................................................. 48 
5.9. Randomization and Blinding ..................................................................................... 48 
5.9.1. Subject Randomization .................................................................................. 48 
5.9.2. Blinding & Unblinding Procedures ................................................................ 48 
6. 
ASSESSMENT OF EFFICACY ......................................................................................... 49 
6.1. Efficacy Evaluation Parameters ................................................................................. 49 
6.1.1. Migraine Headache Pain Severity .................................................................. 49 
6.1.2. Most Bothersome Symptom ........................................................................... 49 
6.1.3. Use of Rescue Medication ............................................................................. 49 
6.1.4. Evaluation of Function & Subjective Impressions .......................................... 50 
6.1.4.1. Functional Impairment Scale ........................................................... 50 
6.1.4.2. 24-hour Migraine Quality of Life Questionnaire .............................. 50 
6.2. Other Evaluations at Office Visits ............................................................................. 50 
6.2.1. Patient Global Impression .............................................................................. 50 
6.2.2. Ease of Use Impression .................................................................................. 50 
6.2.3. Patient Likelihood of Use .............................................................................. 50 
6.2.4. Comparison of Study Medication with Previously Used Migraine 
Medication .................................................................................................... 51 
6.2.5. HIT-6 ............................................................................................................ 51 
6.3. Healthcare Resource Utilization ................................................................................ 51 
7. 
ASSESSMENT OF SAFETY ............................................................................................. 52 
7.1. Safety Parameters ...................................................................................................... 52 
7.1.1. Examinations ................................................................................................. 52 
7.1.1.1. Physical Examinations .................................................................... 52 
7.1.1.2. Height, Weight, and BMI ................................................................ 52 
7.1.1.3. Vital Signs ...................................................................................... 52 
7.1.1.4. Nasal Symptom Assessments/Nasal Exam ...................................... 52 
7.1.1.5. Smell Identification Test ................................................................. 52 
7.1.1.6. Electrocardiogram (ECG) ................................................................ 52 
7.1.1.7. Sheehan Suicidality Tracking Scale ................................................. 53 


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7.1.2. Laboratory Assessments ................................................................................ 53 
7.1.2.1. Hematology .................................................................................... 53 
7.1.2.2. Serum Chemistry ............................................................................ 53 
7.1.2.3. Urinalysis ........................................................................................ 53 
7.1.2.4. Serum Pregnancy Test & FSH ......................................................... 53 
7.1.2.5. Lab Testing for Chest Related Symptoms or Adverse Events .......... 53 
7.2. Adverse Events ......................................................................................................... 54 
7.2.1. AE Relationship to Study Drug ...................................................................... 54 
7.2.2. Assessment of Adverse Event Severity .......................................................... 55 
7.2.3. Serious Adverse Events (SAEs) Recording and Reporting ............................. 55 
8. 
STATISTICS ..................................................................................................................... 57 
8.1. Sample Size Determination ....................................................................................... 57 
8.2. Subject Populations ................................................................................................... 57 
8.2.1. Safety Population........................................................................................... 57 
8.2.2. Efficacy Population ....................................................................................... 57 
8.3. Statistical Analysis .................................................................................................... 57 
8.3.1. Demographic and Baseline Variables ............................................................. 57 
8.3.2. Efficacy Analysis........................................................................................... 58 
8.3.2.1. Efficacy Endpoints .......................................................................... 58 
8.3.2.2. Hypotheses Testing and Significance Level ..................................... 58 
8.3.2.3. Handling of Missing Data ............................................................... 58 
8.3.2.4. Pooling of Centers ........................................................................... 58 
8.3.2.5. Analysis Methods for Efficacy Endpoints ........................................ 59 
8.3.3. Safety Analysis .............................................................................................. 59 
8.3.3.1. Extent of Exposure .......................................................................... 59 
8.3.3.2. Adverse Events ............................................................................... 59 
8.3.3.3. Assessment of Nasal Symptoms ...................................................... 60 
8.3.3.4. Laboratory Evaluations ................................................................... 60 
8.3.3.5. Vital Signs ...................................................................................... 60 
8.3.3.6. ECG Evaluations ............................................................................. 60 
8.3.3.7. Concomitant Medications ................................................................ 60 
8.3.3.8. Sheehan Suicidality Tracking Scale ................................................. 60 


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8.3.4. Interim Analysis ............................................................................................ 60 
9. 
DATA HANDLING AND RECORDKEEPING ................................................................ 61 
9.1. Case Report Forms (CRFs)........................................................................................ 61 
9.2. Retention of Records ................................................................................................. 61 
10. QUALITY CONTROL AND QUALITY ASSURANCE ................................................... 62 
10.1. Study Monitoring ...................................................................................................... 62 
10.2. Audits and Inspections .............................................................................................. 62 
11. ETHICS ............................................................................................................................. 63 
11.1. Ethics Review ........................................................................................................... 63 
11.2. Ethical Conduct of the Study ..................................................................................... 63 
11.3. Written Informed Consent ......................................................................................... 63 
11.4. Disclosure of Data ..................................................................................................... 64 
12. REFERENCES................................................................................................................... 65 


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List of Tables 
Table 1. DHE PK Parameters, mean (±SD); STS101-001, Part 1............................................. 27 
Table 2. DHE PK Parameters, mean (±SD); STS101-001, Part 2............................................. 27 
Table 3. Dosing frequency and PK data for STS101 5.2 mg, IV/IM/SC and IN DHE .............. 29 
Table 4. Laboratory Tests ....................................................................................................... 35 
Table 5. Adverse Event Relationship to Study Drug ................................................................ 55 
Table 6. Assessment of Adverse Event Severity ...................................................................... 55 
List of Figures 
Figure 1. STS101 Device ......................................................................................................... 25 
Figure 2. Dihydroergotamine mesylate chemical structure ........................................................ 26 
List of Appendices 
Appendix A. Schedule of Evaluations ..................................................................................... 67 
Appendix B. Subjective Assessment of Nasal Symptoms ........................................................ 69 
Appendix C. Objective Assessment of Nasal Symptoms ......................................................... 70 
Appendix D. 24-Hour Migraine Quality of Life Questionnaire ................................................ 72 
Appendix E. Headache Impact Test (HIT-6™) ....................................................................... 74 
Appendix F. Sheehan Suicidality Tracking Scale (S-STS) ...................................................... 75 
 
 


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List of Abbreviations and Definitions of Terms 
Abbreviation or specialist term 
Explanation 
24-MQoL 
24-hour Migraine Quality of Life Questionnaire 
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 
CAT 
computer assisted tomography 
CBC 
Complete Blood Count 
CGRP 
Calcitonin Gene-Related Peptide 
CI 
Confidence Interval 
CM 
Concomitant Medication 
Cmax 
Maximum Observed Plasma Concentration 
CRF 
Case Report Form 
DHE 
Dihydroergotamine 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
e-diary 
Electronic diary in handheld device 
FDA 
Food and Drug Administration 
FIS 
Functional Impairment Scale 
FIS 
Functional Impairment Scale 
GCP 
Good Clinical Practice 
hCG 
Human Chorionic Gonadotropin 
HPMC 
Hydroxypropyl Methylcellulose 
HR 
heart rate 
ICF 
Informed Consent Form 
ICHD-3 
International Classification of Headache Disorders, 3rd edition 
IM 
Intramuscular 
IN 
Intranasal 
IRB 
Institutional Review Board 
ITT 
The intent-to-treat 
IV 
Intravenous 


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Abbreviation or specialist term 
Explanation 
MBS 
most bothersome symptom 
MCC 
microcrystalline cellulose 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mitt 
modified intent-to-treat 
MRI 
magnetic resonance imaging 
NOAEL 
No Observed Adverse Effect Level 
PK 
Pharmacokinetic 
PP 
per protocol 
PT 
Preferred Term (in MedDRA dictionary) 
QTcF 
QT corrected with the Fridericia’s formula 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SD 
Standard Deviation 
SIT 
Smell Identification test 
SOC 
System Organ Class (in MedDRA dictionary) 
S-STS 
Sheehan Suicidality Tracking Scale 
T1/2 
Terminal Elimination Half-Life 
TEAE 
Treatment Emergent Adverse Events 
Tmax 
Time to reach Cmax 
VAS 
Visual Analog Scale 
WHO Drug 
World Health Organization Drug Dictionary 


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STUDY PROTOCOL REVISION HISTORY 
Changes in Version 6 (November 24, 2021) 
• Synopsis, Methodology (page 4-5 & 8); Section 2 Study Objectives and Purpose (page 31) 
Section 3.1 Overall Study Design and Plan (page 32); Section 3.2 Study Procedure 
Description (pages 32-36); Section 3.3 Schedule of Observations and Procedures (pages 
40-42); Section 4 Selection and Withdrawal of Subjects (page 43); Section 6.1 Efficacy 
Evaluation Parameters (page 49); Section 8.1 Sample Size Determination (page 57); 
Appendix A Schedule of Evaluations (pages 67-68) 
Allow subjects of the original cohort (enrolled and Visit 2 date before June 30, 2021) to continue 
study for another 6 months after completion of 12-month study. 
Rationale: 
Satsuma would like to collect addtional safety data for up to 18 months. Moreover, 12-month 
data in at least 50 subjects using the second generation STS101 device on average 2 times per 
month may be required by the FDA for approval. Subjects of the original cohort who already 
switched to the second generation device before June 20, 2021 have a high likelihood of 
providing that data in time for the STS101 NDA. 
Changes in Version 5 (June 30, 2021) 
• Synopsis, Methodology (page 4); Number of Subjects (page 5); Section 3.1 Overall Study 
Design and Plan (page 32); Section 4 Selection & Withdrawal of Subjects (page 41); 
Section 8.1 Sample Size Determination (page 55) 
Number of enrolled subjects changed from 300 to 480. 
Rationale: 
The FDA requested from Satsuma in December 2018 to provide repeated use data for STS101 
for at least 150 subjects using STS101 on average 2 times per month for at least 6 months. Due 
to a higher than expected drop out rate a 6 six months, and the introduction of a second 
generation device an additional 180 subjects need to be enrolled and assigned study study 
medication. 
• Synopsis (page 7) and Section 4.2 Subject Exclusion Criteria (page 43) 
Added Exclusion Criteria #19: Score of >0 on any of the questions 1-14 of the Sheehan 
Suicidality Tracking Scale 


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Rationale: 
FDA requirement to explore treatment emergent suicidal ideation and behavior for drugs in 
neurological indications. 
• Section 3.2.15 Sheehan Suicidality Tracking Scale (page 36); Section 3.3.1 Screening Visit 
(page 36); Section 3.3.2 Baseline Visit (page 37); Section 3.3.3 Visits 3 & 4 (page 38); 
Section 3.3.4 Visit 5 (page 38); Section 3.3.5 Visits 6 & 7 (page 39); Section 3.3.6 Visit 8 
(page 39); Section 3.3.7 Visits 9 & 10 (page 40); Section 3.3.8 Final Visit/Early Termination 
(page 40); Section 7.1.1.7 Sheehan Suicidality Tracking Scale (page 51); Section 8.3.3.8 
Safety Analysis - Sheehan Suicidality Tracking Scale (page 58); Appendix A Schedule of 
Evaluations (page 65); Appendix F Sheehan Suicidality Tracking Scale (page 72) 
Added completion of Sheehan Suicidality Tracking Scale at all study visits and analysis of data 
in safety analysis. 
• Section 5.3 Investigational Product Storage (page 45) 
Changed storage temperature from 15-25°C or 59°F-77 to 2-30oC or 36-86°F. 
Rationale: 
Company expanded storage temperature range based on new data from long term stability studies. 
• Section 3.2.7 Vital Signs (page 33); Section 3.3.1 Screening Visit (Visit 1; Day-30 to 
Day -1) (page 36); Section 3.3.2 Baseline Visit (Visit 2; Day 0) (page 37); Section 3.3.3 
Visits 3 & 4 (Month 1 and 2) (page 38); Section 3.3.4 Visit 5 (Month 3) (page 38); 
Section 3.3.5 Visits 6 & 7 (Month 4 & 5) (page 39); Section 3.3.6 Visit 8 (Month 6) 
(page 39); Section 3.3.7 Visits 9 & 10 (Month 8 & 10) (page 40); Section 3.3.8 Final 
Visit/Early Termination (Visit 11; Month 12) (page 40); Section 7.1.1.3 Vital Signs 
(page 50) 
Deleted oral as method for measuring body temperature. 
Rationale: 
No contact temperature taking allowed due to COVID-19 pandemic. 
 
 


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Changes in Version 4 (November 6, 2020) 
• Synopsis, Methodology, page 4; Efficacy Endpoints, page 8; Section 3.1 Overall Study 
Design and Plan, page 30; Section 6.1.1 Migraine Headache Pain Severity, page 45; 
Section 6.1.2 Most Bothersome Symptom, page 45; Section 6.1.4.1 Functional 
Impairment Scale, page 46 
Added evaluations of migraine headache pain severity, most bothersome symptom and 
functional impairment scale at 30 and 60 minutes after dosing 
• Section 6.2.1 Patient Global Impression, page 46 
Added evaluation at Visit 5 (Month 3) 
• Section 6.2.2 Ease of Use Impression, page 46 
Added evaluation at Visit 5 (Month 3) 
• Section 6.2.3 Likelihood of Use Question, page 46 
Added evaluation at Visit 5 (Month 3) 
• Section 6.2.4 Consistency of Study Medication Question, page 47 
Changed section name to 6.2.4 Comparison of study medication with previously used 
migraine medication. Replaced original question with this text: 
The study subjects will be asked to compare the effects of the study medication with their 
previously used migraine medication after 3, (Visit 5), 6 (Visit 8), and 12 (Visit 11/early term) 
months with answers to these four statements:  
Compared to my previous migraine medication, STS101 (the study medication) 
1. 
Allows me to return to normal faster  
2. 
More consistently treats my Migraine 
3. 
Works faster 
4. 
Keeps migraine from coming back 
The answer options for all four statements are: strongly agree; agree; neutral; disagree; strongly 
disagree 
 
 


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Changes in Version 3 (September 25, 2020) 
• Synopsis, Investigational Product, page 7; Section 1.5, Rationale for Dosing Frequency, 
pages 25-27; Section 5.1 Description of Investigational Product and Packaging, page 41; 
Section 5.2 Investigational Product Labeling, page 41; Section 5.9.1 Subject 
Randomization, page 43 
3.9 mg dose strength dropped from study. 
Rationale: Phase 3 efficacy study STS101-002 showed better efficacy for the 5.2 mg dose 
strength versus the 3.9 mg dose strength without significant differences in adverse events. 
• Section 5.1 Description of Investigational Product and Packaging, page 41; Section 3.3.3 
Visits 3 & 4 (Month 1 & 2), page 35; Section 5.4 Investigational Product Administration 
and Training, page 42; Schedule of Evaluations, page 62 
Investigational Product administration training added at Visits 3 and 4 
Rationale: Additional training is expected to result in better administration technique and fewer 
IP administration errors. 
• Section 3.2.11 Clinical Laboratory Test, page 32; Section 3.3.2 Baseline Visit 
(V2, Day 0), page 34 
Added clarification that subject should be instructed to withhold study medication until the site 
has reviewed the Visit 2 laboratory results and confirmed the subject’s eligibility. 
Rationale: Avoid study drug use by subjects who are not eligible 
• Synopsis, Statistical Methods Safety, page 10; Section 3.3.1 Screening Visit (V1, Day30 
to Day -1), page 33; Section 3.3.2 Baseline Visit (V2, Day 0), page 34; Section 7.2. 
Adverse Events, page 49; Section 8.3.3.2 Safety Analysis - Adverse Events, page 54; 
Schedule of Evaluations, page 62 
AE collection will begin after the signing of the Informed Consent Form (Visit 1) 
Rationale: Subjects will administer placebo/MCC filled devices during administration training 
starting at Visit 1. 
 


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Changes in Version 2 (May 11, 2020) 
• Synopsis, Number of Subjects, page 5; Section 4, Selection and Withdrawal of Subjects, 
page 36; Section 8.1, Sample Size Determination (page 52) 
Clarification that at least 150 and 50 subjects are planned to complete 6 and 12 months of 
treatment, respectively. 
• Synopsis, Exclusion Criteria, page 7; Section 4.2, Exclusion Criteria, page 38 
Changed note in Exclusion criterion #14 to clarify that subjects who have participated in study 
STS101-002 are exempt from this exclusion. 
• Synopsis, Duration of study, page 7); Section 3.3.1, Screening Visit, page 31; Appendix A, 
Schedule of Evaluations (page 62) 
Changed maximum duration of screening period to 30 days. 
• Section 1.5, Rationale for Dosing Frequency, pages 24 and 25 
Added 2 times 3.9 mg STS101 to dosing frequency rationale. 
• Section 3.3.2, Baseline Visit (Visit 2; Day 0), page 33 
“Weight” and “Documentation of Health Care resource utilization (HCRU) in 6 months before 
screening” was added to list of procedures. Both procedures were inadvertently omitted in 
previous version. 
• Section 3.3.3, Visits 3 & 4 (Month 1 and 2), page 32; Section 3.3.4, Visit 5 (Month 3), 
page 33; Section 3.3.5, Visits 6 & 7 (Month 4 and 5), page 33; Section 3.3.6, Visit 8 
(Month 6), page 34; Section 3.3.7, Visits 9 & 10 (Month 8 and 10), page 34; Section 
3.3.8, Final Visit/Early Termination Visit (Visit 11; Month 12), page 35 
“Weight” and “Documentation of Health Care resource utilization since last visit (HCRU)” was 
added to list of procedures. Both were inadvertently omitted in previous version. Both 
procedures were inadvertently omitted in previous version. 
• Section 3.3.1, Screening Visit (Visit 1; Day-15 to Day -1), page 31; Section 3.3.2, 
Baseline Visit (Visit 2; Day 0); Section 3.3.4, Visit 5 (Month 3), page 33; Section 3.3.6, 
Visit 8 (Month 6), page 34, and Section 3.3.8, Final Visit/Early Termination Visit 
(Visit 11; Month 12), page 35 
Deleted “Urine drug and alcohol screen” since this procedure is not part of the protocol. 
• Section 3.3.3, Visits 3 & 4 (Month 1 and 2), page 32 
Added “Review electronic diary and confirm subject properly recorded headache and migraine 
information and post treatment assessments” to list of procedures. Procedure was inadvertently 
omitted in previous version. 
• Section 3.3.7, Visits 9 & 10 (Month 8 and 10), page 34 
Added “Clinical laboratory tests and urinalysis” to list of procedures. Procedures were 
inadvertently omitted in previous version. 
• Appendix A, Schedule of Evaluations, page 62 
“Health Care Resource Utilization” added to Schedule of Evaluations


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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 by 
blocking 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 (Burstein 2004; Dahlöf 2012; González-Hernández 
2018; Hoskin 1996; Silberstein 2003;). 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 (Aurora 2011; Carleton 1998; Edwards 2001; Gallagher 1996; Raskin 1986; 
Winner 1996). 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 (Migranal® Prescribing Information 2017; 
Tfelt‑Hansen 2013) 
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 blocking 
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 (Burstein 2004; Dahlöf 2012; González-Hernández 2018; 
Hoskin 1996; Silberstein 2003). 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 
marketed DHE mesylate formulations and other data regarding Migranal and DHE mesylate 
Injectable solution can be found in the STS101 Investigator’s Brochure. 


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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 (Humbert 1996; Schran 1994; 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 
(Aurora 2011; Gallagher 1996; Winner 1996). 
This study is being conducted as part of the clinical development program for STS101 to 
demonstrate the safety and tolerability of repeat dose use of STS101 for up to 12 months in the 
treatment of acute migraine attacks with or without aura. 
1.5. Rationale for Dosing Frequency 
The DHE dose of STS101 in study STS101-003 (5.2 mg, which is equivalent to 6.0 mg DHE 
mesylate, USP, respectively) is the dose selected for efficacy and safety evaluation in Phase 3. 
The dosing frequency takes into consideration the following: 
• Plasma Exposure (PK) of DHE when administered as STS101 
• Maximum daily/weekly doses per Prescribing Information for DHE by all routes 
• Toxicology evaluations for systemic and local effects 


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The dosing schedule in Study STS101-003 will allow subjects to administer up to 2 doses of 
STS101 5.2 mg within a 24-hour period and up to 12 doses per month. 
This use frequency is primarily based on the comparison of the plasma concentrations after 
STS101 5.2 mg with those after IV and IM injection of D.H.E 45® solution. 
The table below provides comparison of the dosing frequency and PK data for STS101 5.2 mg 
and IV and IM DHE. 
Table 3. Dosing frequency and PK data for STS101 5.2 mg, IV/IM/SC and IN DHE 
Route of Administration 
IV 
IM/SC 
IN 
STS101 
Dose per administration 
1 mg 
1 mg 
2 mg 
5.2 mg 
Maximum dose per day/month  
2/24 mg 
3/24 mg 
3/16 mg 
2 x 5.2 mg 
12 x 5.2 mg 
Single dose Cmax 
(pg/mL) 
54,189 
3368 
961 
2175 
Single dose AUC0-inf 
(h*pg/mL)  
12,894 
13650 
6498 
12030 
Source: STS101-001 Data Tables, February 2019; D.H.E. 45® Prescribing Information 2017; Kellerman 2013 
 
The plasma concentrations and PK parameters after 5.2. mg STS101, specifically Cmax and AUC, 
fall within boundaries of the PK of the approved injectable (IV, IM & SC) DHE regimen. 
Specifically, the maximum DHE plasma concentrations after 5.2 mg STS101 were below those for 
1.0 mg DHE mesylate IM in Study STS101-001 (Cmax of 2175 vs 3368 pg/mL, respectively) and 
well below maximum plasma concentrations reported after IV DHE mesylate (Kellerman 2013), 
providing a large margin of safety. 
The Phase 1 study, STS101-001, did not identify any unexpected adverse events after 
administration of up to 5.2 mg STS101. As expected, most of the adverse events after STS101 
were localized in the nose, rated as mild, transient, and not considered clinically relevant. The 
low scores in the subjective nasal symptom assessments and no significant findings in the 
objective nasal assessments further demonstrate the local tolerability of STS101. The incidences 
of DHE-related adverse events in the nose and taste sensations for 5.2 mg STS101 are comparable 
to those previously reported for Migranal (Migranal® Prescribing Information 2017). 
In support of repeated dosing, the concentration-time profiles and pharmacokinetic parameters 
have been projected. The estimated Cmax following 2 times 5.2 mg (re-dosed at 2 hours) is 
3060 pg/mL compared to the observed Cmax of 2175 pg/mL and 3368 pg/mL, after single doses 
of 5.2 mg STS101 and 1.0 mg IM DHE, respectively (STS101-001). 
The estimated AUC0-4h following 2 times 5.2 mg (re-dosed at 2 hours) is 7800 pg*h/mL compared 
to the observed AUC0-4h (based on mean concentration-time profile) of 4810 and 7214 pg*h/mL 
following single doses of 5.2 mg STS101 and 1.0 mg IM DHE, respectively (STS101-001 
Clinical Study Report, 2019 and subsequent simulations). 


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A total of two 5.2 mg administrations in a 24-hour period is therefore within the exposures that 
have been demonstrated to be safe and well tolerated with the approved injectable DHE product. 
DHE mesylate-related side effects, especially nausea, are unlikely to occur, as peak plasma 
concentrations are expected to not exceed 6000 pg/mL (Cook et al., 2009). 
Additionally, repeated dosing of STS101 is within the margins of safety as established by a 2-week 
(i.e. 14 consecutive days) intranasal study in dogs (>20-fold based on mg/kg/day, ~5-fold based 
on DHE plasma AUC, and ~2-fold based on nasal cavity surface exposure; Study FY18-020b; 
see the Investigator’s Brochure for more details on the nonclinical safety overages). Additionally, a 
6-month toxicity study in dogs via nasal-only inhalation at doses up to 0.825 mg/kg/day resulted 
in minimal treatment related effects (Armer 2011). 
When the total daily and total weekly allowances with approved DHE products and routes of 
administration are compared, the DHE mesylate amount for daily and weekly proposed 
frequency for STS101 is no greater than for oral DHE dosing (10 mg/day and 70 mg/week) 
Dihydergot Prescribing Information, 2011. 
In conclusion, STS101 dosing of up to 2 times 5.2 mg STS101 within 24 hours and up to 12 times 
5.2 mg per month is supported by the safety profile of single dosing at the proposed dose levels, 
the projected DHE systemic exposure that is within the range of injectable DHE products with 
repeated dosing, and the repeat dose toxicology NOAELs for systemic and local effects. The total 
number of doses per month will be limited to 12. 


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2. 
STUDY OBJECTIVES AND PURPOSE 
The objectives of this study are: 
Primary 
• To assess the safety and tolerability of STS101 in the acute treatment of migraine attacks 
over 12 months and up to 18 months in a sub-set of subjects. 
Secondary 
• To describe the efficacy of STS101 in the acute treatment of migraine attacks over 
12 months. 


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3. 
STUDY DESIGN 
3.1. Overall Study Design and Plan 
This study will be a multi-center, multiple dose (PRN), open-label, 12-month study in approximately 
480 subjects with migraine (ages 18 to 65 years). After establishing eligibility, the study participants 
will use STS101 (DHE nasal powder) on a PRN basis to treat migraine attacks for 12 months. 
Study participants will be able to use up to 2 doses of STS101 to treat a single migraine attack 
within 24 hours and can use up to 12 doses of STS101 per month for 12 months. Subjects of the 
original cohort (enrolled before June 30, 2021) will be offered to continue use of study medication 
for another 6 months after the completion of the original 12-month period. Only safety data will 
be collected during this additional 6-month period. 
The study participants will document the pain severity of their migraine attacks, presence and 
severity of symptoms (photophobia, phonophobia, nausea) and functionality status over the 
48-hour period after study drug administration. Specifically, headache pain severity data and 
symptom presence will be collected at the onset of the migraine attack, immediately before drug 
administration (time 0), 30 and 60 minutes, 2, 4, 24, and 48 hours after study drug administration. 
Migraine attacks not treated with study medication will also be documented. Use of rescue 
medication is allowed, but triptans or other DHE products as rescue medications should be 
avoided for 24 hours after study drug administration (24 hours after the second dose if a repeat 
dose of STS101 is administered). 
Adverse events, nasal and physical examination data, safety laboratory data, vital sign data and 
ECGs will be recorded to describe the tolerability and safety of STS101. Additionally, subjective 
and objective nasal symptom assessments and the Smell Identification Test (SIT) will be 
documented during the treatment period. 
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. Subjects continuing for another 6 months after 
the original 12-month treatment period will need to sign an additional informed consent form. 
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. 


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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 
race and ethnicity. Prior medications will include all medications taken for 30 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 at 
the Baseline visit (Visit 2) and throughout the study: 
• Timing and duration of last menstruation 
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 Baseline Visit (Visit 2) and at Visits 5, 8 and 11, subjects will complete the 6-question 
Headache Impact Test (Appendix E), a tool for assessing the impact of headache on daily life in 
subjects with migraine (Yang 2010). 
3.2.6. 
Physical Examination 
A full physical examination will be performed at Screening (Visit 1), Baseline (Visit 2), at 
6 months (Visit 8), 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. A focused neurological exam (motor and 
sensory skills, hearing and speech, vision, coordination, and balance) will be done at Visits 3-7, 
9 and 10. Examination of other body organ systems at Visits 3-7, 9 and 10 should be done as 
appropriate at the discretion of the investigator, e.g., to evaluate sequelae of adverse events. In 
subjects continuing for another 6 months after the original 12-month treatment period: focused 
neurological exam at Visits 12 and 13 and full physical examination at Visit 14. 
3.2.7. 
Vital Signs 
Vital signs will be obtained at Screening (Visit 1), Baseline (Visit 2), at each of the Visits 3-10 and 
at the Final/Early termination visit. Vital signs will include temperature, sitting blood pressure 


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(to be taken after 5 minutes of sitting), and pulse rate. In subjects continuing for another 6 
months after the original 12-month treatment period: vital signs will be collected at Visits 12-14. 
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, Baseline, all visits and the final/early termination visits. Subject height 
will only be measured at the Screening Visit without shoes. Subjects will have their BMI calculated 
at the Screening Visit (Visit 1) using the following formula: BMI = weight (kg)/height (m2). 
3.2.9. 
Evaluations of Effects in the Nose 
3.2.9.1. 
Subjective Assessment of Nasal Symptoms 
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 questionnaire and completion instructions are shown in Appendix B. 
The subjective assessment of nasal symptoms will be performed at the following times: 
Screening (Visit 1), Baseline (Visit 2), Visits 5, Visit 8 and at the Final/early termination Visit 
(Visit 11). In subjects continuing for another 6 months after the original 12-month treatment 
period: subjective assessment of nasal symptoms will be performed at Visit 14. 
All VAS assessments will be converted to a numerical value in millimeters (range 0-100). 
3.2.9.2. 
Objective Assessment of Symptoms 
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 symptoms will be performed at the following times: Screening 
(Visit 1), Baseline (Visit 2), Visits 3 through 10 and at the Final/early termination Visit. In 
subjects continuing for another 6 months after the original 12-month treatment period: objective 
assessment of nasal symptoms will be performed at Visits 12-14. Assessment sheets must be 
retained for all subjects. The person performing the assessments should be the same at all visits. 
3.2.10. Smell Identification Test™ 
The Smell Identification Test™ (SIT) is our comprehensive 40-item test of olfactory function. 
The SIT will be administered according to the Smell Identification Test Administration Manual 
(Sensonics International; Haddon Heights, NJ, USA) at the following times: Baseline (Visit 2) 
and at the Final/early termination Visit (Visit 11). In subjects continuing for another 6 months 
after the original 12-month treatment period: SIT will be administered at Visit 14. 


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3.2.11. Clinical Laboratory Tests 
A designated central laboratory will perform the hematology, biochemistry, urinalysis and 
diagnostic tests as specified in Table 4. 
Samples for clinical laboratory tests will be taken at Screening (Visit 1), Baseline (Visit 2), 
Visits 5, 8-10 and at the Final/early termination visit (Visit 11). In subjects continuing for 
another 6 months after the original 12-month treatment period: clinical laboratory tests will be 
taken at Visits 12-14. All samples will be collected in accordance with the Study Laboratory 
Manual and shipped to the designed central laboratory. 
The subjects should be instructed to withhold study medication until the site has confirmed that 
the laboratory test results at Visit 2 meet study eligibility criteria. The serum pregnancy test 
(HCG) will be performed in all female subjects at Screening (Visit 1) and at the Final/early 
termination visit (Visit 11). The serum pregnancy test (HCG) will be performed at every visit 
(Visit 1 through 11) in women of childbearing potential. 
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 Baseline Visit or Follow-up visit will be followed until they return to normal or 
become medically stable. 
Table 4. 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 (HCG) 
FSH 
Appearance 
Color 
pH 
Specific Gravity 
Protein  
Glucose  
Ketones 
Occult Blood 
Nitrites 
Urobilinogen 
Leukocytes 
Bilirubin 
Urine microscopy, if necessary 
Note: If deemed medically necessary, repeats of laboratory tests may be granted by the Medical Monitor. 
 


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3.2.12. Electrocardiogram 
A 12-lead ECG will be performed at Screening (Visit 1), Baseline (Visit 2), Visits 5, 8-10 and 
at the Final/early termination Visit (Visit 11). In subjects continuing for another 6 months after 
the original 12-month treatment period: ECGs will be performed at Visits 12-14. All ECGs will 
be done in triplicate and reviewed by the investigator or a qualified delegate to assure subject 
eligibility and safety. 
3.2.13. Adverse Events Recording 
Adverse events will be recorded and assessed as specified in Section 7. 
3.2.14. Electronic Headache Diary 
Study participants will receive a handheld device for collection of electronic diary data. At the 
Baseline visit (Visit 2), study participants will receive training in the use of the device. 
During the treatment period, the study participants will document signs and symptoms 
identifying a migraine headache, the pain severity of their treated migraine attack, presence and 
severity of symptoms (e.g., photophobia, phonophobia, nausea), rescue medication use and 
functional status over the 48-hour period after study drug administration in the e-diary. 
The complete content and the training procedures for the electronic diary device will be 
described in separate documents. 
3.2.15. Sheehan Suicidality Tracking Scale (S-STS) 
All study subjects will complete the Sheehan Suicidality Tracking Scale (S-STS) (Appendix F) 
at all visits. 
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 Visit (Visit 1; Day-30 to Day -1) 
Screening procedures to determine if subjects qualify for the study include: 
a. Signing of informed consent 
b. Review of inclusion/exclusion criteria 
c. Recording of demographic data 
d. Medical history, including concomitant medications 
e. Full physical examination 


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f. Adverse Event Recording 
g. Vital signs (including pulse rate, sitting blood pressure and temperature) 
h. Body weight, height and BMI calculation 
i. Nasal examination including Objective Assessment of Nasal Symptoms 
j. Subjective Assessment of Nasal Symptoms 
k. Completion of Sheehan Suicidality Tracking Scale 
l. STS101 device training  
m. Clinical laboratory tests 
n. Urinalysis 
o. Serum pregnancy test (all females) 
p. 12-lead ECG (in triplicate) 
3.3.2. 
Baseline Visit (Visit 2; Day 0)  
a. Review of eligibility criteria 
b. Full physical examination 
c. Vital signs (including pulse rate, sitting blood pressure and temperature) 
d. Weight 
e. Concomitant medication review 
f. Adverse Event Recording 
g. Clinical laboratory tests and urinalysis 
h. Serum pregnancy test (females of childbearing potential only) 
i. 12-lead ECG (in triplicate) 
j. Nasal examination including Objective Assessment of Nasal Symptoms 
k. Subjective Assessment of Nasal Symptoms 
l. Completion of Sheehan Suicidality Tracking Scale 
m. Smell Identification test 
n. Completion of HIT-6 instrument 
o. Documentation of Health Care resource utilization (HCRU) in 6 months before screening 
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. 


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If the subject still meets all eligibility criteria for study participation, the following procedures 
will be done: 
a. STS101 device and administration training 
b. Dispense Investigational Product 
c. Electronic headache diary use training and dispensation of electronic diary 
d. Instruct subject to withhold study medication until the site has confirmed that the 
laboratory test results at Visit 2 meet study eligibility criteria. 
3.3.3. 
Visits 3 & 4 (Month 1 and 2) 
a. Focused neurological examination 
b. Vital signs (including pulse rate, sitting blood pressure and temperature) 
c. Weight 
d. Nasal examination including Objective Assessment of Nasal Symptoms 
e. Completion of Sheehan Suicidality Tracking Scale 
f. Concomitant medication review 
g. Adverse Event Recording 
h. STS101 device and administration training 
i. Serum pregnancy test (females of childbearing potential only) 
j. Documentation of Health Care resource utilization (HCRU) since last visit 
k. Review electronic diary and confirm subject properly recorded headache and migraine 
information and post treatment assessments. Counsel subject as needed Adverse Event 
recording 
l. Study drug supply/Drug Accountability 
3.3.4. 
Visit 5 (Month 3) 
a. Focused neurological examination 
b. Vital signs (including pulse rate, sitting blood pressure and temperature) 
c. Weight 
d. Concomitant medication review 
e. Clinical laboratory tests and urinalysis 
f. Serum pregnancy test (females of childbearing potential only) 
g. 12-lead ECG (in triplicate) 
h. Nasal examination including Objective Assessment of Nasal Symptoms 
i. Subjective Assessment of Nasal Symptoms 


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j. Completion of Sheehan Suicidality Tracking Scale 
m. Completion of HIT-6 instrument 
n. Documentation of Health Care resource utilization (HCRU) since last visit 
o. Review electronic diary and confirm subject properly recorded headache and migraine 
information and post treatment assessments. Counsel subject as needed.  
m. Adverse Event recording 
n. Study drug supply/Drug Accountability 
3.3.5. 
Visits 6 & 7 (Month 4 & 5) 
a. Focused neurological examination 
b. Vital signs (including pulse rate, sitting blood pressure and temperature) 
c. Weight 
d. Nasal examination including Objective Assessment of Nasal Symptoms 
e. Completion of Sheehan Suicidality Tracking Scale 
f. Concomitant medication review 
g. Serum pregnancy test (females of childbearing potential only) 
h. Review electronic diary and confirm subject properly recorded headache and migraine 
information and post treatment assessments. Counsel subject as needed. 
i. Documentation of Health Care resource utilization (HCRU) since last visit 
j. Adverse Event recording 
k. Study drug supply/Drug Accountability 
3.3.6. 
Visit 8 (Month 6) 
a. Full physical examination 
b. Vital signs (including pulse rate, sitting blood pressure and temperature) 
c. Weight 
d. Concomitant medication review 
e. Clinical laboratory tests and urinalysis 
f. Serum pregnancy test (females of childbearing potential only) 
g. 12-lead ECG (in triplicate) 
h. Nasal examination including Objective Assessment of Nasal Symptoms 
i. Subjective Assessment of Nasal Symptoms 
j. Completion of Sheehan Suicidality Tracking Scale 


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k. Completion of HIT-6 instrument 
l. Subject Impression of Study Medication Questions (see Section 6.2) 
m. Review electronic diary and confirm subject properly recorded headache and migraine 
information and post treatment assessments. Counsel subject as needed. 
n. Documentation of Health Care resource utilization (HCRU) since last visit 
o. Adverse Event recording 
p. Study drug supply/Drug Accountability 
3.3.7. 
Visits 9 & 10 (Month 8 & 10) 
a. Focused neurological examination 
b. Vital signs (including pulse rate, sitting blood pressure and temperature) 
c. Weight 
d. Nasal examination including Objective Assessment of Nasal Symptoms 
e. Completion of Sheehan Suicidality Tracking Scale 
f. 12 Lead ECG (in triplicate) 
g. Concomitant medication review 
h. Clinical laboratory tests and urinalysis 
i. Serum pregnancy test (females of childbearing potential only) 
j. Review electronic diary and confirm subject properly recorded headache and migraine 
information and post treatment assessments. Counsel subject as needed. 
k. Documentation of Health Care resource utilization (HCRU) since last visit 
l. Adverse Event recording 
m. Study drug supply/Drug Accountability 
3.3.8. 
12-Month Visit/Early Termination (Visit 11; Month 12) 
At the final visit/early termination procedures will comprise the following: 
a. Full physical examination 
b. Vital signs (including pulse rate, sitting blood pressure and temperature) 
c. Weight 
d. Concomitant medication review 
e. Clinical laboratory tests and urinalysis 
f. Serum pregnancy test (All females) 
g. 12-lead ECG (in triplicate) 
h. Nasal examination including Objective Assessment of Nasal Symptoms 
i. Subjective Assessment of Nasal Symptoms 


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j. Completion of Sheehan Suicidality Tracking Scale 
k. Smell Identification Test 
l. Completion of HIT-6 instrument 
m. Subject Impression of Study Medication Questions (see Section 6.2) 
n. Documentation of Health Care resource utilization (HCRU) since last visit 
o. Adverse Event recording 
p. Collect electronic diary device 
q. For subjects assigned study medication (Visit 2) before June 30, 2021, check if subject 
wants to continue study for another 6 months. If subject agrees, they will sign the 
appropriate informed conenst form.  
r. In subjects not continuing: Collect used and unused Investigational Product (STS101 
devices)/Drug Accountability 
s. In subjects continuing: Study drug supply/Drug Accountability 
3.3.9. 
Visits 12 & 13 (Month 14 & 16) 
a. Focused neurological examination 
b. Vital signs (including pulse rate, sitting blood pressure and temperature) 
c. Weight 
d. Nasal examination including Objective Assessment of Nasal Symptoms 
e. Completion of Sheehan Suicidality Tracking Scale 
f. 12 Lead ECG (in triplicate) 
g. Concomitant medication review 
h. Clinical laboratory tests and urinalysis 
i. Serum pregnancy test (females of childbearing potential only) 
j. Adverse Event recording 
k. Study drug supply/Drug Accountability 
3.3.10. Final Visit/Early Termination (Visit 14; Month 18) 
At the final visit/early termination procedures will comprise the following: 
a. Full physical examination 
b. Vital signs (including pulse rate, sitting blood pressure and temperature) 
c. Weight 
d. Concomitant medication review 
e. Clinical laboratory tests and urinalysis 
f. Serum pregnancy test (All females) 
g. 12-lead ECG (in triplicate) 


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h. Nasal examination including Objective Assessment of Nasal Symptoms 
i. Subjective Assessment of Nasal Symptoms 
j. Completion of Sheehan Suicidality Tracking Scale 
k. Smell Identification Test 
l. Completion of HIT-6 instrument 
t. Adverse Event recording 
u. Collect used and unused Investigational Product (STS101 devices)/Drug Accountability 
 


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4. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
A total of approximately 480 adult male and female subjects aged 18 to 65 years with episodic 
migraine headaches. At least 150 and 50 subjects are planned to complete at least 6 and 12 months, 
respectively. Approximately 20 subjects are expected to complete 18 months. 
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 
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. History of 4 - 12 migraine attacks per month in each of the 3 months prior to Screening 
Visit 
c. History <15 headache days per month in each of the 3 months prior to Screening Visit 
4. Female subjects will be included if they are post-menopausal (at least 1 year since last 
menses with an FSH >40 IU/mL) 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 one of the following 
medically acceptable contraceptive methods during the course of this study: 
a. Simultaneous use of male condom and intra-uterine contraceptive device placed at least 
4 weeks prior to screening (Visit 1) 
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 1) 
d. Surgical sterilization of their partner(s) at least 6 months prior to screening (Visit 1) 
5. Intact nasal mucosa (Appendix C, Objective Assessment of Nasal Symptoms: no ulceration; 
no bleeding; no or mild erythema, no or mild swelling and no or mild rhinorrhea) at baseline 
(Visit 2) 
6. Willing and able to comply with the requirements of the protocol and follow directions from 
the clinic staff 
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 but not 
limited to diagnosis of basilar migraine (aka migraine with brainstem aura) or hemiplegic 
migraines, medication overuse headache or cluster headache 


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4. Clinically significant abnormal physical findings 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 for 
complications from ischemic heart disease 
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. Diagnosis of hypertension or receiving antihypertensive medication for treatment of 
hypertension 
b. Diagnosis of hypercholesteremia, or 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 screening (Visit 1) or Baseline (Visit 2). 
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) at screening (Visit 1) or Baseline (Visit 2). 
10. Screening 12-lead ECG showing any clinically significant abnormalities at screening 
(Visit 1) or Baseline (Visit 2). 
11. Systolic blood pressure lower than 90 or over 140 mmHg, diastolic blood pressure lower than 
50 or over 90 mmHg, at screening (Visit 1) or Baseline (Visit 2). 
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 
14. Participation in another drug research study within 30 days of screening (Visit 1) or within 
less than 5 half-lives of tested drug (whichever is longer). Note: Subjects who have 
participated in study STS101-002 are exempt from this. 


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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 two preventive migraine medications 
18. Concomitant daily use of peripheral and central vasoconstrictors including but not limited to 
amphetamines, phenylephrine, pseudoephedrine, propranolol and nicotine (from smoking, 
vaping or smokeless products) 
19. Score of  >0 on any of the questions 1-14 of the Sheehan Suicidality Tracking Scale 
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 11 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. Inadequate number of migraine attacks: Subjects may be discontinued from the study 
if they experience and treat less than two migraine attacks on average per month over the 
first three months of the study.  
i. 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 off-white powder. 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: 
• 5.2 mg STS101 dose strengths (equivalent to 6.0 mg DHE mesylate USP) as unit dose in 
a labeled foil wrap. 
The non-investigational product will be made available for training during the following Visits: 
Visit 1, 2, 3, and 4 
• STS101 Empty Training Devices (empty STS101 Device). 
• STS101 Filled Training Devices (STS101 Device containing microcrystalline cellulose). 
5.2. Investigational Product Labeling 
The foil wrap will be labeled with a label designating: 
• STS101 dose strength (5.2 mg) 
• 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 (2-30oC or 36-86°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 Visits 1, 2, 3, and 4 study personnel will train the subject in the study drug preparation and 
administration. Instructions for Use, an instructional video, STS101 Empty Training Devices and 
STS101 Filled Training Devices will be used for training of the study subject at all of these 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. 
Subjects will be instructed to: 
• Place Nozzle 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. 
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. 


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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 24 hours before and after study drug 
administration. 
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) are not allowed. 
The concomitant use of more than two prevention medications for migraine is not allowed. 
The concomitant use of a peripheral and central vasoconstrictive medication is not allowed. 
5.8. Treatment Compliance 
All used or unused Investigational Product will be returned to the site at each study visit at which 
time the dispensed Investigational Product will be reconciled in the drug accountability log. 
5.9. Randomization and Blinding 
5.9.1. 
Subject Randomization 
There is no randomization. All subjects will be assigned to receive 5.2 mg STS101. 
5.9.2. 
Blinding & Unblinding Procedures 
This is an open label study. 


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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. Note: No efficacy 
data will be collected in subjects who continue for another 6 months after the original 12-month 
treatment period. 
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 30 and 60 minutes, 2, 4, 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 30 and 60 minutes, 2, 4, 24, and 48 hours 
after study drug administration. 
6.1.3. 
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. 


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6.1.4. 
Evaluation of Function & Subjective Impressions 
6.1.4.1. 
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 30 and 60 minutes, 2, 4, 24, and 48 hours after study drug 
administration. 
6.1.4.2. 
24-hour Migraine Quality of Life Questionnaire 
For one treated attack per month, the study subjects will be prompted to complete the 24-hour 
Migraine Quality of Life Questionnaire (24-MQoL) (Appendix D) at 24 hours after drug 
administration. 
6.2. Other Evaluations at Office Visits 
6.2.1. 
Patient Global Impression 
The study subjects will be asked to rate the global impression of the study treatment at Visit 5 
(Month 3), Visit 8 (Month 6) and Visit 11/Early Term (Month 12) 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 good, good, no opinion, poor, very poor. 
6.2.2. 
Ease of Use Impression 
The study subjects will be asked to rate the ease of use of the study medication at Visit 5 (Month 
3), Visit 8 (Month 6), and Visit 11/Early Term (Month 12) with this question: “How easy was 
the administration of the study medication?” 
The subject’s rating will be documented on a five-point verbal Likert scale with these response 
options: very easy, easy, no opinion, not easy, not easy at all. 
6.2.3. 
Patient Likelihood of Use 
The study subjects will be asked to rate the likelihood of using the study medication at Visit 5 
(Month 3), Visit 8 (Month 6) and Visit 11/Early Term (Month 12) months with this question: 


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“How likely is it that you would use the study medication to treat your migraine if it were 
available?” 
The subject’s rating will be documented on a five-point verbal Likert scale with these response 
options: very likely, likely, no opinion, unlikely, very unlikely. 
6.2.4. 
Comparison of Study Medication with Previously Used Migraine 
Medication 
The study subjects will be asked to compare the effects of the study medication with their 
previously used migraine medication after 3, (Visit 5), 6 (Visit 8), and 12 (Visit 11/early term) 
months with answers to these four statements:  
Compared to my previous migraine medication, STS101 (the study medication) 
1. Allows me to return to normal faster  
2. More consistently treats my Migraine 
3. Works faster 
4. Keeps migraine from coming back 
The answer options for all four statements are: strongly agree; agree; neutral; disagree; strongly 
disagree 
6.2.5. 
HIT-6 
The subjects will complete the HIT-6 instrument at Visit 2 (baseline), Visit 5 (3 months), Visit 8 
(6 months), and Visit 11/early term (12 months). 
6.3. Healthcare Resource Utilization 
Subjects will be asked at baseline (Visit 2) to provide information on their healthcare resource 
utilization over the prior 6 months. This should include: 
• Any migraine specific office-based consultations (primary care, nurse 
practitioner/physician assistant, neurologist) 
• Any visits to pain clinic, headache clinic, mental health clinic and chiropractor/alternative 
medicine, urgent care or emergency department 
• Any hospitalizations or overnight hospital/emergency department stays 
• Any diagnostic services including computer assisted tomography (CAT) scans, magnetic 
resonance imaging (MRI). 
At each follow up visit the subjects will be asked to provide information reg. their healthcare 
resource utilization over the period since their last visit. 


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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, Baseline 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, and 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 Symptom Assessments/Nasal Exam 
An assessment of subjective nasal symptoms will be performed based on data recorded with the 
Subjective Assessment of Nasal Symptoms form (Appendix B). A nasal exam will be completed 
along with an assessment of objective nasal symptoms will be performed based on data recorded 
with the Objective Assessment of Nasal Symptoms form (Appendix C). 
7.1.1.5. 
Smell Identification Test 
Olfactory function will be assessed based on the Smell Identification Test. 
7.1.1.6. 
Electrocardiogram (ECG) 
Standard 12-lead ECG will be performed in triplicate approximately 1 minute apart. All ECGs 
will be reviewed by a competent physician who will comment on any abnormal findings. 


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Clinically significant findings if found at Screening (Visit 1) or Baseline (Visit 2) may be a 
reason to exclude the subject. 
In subjects who report chest related symptoms or adverse events, an ECG (in triplicate) should 
be recorded if symptoms are reported to the site within 48 hours of onset. 
7.1.1.7. 
Sheehan Suicidality Tracking Scale 
The S-STS is a 16-item scale that assesses the seriousness of suicidality risk using a 5-point 
Likert scale from “not at all” (0) to “extremely” (4) (Sheehan 2014). The S-STS will be 
completed by all subjects at all study visits. 
7.1.2. 
Laboratory Assessments 
Central laboratory tests results will be reviewed for any clinically significant abnormalities by a 
qualified physician. Labs can be reviewed by a Physician Assistant (PA) or Nurse Practitioner 
(NP); however, they should be signed/dated by an MD. If any clinically significant findings are 
present at Screening (Visit 1) or Baseline (Visit 2), 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. 
Serum Pregnancy Test & FSH 
Serum HCG pregnancy & FSH tests results in female subjects. 
7.1.2.5. 
Lab Testing for Chest Related Symptoms or Adverse Events 
In subjects who report chest related symptoms or adverse events, the following markers should 
be evaluated (if symptoms are reported to the site within 48 hours of onset): total creatine kinase 


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(CK), CK‑myocardial band (CK- MB), aspartate aminotransferase (AST), lactate dehydrogenase 
(LDH), cardiac troponins (Troponin T; Troponin I), and myoglobin. A blood sample for analysis 
of DHE plasma concentration should also be drawn. 
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. 
AEs will be recorded as volunteered by the subject or solicited through indirect questioning. 
AE collection will begin after the signing of the Informed Consent Form (Visit 1) and 
continue until the final/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 ongoing AEs at the subject’s last 
visit will be followed, until it resolves, stabilizes or returns to baseline levels. 
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 5. 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. 


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Table 5. 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). 
 
7.2.2. 
Assessment of Adverse Event Severity 
Table 6 shows the guidelines for rating severity of AEs may be used: 
Table 6. 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. 


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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. 
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 early termination). 


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8. 
STATISTICS 
8.1. Sample Size Determination 
A total of approximately 480 adult male and female subjects (18 to 65 years of age) with migraine 
will be enrolled. At least 150 and 50 subjects are anticipated to complete at least 6 and 12 months, 
respectively and about 20 subjects to complete 18 months. With a sample size of 300 subjects, 
there is a 95% probability to detect clinically important adverse events with event rate of 1% or 
higher. This sample size is expected to adequately characterize the safety and tolerability of 
STS101 in the acute treatment of migraine. 
8.2. Subject Populations 
The analysis populations to be used in the study are defined below. 
8.2.1. 
Safety Population 
The safety population will include all subjects who have received the study medication. This 
population will be the primary analysis population for the study.  
8.2.2. 
Efficacy Population 
The efficacy population will include all subjects who received the study drug to treat at least one 
episode and reported a post-treatment efficacy evaluation for at least 1 time point.  
8.3. Statistical Analysis 
All study data will be summarized 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. 
8.3.1. 
Demographic and Baseline Variables 
Demographics and baseline characteristics will be summarized descriptively for the safety and 
efficacy populations. 


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8.3.2. 
Efficacy Analysis 
8.3.2.1. 
Efficacy Endpoints 
The following efficacy endpoints will be analyzed. 
1. Proportion of subjects free from headache pain (defined as moderate or severe headache 
pain becoming none on a 4-point scale) at 2, 4, 24 and 48 hours post dose 
2. Proportion of subjects free from most bothersome symptom (MBS) (defined as the MBS 
identified prior to dosing being absent) at 2, 4, 24 and 48 hours post dose 
3. Proportion of subjects with relief from headache pain at 2, 4, 24 and 48 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]) 
4. Proportion of subjects free from headache pain at 2, 4, 24 and 48 hours post dose by 
study month 
5. Proportion of subjects free from most bothersome symptom (MBS) (defined as the MBS 
identified prior to dosing being absent) at 2, 4, 24 and 48 hours post dose by study month 
6. Proportion of subjects with headache relief at 2, 4, 24 and 48 hours post dose by study month 
7. Proportion of subjects free from headache pain at 2 hours post dose and remain headache 
free at 24 and 48 hours post dose by study month 
8. Frequency of migraine headaches treated with STS101 by study month 
9. Frequency of migraine headaches by study month 
10. Proportion of subjects with headache relapse within 48 hours post dose (defined as the 
return of headache of any severity within 48 hours after administration of the investigational 
drug, when the patient was pain-free at 2 hours after investigational drug administration) 
11. Mean change in scores on Functional Impairment Scale (FIS) by study month. 
12. Mean change in scores on 24-hour Migraine Quality of Life Questionnaire by study month. 
13. Satisfaction with treatment questions 
14. Mean change from baseline in HIT-6 
8.3.2.2. 
Hypotheses Testing and Significance Level 
No formal hypotheses testing is planned for this study. When appropriate, exploratory hypotheses 
testing may be conducted at the significance level of 0.05. No adjustment for multiplicity will be 
employed. 
8.3.2.3. 
Handling of Missing Data 
For the analysis of the efficacy endpoints, data will be summarized descriptively with available 
data. Missing data will not be imputed. 
8.3.2.4. 
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. 


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8.3.2.5. 
Analysis Methods for Efficacy Endpoints 
For efficacy endpoints #1 - #10, and #13 as numbered in Section 8.3.2.1, frequencies and percentages 
of each category will be tabulated. For endpoints #1 - #7, and #10, the analysis will be a responder 
analysis with the responder defined by meeting the criteria for respective endpoints. For responder 
analysis, the proportions of responders and their 95% confidence intervals will be presented. 
For efficacy endpoints #11, #12, and #14, the change from baseline will be summarized 
descriptively. Exploratory hypothesis testing of the mean change from baseline may be 
conducted using the paired t-test. 
8.3.3. 
Safety Analysis 
Safety analyses will be conducted for the safety population. 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 the study medication will be summarized. The frequency and 
duration of exposure will also be summarized. 
8.3.3.2. 
Adverse Events 
A TEAE is defined as an AE that begins after the dosing of study drug. Adverse events reported 
after the administration of the filled training devices during Visits 1 – 4 will be summarized in 
separate tables. 
An overview of adverse events will be presented, 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. 
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: 
• 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. 


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8.3.3.3. 
Assessment of Nasal Symptoms 
The data from the Subjective and Objective Assessment of Nasal Symptoms will be summarized. 
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. Frequency counts and percentages of out-of-range alerts will be summarized over 
time. Shift-tables from baseline to each post-baseline time point will be presented. 
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. 
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 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. 
The number and percentage of subjects with other clinically significant ECG findings will also 
be summarized at each post baseline time point. 
8.3.3.7. 
Concomitant Medications 
Concomitant medication usage will be summarized. 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. 
8.3.3.8. 
Sheehan Suicidality Tracking Scale 
Reported data at each time point and the change from baseline (Visit 1) at each study visit will be 
summarized by treatment groups. 
8.3.4. 
Interim Analysis 
An interim analysis is planned for this study at the time when 150 subjects have completed 
6 months of treatment. This data is intended for the STS101 NDA submission. 


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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 approximately 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. Each participant will be given a copy of the fully executed ICF. 
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. 
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. 


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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 
Dihydergot Prescribing Information, 2011. 
Armer TA, Lynch M, Moutvic R, Singer A. Toxicological assessment of dihydroergotamine 
after chronic inhalation in dogs. Toxicol Pathol. 2011;39(3):544-52. 
doi: 10.1177/0192623311399786. 
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. Bridgewater (NJ): Valeant Pharmaceuticals; 2017 Nov. 
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. 
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. 
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. 


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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. 
Kellerman DJ, Forst A, Combs DL, Borland S, Kori S. Assessment of the consistency of 
absorption of dihydroergotamine following oral inhalation: pooled results from four clinical 
studies. J Aerosol Med Pulm Drug Deliv. 2013;26(5):297-306. doi: 10.1089/jamp.2012.0999. 
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. 
Migranal® Prescribing Information. Aliso Viejo (CA): Valeant Pharmaceuticals. 
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. 
Sheehan DV, Giddens JM, Sheehan IS. Status Update on the Sheehan-Suicidality Tracking Scale 
(S-STS) 2014. Innovations in clinical neuroscience. 2014;11(9-10):93-140. 
Shrewsbury SB, Cook RO, Taylor G, Edwards C, Ramadan NM. Safety and pharmacokinetics of 
dihydroergotamine mesylate administered via a Novel (Tempo) inhaler. Headache. 
2008;48(3):355-67. doi: 10.1111/j.1526-4610.2007.01006.x. 
Silberstein SD, McCrory DC. Ergotamine and dihydroergotamine: history, pharmacology, and 
efficacy. Headache. 2003;43(2):144-66. 
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 Evaluations 
Visit # 
1 
2 
3 
4 
5 
6  
7 
8 
9 
10 
11 
Screening Baseline 
 
 
 
 
 
 
 
 
Final 
(12-Month) / 
Early Term 
Timing of Visit 
Allowable Visit Window (±days) 
Day  
-30 to -1 
Day  
0 
Month 1 
(7 days) 
Month 2  
(7 days) 
Month 3 
(7 days) 
Month 4 
(7 days) 
Month 5 
(7 days) 
Month 6 
(7 days) 
Month 8 
(14 days) 
Month 10  
(14 days) 
Month 12 
(14 days) 
Informed Consent Form 
X 
 
 
 
 
 
 
 
 
 
 
Demographics/Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Physical examinationa 
X 
X 
Xa 
Xa 
Xa 
Xa 
Xa 
X 
Xa 
Xa 
X 
Vital signsb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology, clinical chemistry, urinalysis 
X 
X 
 
 
X 
 
 
X 
X 
X 
X 
Serum pregnancy test 
X 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
X 
12-lead ECG 
X 
X 
 
 
X 
 
 
X 
X 
X 
X 
Nasal Examination & Objective Assessment 
of Nasal Symptoms 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Subjective Assessments of Nasal Symptoms 
X 
X 
 
 
X 
 
 
X 
 
 
X 
HIT-6 Questionnaire 
 
X 
 
 
X 
 
 
X 
 
 
X 
Sheehan Suicidality Tracking Scale (S-STS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Smell Identification Test™  
 
X 
 
 
 
 
 
 
 
 
X 
Subject Impression Questions 
 
 
 
 
X 
 
 
X 
 
 
X 
Determine / review eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Health Care Resource Utilization 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
STS101 Device training/Collection 
X 
X 
X 
X 
 
 
 
 
 
 
 
Handheld Device (eDiary) 
Training/Dispensing/Review/Collection 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug supply/Drug Accountability 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a Focused neurological examination; b Height & BMI calculation only at Screening (Visit 1). Weight at all visits; c Females of childbearing potential only  


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Appendix A.  Schedule of Evaluations (continued) 
For original cohort subjects continuing for 6 months after Visit 11 
Visit # 
12 
13 
14 
 
 
Final / Early Term 
Timing of Visit 
Allowable Visit Window (±days) 
Month 14 
(14 days) 
Month 16  
(14 days) 
Month 18 
(14 days) 
Informed Consent Form 
 
 
 
Demographics/Medical history 
 
 
 
Physical examinationa 
Xa 
Xa 
X 
Vital signsb 
X 
X 
X 
Hematology, clinical chemistry, urinalysis 
X 
X 
X 
Serum pregnancy test 
Xc 
Xc 
X 
12-lead ECG 
X 
X 
X 
Nasal Examination & Objective Assessment of Nasal Symptoms 
X 
X 
X 
Subjective Assessments of Nasal Symptoms 
 
 
X 
Sheehan Suicidality Tracking Scale (S-STS) 
X 
X 
X 
Smell Identification Test™  
 
 
X 
Concomitant medications 
X 
X 
X 
Study drug supply/Drug Accountability 
X 
X 
X 
Adverse events 
X 
X 
X 
a Focused neurological examination; b Height & BMI calculation only at Screening (Visit 1). Weight at all visits; c Females of childbearing potential only  


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Appendix B. 
Subjective Assessment of Nasal Symptoms 
 
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 Symptoms 
 
 
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 
 
 
(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. 24-Hour Migraine Quality of Life Questionnaire  
 


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Reference: Hartmaier 1995 


Dihydroergotamine intranasal powder (STS101) 
Satsuma Pharmaceuticals, Inc. 
Clinical Trial Protocol: STS101-003, November 24, 2021 (Version 6) 
Page 74 of 77 
Confidential 
Appendix E. 
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 


Dihydroergotamine intranasal powder (STS101) 
Satsuma Pharmaceuticals, Inc. 
Clinical Trial Protocol: STS101-003, November 24, 2021 (Version 6) 
Page 75 of 77 
Confidential 
Appendix F. 
Sheehan Suicidality Tracking Scale (S-STS) 
 


Dihydroergotamine intranasal powder (STS101) 
Satsuma Pharmaceuticals, Inc. 
Clinical Trial Protocol: STS101-003, November 24, 2021 (Version 6) 
Page 76 of 77 
Confidential 
 


Dihydroergotamine intranasal powder (STS101) 
Satsuma Pharmaceuticals, Inc. 
Clinical Trial Protocol: STS101-003, November 24, 2021 (Version 6) 
Page 77 of 77 
Confidential 
 

SAP_001.pdf: 
ST·ATISTICAL ANALYSIS PLAN 
Satsuma Pharmaceuticals, Inc. 
400 Oyster Point Boulevard, Suite 221 
South San Francisco, CA 94080 
An Open-Label, 12-Month Study to Evaluate the Safety and 
Tolerability ofSTSl0l (Dihydroergotamine Nasal Powder) in the 
Acute Treatment of Migraine 
Clinical Study Protocol No. STSl0l-003 
Final v4 September 19, 2022 
Prepared by 
Shelia Ligozio 
Instat Clinical Research 
This document contains confidential information of Satsuma Pharmaceuticals, Inc. Any viewing 
or disclosure of such information that is not authorized in writing by Satsuma Pharmaceuticals, 
Inc., is strictly prohibited. Such information may be used solely for the purpose of reviewing or 
performing this study. 


STATISTICAL ANALYSIS PLAN 
SIGNATURE PAGE 
Satsuma Pharmaceuticals, Inc. 
400 Oyster Point Boulevard, Suite 221 
South San Francisco, CA 94080 
An Open-Label, 12-Month Study to Evaluate the Safety and 
Tolerability ofSTSl0l (Dihydroergotamine Nasal Powder) in the 
Acute Treatment of Migraine 
Clinical Study Protocol No. STSl0l-003 
~ 
Michelle Secic (Sep 23, 202214:48 EDT) 
Michelle Secic 
Secic Statistical Consulting 
Detlef Albrecht (Sep 20, 2022 09:37 EDT) 
Detlef Albrecht, MD 
Satsuma Pharmaceuticals 
Shelia Ligozio 
Instat Clinical Research 
CONFIDENTIAL 
Sep 23, 2022 
Approval Date 
Sep 20, 2022 
Approval Date 
Sep 20, 2022 
Approval Date 
Final v4: September 19, 2022 


Satsuma Pharmaceuticals, Inc. - STSl0l-003 
Statistical Analysis Plan 
TABLE OF CONTENTS 
Page 1 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .................................................................... 2 
1. 
INTRODUCTION ............................................................................................................................. 3 
1.1. 
Study Objectives .......................................................................................................................... 3 
1.2. 
Study Design ................................................................................................................................ 3 
1.3. 
Study Visits and Procedures ......................................................................................................... 4 
2. 
STUDYPOPULATIONS .................................................................................................................. 5 
3. 
DEFINITIONS AND DERIVED VARIABLES ............................................................................... 7 
4. 
SAFETYPARAMETERS ................................................................................................................. 9 
5. 
EFFICACYPARAMETERS ........................................................................................................... 10 
6. 
STATISTICAL METHODOLOGY ................................................................................................ 11 
6.1. 
Statistical and Analytical Issues ................................................................................................. 11 
6.1.1. 
Statistical Methods ......................................................................................................... 11 
6.1.2. 
Handling of Dropouts and Missing Data ........................................................................ 11 
6.1.3. 
Pooling of Investigator Sites .......................................................................................... 12 
6.1 .4. 
Determination of Sample Size ........................................................................................ 12 
6.2. 
Subject Characteristics ............................................................................................................... 12 
6.2.1. 
Subject Disposition ........................................................................................................ 12 
6.2.2. 
Protocol Deviations ........................................................................................................ 12 
6.2.3. 
Background and Demographic Characteristics .............................................................. 12 
6.2.4. 
Medical History .............................................................................................................. 13 
6.2.5. 
Migraine History ............................................................................................................ 13 
6.2.6. 
Baseline Attack Symptoms ............................................................................................ 13 
6.3. 
Safety Analysis ........................................................................................................................... 13 
6.3.1. 
Treatment Exposure ....................................................................................................... 13 
6.3.2. 
Adverse Events ............................................................................................................... 15 
6.3.3. 
Assessment ofNasal Symptoms .................................................................................... 16 
6.3.4. 
Physical Examination ..................................................................................................... 16 
6.3.5. 
Vital Signs ...................................................................................................................... 16 
6.3.6. 
Electrocardiogram .......................................................................................................... 17 
6.3.7. 
Laboratory Parameters ................................................................................................... 17 
6.3.8. 
Smell Identification Test ................................................................................................ 17 
6.3 .9. 
Sheehan Suicidality Tracking Scale ............................................................................... 17 
6.3.10. 
Prior and Concomitant Medications and Therapies ....................................................... 18 
6.4. 
Efficacy Analysis ....................................................................................................................... 18 
6.4.1. 
Freedom from Headache Pain ........................................................................................ 18 
6.4.2. 
Freedom from MBS ....................................................................................................... 20 
6.4.3. 
Relief from Headache Pain ............................................................................................ 20 
6.4.4. 
Freedom from Photophobia, Phonophobia, and Nausea ................................................ 21 
6.4.5. 
Sustained Freedom from Headache Pain and MBS ....................................................... 21 
6.4.6. 
Rescue Medications ........................................................................................................ 22 
6.4.7. 
Frequency of Migraine Attacks ...................................................................................... 22 
6.4.8. 
Relapse in Headache Pain .............................................................................................. 22 
6.4.9. 
Functional Impairment Scale ......................................................................................... 22 
6.4.10. 
24-hour Migraine Quality of Life Questionnaire ........................................................... 22 
6.4.11. 
Subject Impression Questions ........................................................................................ 23 
6.4.12. 
Headache Impact Test .................................................................................................... 23 
6.4.13. 
Healthcare Resource Utilization ..................................................................................... 23 
6.4.14. 
Subgroup Analyses ......................................................................................................... 24 
6.5. 
Interim Analysis ......................................................................................................................... 24 
7. 
TABLES, LISTINGS, AND FIGURES .......................................................................................... 24 
CONFIDENTIAL 
Final v4: September 19, 2022 


Satsuma Pharmaceuticals, Inc. - STSl0l-003 
Statistical Analysis Plan 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Explanation 
AE 
adverse event 
ATC 
Anatomical Therapeutic Chemical 
BMI 
body mass index 
CRF 
case report form 
CSR 
clinical study report 
DHE 
dihydroergotamine 
ECG 
electrocardiogram 
e-Diarv 
electronic diary 
FIS 
Functional Impairment Scale 
HIT-6 
Headache Impact Test 
HR 
heart rate 
max 
maximum 
MBS 
most bothersome symptom 
MedDRA 
Medical Dictionarv for Regulatory Activities 
.. 
mm 
mlillmum 
mITT 
Intent-to-Treat 
n 
number of subjects 
PGI 
Patient Global Impression 
PRN 
pro re nata 
PT 
preferred term 
QTcF 
QT corrected with the Fridericia's formula 
TEAE 
treatment emergent adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SIT 
Smell Identification Test 
soc 
system organ class 
WHO Drug 
World Health Organization Drug Dictionary 
24-MQoL 
24-hour Migraine Quality of Life Questionnaire 
Page2 
CONFIDENTIAL 
Final v4: September 19, 2022 


Satsuma Pharmaceuticals, Inc. - STSl0l-003 
Statistical Analysis Plan 
1. 
INTRODUCTION 
Page 3 
The purpose of this statistical analysis plan (SAP) is to ensure the statistical methodologies that 
will be used are complete and appropriate to allow valid conclusions regarding the study 
objectives. Results obtained from the analyses outlined in this document will be the basis of the 
final clinical study report (CSR) for this protocol. 
1.1. 
Study Objectives 
The primary objective of the study is to assess the safety and tolerability of STSlOl in the acute 
treatment of migraine attacks over 12 months. 
The secondary objective of this study is to describe the efficacy of STSlOl in the acute treatment 
of migraine attacks over 12 months. 
1.2. 
Study Design 
This study will be a multi-center, multiple dose (PRN), open-label, 12-month study in 
approximately 480 subjects with migraine (ages 18 to 65 years). An amendment to the protocol 
allowed for subjects of the original cohort (enrolled before June 30, 2021) to continue use of 
study medication for an additional 6 months after completion of the original 12-month period. 
Only safety data will be collected during this period. 
After establishing eligibility, the study participants will use STSlOl (DHE nasal powder) on a 
PRN basis to treat migraine attacks for 12 months. Study participants will be able to use up to 2 
doses of STS 101 to treat a single migraine attack within 24 hours and can use up to 12 doses of 
STSlOl per month for 12 months. 
The study participants will document the pain severity of their migraine attacks, presence and 
severity of symptoms (photophobia, phonophobia, nausea) and functionality status over the 48-
hour period after study drug administration. Specifically, headache pain severity data and 
symptom presence will be collected at the onset of the migraine attack, immediately before drug 
administration (time 0), 30 and 60 minutes, 2, 4, 24, and 48 hours after study drug 
administration. 
Migraine attacks not treated with study medication will also be documented. Use of rescue 
medication is allowed, but triptans or other DHE products as rescue medications should be 
avoided for 24 hours after study drug administration (24 hours after the second dose if a repeat 
dose of STS101 is administered). 
Adverse events, nasal and physical examination data, safety laboratory data, vital sign data and 
electrocardiogram (ECG) will be recorded to describe the tolerability and safety of STS101. 
Additionally, subjective and objective nasal symptom assessments and the Smell Identification 
Test (SIT) will be documented during the treatment period. 
CONFIDENTIAL 
Final v4: September 19, 2022 


Satsuma Pharmaceuticals, Inc. - STSl0l-003 
Statistical Analysis Plan 
1.3. 
Study Visits and Procedures 
Page4 
A complete description of procedures at each visit can be found in the protocol. The Schedule of 
Events is presented in Table 1 below. 
Table 1: Schedule of Evaluations 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Screening 
Baseline 
Timing of Visit/ 
Day-30 
Day0 
Month 1 
Month2 
Month 3 
Month4 
Month 5 
Month6 
Month 8 
Month 
Allowable Visit 
to -1 
(7 days) 
(7 days) 
(7 days) 
(7 days) 
(7 days) 
(7 days) 
(14 
10 (14 
Window (:I- davs) 
days) 
days) 
Informed Consent 
X 
Form 
Demographics/ 
X 
Medical history 
Phvsical examination• 
X 
X 
X" 
X" 
X" 
X" 
X" 
X 
X" 
X" 
Vital sifmsb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology, clinical 
X 
X 
X 
X 
chemistry, urinalysis 
Serwn prel/;llancv test 
X 
X" 
X" 
X" 
X" 
X" 
X" 
X" 
X" 
X" 
12-leadECG 
X 
X 
X 
X 
Nasal Examination & 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Objective Assessment 
ofNasal Svmntoms 
Subjective 
X 
X 
X 
X 
Assessments ofNasal 
Svmotoms 
HIT-6 Onestionnaire 
X 
X 
X 
Sheehan Suicidality 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tracking Scale 
Smell Identification 
X 
Test™ 
Subject Impression 
X 
X 
Ouestions 
Determine / review 
X 
X 
elie;ibilitv 
Concomitant 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
medications 
Health Care Resource 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Utilization 
STSlOl Device 
X 
X 
X 
X 
X 
X 
X 
X 
training/Collection 
Handheld Device 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(eDiary) Training/ 
Dispensing/Review/ 
Collection 
Study drug 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
supply/Drug 
Accountability 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a. 
Focused neurological examination 
b. 
Height and BMI calculation only at Screening (Visit 1) 
c. 
Females of childbearing potential only 
CONFIDENTIAL 
Final v4: September 19, 2022 
11 
Final/ 
Early 
Term 
Visit 
Month 
12 (14 
days) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Satsuma Pharmaceuticals, Inc. - STSl0l-003 
Statistical Analysis Plan 
Page 5 
Table 1 (cont'd): Schedule of Evaluations for Subjects continuing for 6 months after Visit 11 
Visit 
12 
13 
14 
Final/Early Term Visit 
Timing of Visit/ 
Month 14 (14 days) 
Month 16 (14 days) 
Month 18 (14 days) 
Allowable Visit Window(± days) 
Physical examination• 
X" 
X" 
X 
Vital siimsb 
X 
X 
X 
Hematology, clinical chemistrv, urinalvsis 
X 
X 
X 
Serwn nremancv test 
X" 
X" 
X 
12-leadECG 
X 
X 
X 
Nasal Examination & Objective Assessment of Nasal 
X 
X 
X 
Svmntoms 
Subiective Assessments of Nasal Svmntoms 
X 
Sheehan Suicidalitv Trackinf! Scale 
X 
X 
X 
Smell Identification Test™ 
X 
Concomitant medications 
X 
X 
X 
Study dru11; supply/Dru11; Accountability 
X 
X 
X 
Paper Diarv Traininf!!Dispensin!!/Review/Collection 
X 
X 
X 
Adverse events 
X 
X 
X 
2. 
STUDY POPULATIONS 
The analysis populations to be used in the study are defined below. The safety data will be 
analyzed using six different populations: 6-Month Completers Mk2 (Cohort 1), 12-Month 
Completers Mk2 (Cohort 2), All Subjects Mk2 (Cohort 3), 6-Month Completers Mkl/Mk2 
(Cohort 4), 12-Month Completers Mkl/Mk2 (Cohort 5), and All Subjects Mkl/Mk2 (Cohort 6). 
The efficacy data will be analyzed using the Modified Intent-to-Treat (mITT) population. Some 
efficacy endpoints may be analyzed on the 6-Month Completers Mk2 and 12-Month Completers 
Mk2 populations. An additional analysis population, Cohort 7, will also be used to summarize 
select efficacy and safety endpoints. These will be specified in the appropriate sections of the 
document. The table below gives a summary of the safety populations. 
Table 2: Safety Populations Summary 
Study Cohort Population 
Definition 
1 
6-Month Completers 
Treated at least 12 migraines with study medication 
Mk2 
from the Mk2 device over a 6-month continuous 
period 
2 
12-Month Completers 
Treated at least 24 migraines with study medication 
Mk2 
from the Mk2 device, completed the study, and did 
not enter extension or entered extension and treated 
at least 24 migraines with study medication from the 
Mk2 device over a 12-month continuous period 
3 
All Subjects Mk2 
Treated at least one migraine with study medication 
from the Mk2 device 
4 
6-Month Completers 
Treated at least 12 migraines with either study 
Mkl/Mk2 
medication device over a 6-month continuous period 
5 
12-Month Completers 
Treated at least 24 migraines with either study 
Mkl/Mk2 
medication device, completed the study, and did not 
CONFIDENTIAL 
Final v4: September 19, 2022 


Satsuma Pharmaceuticals, Inc. - STSl0l-003 
Statistical Analysis Plan 
Page 6 
Study Cohort Population 
Definition 
enter extension or entered extension and treated at 
least 24 migraines with either study medication 
device over a 12-month continuous period 
6 
All Subjects Mkl/Mk2 Treated at least one migraine with either study 
medication device 
7 
All Expansion 
All subjects who emolled in the expansion phase of 
Subjects 
the study (Mk:2 device was the only study medication 
device dispensed) 
The primary analysis will be conducted on the 6-Month Completers Mk2 safety population 
(Cohort 1). It is defined as all subjects who used study medication from the Mk2 device on 
average~ 2 times per month (minimum of 12 treated migraine attacks) over a 6-month 
continuous period. The 6-Month Completers Mkl/Mk2 safety population (Cohort 4) is defined 
as all subjects who used study medication from either the Mkl or Mk2 device on average~ 2 
times per month over a 6-month continuous period. 
Six months of exposure will be defined as: last kit return date - day 0 visit date+ 1 ~ 173. 
Subjects who meet these criteria will be considered for population inclusion. Study medication 
uses will be summed over a 187-day period starting at day 1 and increasing in increments of 1 
day until day 187. The first 6-month period checked will be days 1 to 187. If a subject has 12 
treated migraine attacks, the subject is included in the population. For subjects who do not have 
12 treated migraine attacks, the next 6-month period, days 2 to 188, will be checked. This will 
continue until the last interval, days 366 to 552 (545+7 days), has been checked. The last day 
interval may be increased if subjects have data greater than day 552 and there are still subjects 
who could potentially be included in the population. 
The 12-Month Completers Mk2 safety population (Cohort 2) is defined as all subjects who 
completed 12 months of study participation and used study medication from the Mk2 device on 
average~ 2 times per month (minimum of24 treated migraine attacks in the 12-month duration). 
The 12-Month Completers Mkl/Mk2 safety population (Cohort 5) is defined as all subjects who 
completed 12 months of study participation and used study medication from either the Mkl or 
Mk2 device on average~ 2 times per month. 12-Month study participation will be defined 
completing the Month 12 (Visit 11) visit as reported in the database for subjects who did not 
participate in the extension. Since the extension was added while the study was ongoing, subjects 
who continued into the extension, will be have a 12 month exposure defined and the number of 
treated attacks checked for each similar to the method described above for the 6 month exposure. 
Twelve months of exposure will be defined as: last kit return date-day 0 visit date= 1 ~ 358 
days. Study medication uses will be summed over a 3 72-day period starting at day 1. The final 
interval will be 180 to 552 days. The final interval may increase depending on available data. 
The All Subjects Mk2 safety population (Cohort 3) is defined as all subjects who treat at least 
one migraine attack with study medication from the Mk2 device. The All Subjects Mkl/Mk2 
safety population (Cohort 6) is defined as all subjects who treat at least one migraine attack with 
either the Mkl or Mk2 device. 
CONFIDENTIAL 
Final v4: September 19, 2022 


Satsuma Pharmaceuticals, Inc. - STSl0l-003 
Statistical Analysis Plan 
Page 7 
All available study medication information (from drug accountability and e-diary data) will be 
used to determine the number of doses taken. 
The exposure and adverse event summaries for Cohorts 1-3 will only include the data on the 
Mk2 device. 
The Modified Intent-to-Treat population is defined as all subjects who treated at least one 
migraine attack and who reported at least one post-treatment efficacy data in the After Treatment 
Diaries at any time point. 
The All Expansion Subjects population is defined as all subjects who enrolled in the expansion 
phase of the study. These subjects are denoted in the database with a subject number starting 
with the digit 3 after the site number (i.e., 001-301). 
3. 
DEFINITIONS AND DERIVED VARIABLES 
• 
The reference start date will be derived using the maximum of the first dose date 
recorded by the subject in the eDiary or the first kit dispense date where drug was used 
according to drug accountability. 
• 
The reference end date will be derived using the maximum of the last dose date recorded 
by the subject in the eDiary or the last kit dispense date where drug was used according 
to drug accountability. 
• 
The baseline measurement for a variable is defined as the last non-missing value from the 
baseline visit measured prior to the first dose of the study drug. If a subject has repeated 
measurements from the baseline visit, then the last repeated non-missing value will be 
used. 
• 
Body mass index (BMI) will be derived from the recorded height at screening and weight 
at screening/baseline (last non-missing measurement). It is calculated as weight in 
kilograms divided by height in meters squared. 
• 
Age will be derived as the integer value of informed consent date minus birth date plus 
one, then divided by 365.25. 
• 
Free from headache pain (0=None, l=Mild, 2=Moderate, 3=Severe) is defined as mild 
(1), moderate (2) or severe (3) headache pain at time 0 becoming none (0). 
• 
Relief from headache pain is defined as a reduction in headache pain from moderate (2) 
or severe (3) pain at time Oto mild (1) or none (0) or from mild (1)] at time Oto none (0). 
• 
Sustained Freedom from Headache Pain up to a time point (e.g., 24, or 48 hours) is 
defined as a headache pain score of 0 from the 2 hours post dose time point to the time 
point of interest, e.g., 24 hours, with no use of rescue medication or a second dose of 
CONFIDENTIAL 
Final v4: September 19, 2022 


Satsuma Pharmaceuticals, Inc. - STSl0l-003 
Statistical Analysis Plan 
Page 8 
study medication. All non-missing scores at the time points between the 2 and 24 or 48 
hours post dose must be 0. 
• 
Headache relapse is defined as the return of headache of any severity within the specified 
hours of the endpoint (e.g., 48 hours), when the patient was pain-free at 2 hours after 
investigational drug administration. The endpoint of interest, e.g., 48 hours must be non-
m1ssmg. 
• 
Most Bothersome Symptom (MBS) is defined as the most bothersome symptom 
(photophobia, phonophobia, or nausea) as reported prior to dosing. If only one symptom 
is present, then that symptom will be considered the MBS. 
• 
Sustained Freedom from MBS up to a time point (24 or 48 hours) is defined as freedom 
from MBS at 2 hours post dose time point to the time point of interest, e.g., 24 hours, 
with no use of rescue medication or a second dose of study medication. All non-missing 
scores at the time points between the 2 and 24 or 48 hours post dose must be 0. 
• 
Rescue medication is defined as any medication taken to treat migraine headaches after 
dosing with study medication. This will be derived from the headache medication diary. 
• 
24-hour Migraine Quality of Life Questionnaire domains are defined as: Work 
Functioning (questions 7, 8, 9), Social Functioning (questions 10, 11, 12), 
EnergyNitality (questions 13, 14, 15), Migraine Symptoms (questions 1, 2, 3), and 
Feelings/Concerns (questions 4, 5, 6). The domain scores are derived by summing the 
values of the responses to the specified questions. The total score will be the sum of all 
domains. The values of the responses are the recorded numeric values in the electronic 
handheld device (e-Diary). 
• 
Headache Impact Test (HIT-6) total score is calculated as the sum of the points for each 
response given by a subject. Points for each response are as follows: Never=6, Rarely=8, 
Sometimes=lO, Very Often=l 1, and Always=13. 
• 
The HIT-6 overall score will be categorized into the following categories: Severe Impact, 
defmed as a total score >=60, Substantial Impact, defined as a total score >=56 to <60, 
Some Impact, defined as a total score >=50 to <56, and Little or No Impact, defined as a 
total score <50. 
• 
Number of years experiencing a migraine will be defined as the date of informed consent 
minus the date of migraine onset plus 1. 
• 
Duration of exposure is defined as last study medication dose date minus first study 
medication dose date plus one. 
CONFIDENTIAL 
Final v4: September 19, 2022 


Satsuma Pharmaceuticals, Inc. - STSl0l-003 
Statistical Analysis Plan 
Page 9 
• 
Study duration is defined as the date of completion/discontinuation as recorded on the 
End of Study case report form (CRF) minus the informed consent date plus one. If the 
completion/discontinuation date is unknown or missing, the last available date the subject 
reported data will be used. 
4. 
SAFETY PARAMETERS 
• 
Mean drug exposure duration ( overall and by device) 
• 
Frequency and percentage of subjects taking one and two doses ( overall and by device) 
• 
Number of attacks treated with study medication ( overall and by device) 
• 
Number of attacks treated with second dose of study medication ( overall and by device) 
• 
Frequency and percentages in Treatment Emergent Adverse Events (TEAEs) based on 
subjects (overall and by device) 
• 
Frequency and percentages in Treatment Emergent Adverse Events (TEAEs) based on 
attacks ( overall and by device) 
• 
Frequency and percentages in TEAE with a second dose within 2 hours of first dose based on 
subjects (overall and by device) 
• 
Frequency and percentages in Cardiovascular TEAE based on subjects ( overall and by 
device) 
• 
Frequency and percentages in Treatment Emergent Adverse Events (TEAEs) based on 
attacks ( overall and by device) by study month (3 month intervals) 
• 
Frequency and percentages in Cardiovascular TEAE based on subjects ( overall and by 
device) by study month (3 month intervals) 
• 
Frequency and percentages in Cardiovascular TEAE based on attacks ( overall and by device) 
• 
Frequency and percentages in Local TEAE based on subjects (overall and by device) 
• 
Frequency and percentages in Local TEAE based on attacks ( overall and by device) 
• 
Frequency and percentages in Local TEAE based on subjects with history of allergic rhinitis 
( overall and by device) 
• 
Frequency and percentages in Local TEAE by timing of second dose based on subjects (Mk2 
device only) 
• 
Frequency and percentages in Local TEAE by timing of second dose based on attacks (Mk2 
device only) 
• 
Mean Change in Subjective nasal symptom assessment by study visit 
• 
Shifts in Objective nasal symptom evaluation by study visit 
• 
Mean Change in Smell Identification Test (SIT) 
CONFIDENTIAL 
Final v4: September 19, 2022 


Satsuma Pharmaceuticals, Inc. - STSl0l-003 
Statistical Analysis Plan 
• 
Observed Mean in Sheehan Suicidality Tracking Scale by study visit 
Page 10 
• 
Mean Change in blood tests for hematology, serum chemistry, and quantitative urinalysis by 
study visit 
• 
Mean Change in Vital signs, including weight by study visit 
• 
Mean Change in 12-lead ECG by study visit 
• 
Frequency and percentages in Concomitant Medications taken 
5. 
EFFICACY PARAMETERS 
• 
Proportion of attacks with freedom from headache pain at 30 minute, 1, 2, 4, 24, and 48 
hours post dose 
• 
Proportion of attacks with freedom from most bothersome symptom at 30 minute, 1, 2, 4, 24, 
and 48 hours post dose 
• 
Proportion of attacks with relief from headache pain at 30 minute, 1, 2, 4, 24, and 48 hours 
post dose 
• 
Proportion of attacks with freedom from photophobia at 30 minute, 1, 2, 4, 24, and 48 hours 
post dose 
• 
Proportion of attacks with freedom from phonophobia at 30 minute, 1, 2, 4, 24, and 48 hours 
post dose 
• 
Proportion of attacks with freedom from nausea at 30 minute, 1, 2, 4, 24, and 48 hours post 
dose 
• 
Proportion of attacks with sustained freedom from headache pain 2- 24 and 2-48 hours post 
dose 
• 
Proportion of attacks with sustained freedom from most bothersome symptom 2- 24 and 2-48 
hours post dose 
• 
Proportion of attacks with freedom from headache pain at 30 minutes and 1, 2, 4, 24, and 48 
hours post dose by study month 
• 
Proportion of attacks with freedom from most bothersome symptom at 30 minutes, 1, 2, 4, 
24, and 48 hours post dose by study month 
• 
Proportion of attacks with relief from headache pain at 30 minutes 1, 2, 4, 24, and 48 hours 
post dose by study month 
• 
Proportion of attacks with sustained freedom from headache pain at 2-24 and 2-48 hours post 
dose by study month 
• 
Proportion of attacks with sustained freedom from most bothersome symptom at 2-24 and 2-
48 hours post dose by study month 
• 
Proportion of attacks with use of rescue medication within 24 and 48 hours post dose 
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• 
Proportion of attacks with use of second dose of study medication within 24 and 48 hours 
post dose 
• 
Frequency of migraine attacks treated with STS101 by study month 
• 
Frequency of migraine attacks by study month 
• 
Proportion of attacks with headache relapse within 24 and 48 hours post dose 
• 
FIS distribution for attacks at 30 minutes, 1, 2, 4, 24, and 48 hours post dose 
• 
Mean total score on 24-hour Migraine Quality of Life Questionnaire (24-MQoL) at 24 hours 
post dose by study month 
• 
Frequency and percentages of responses to satisfaction with treatment questions 
• 
Mean change from baseline in HIT-6 
• 
Mean change from baseline in Healthcare Resource Utilization 
6. 
STATISTICAL METHODOLOGY 
6.1. 
Statistical and Analytical Issues 
6.1.1. Statistical Methods 
All study data will be summarized 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 
frequency counts and percentages. Missing values will not be considered in percentages unless 
otherwise noted in a footnote. 
All summaries, statistical analyses, and individual subject data listings described below will be 
completed using Version 9 .3 or later of the SAS Statistical Analysis System (SAS Institute, Inc. 
Cary, NC). 
No formal hypothesis testing will be performed, and as such, there will be no adjustments for 
multiplicity. Any statistical analyses performed will be exploratory, conducted at a significance 
level of 0.05, and described fully within that section. 
6.1.2. Handling of Dropouts and Missing Data 
Missing data will not be imputed. Summaries will be based on the available data only. 
For incomplete dates needed in derivations (i.e., related to adverse events, concomitant 
medications, or onset date of migraine in migraine history), the dates will be imputed as follows: 
If the incomplete date is a start/onset date: 
(1) if the month and year are present, then the first day of the month will be used for day. 
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(2) if only the year is present, then the first day of January will be used for month and day. 
If the incomplete date is an end date: 
(1) if the month and year are present, then the last day of the month will be used for day. 
(2) if only the year is present, then the last day of December will be used for month and day. If 
the reported year is the same as the informed consent year, then the informed consent date will 
be used. 
Missing dates will not be imputed. 
6.1.3. Pooling of Investigator Sites 
Data for all sites will be pooled for analysis. Analyses will not be performed by sites and will not 
include adjustment for sites. 
6.1.4. Determination of Sample Size 
A total of approximately 480 adult male and female subjects (18 to 65 years of age) with 
migraine will be enrolled. At least 150 and 50 subjects are anticipated to complete at least 6 and 
12 months, respectively. This sample size is expected to adequately characterize the safety and 
tolerability of STSlOl in the acute treatment of migraine. A formal sample size calculation was 
not performed. However, it is assumed that a sample size of 480 subjects is sufficient to detect 
clinically important adverse events with an event rate of 1 % or higher. 
6.2. 
Subject Characteristics 
6.2.1. Subject Disposition 
The number of all enrolled subjects, number and percentage of subjects in each analysis 
population along with reasons for population exclusion, and number of subjects previously 
enrolled in STSlOl-002/STSlOl-007 study will be presented. In addition, number of subjects 
who completed/prematurely discontinued and reason for discontinuation will also be presented 
for each analysis population. 
6.2.2. Protocol Deviations 
Protocol deviations will be collected, including the deviation category, classification, and the 
start date. The deviations will be presented in a data listing for all subjects. 
6.2.3. Background and Demographic Characteristics 
Demographics and baseline characteristics ( age, sex, race, ethnicity, height, weight, BMI) will be 
summarized descriptively for the seven safety population cohorts. The childbearing potential, 
smoking classification, alcohol use, and caffeine use will also be included in the summary. 
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6.2.4. Medical History 
Page 13 
Medical history will be coded using Med.DRA version 23.1 and listed by System Organ Class 
(SOC), Preferred Term (PT), and verbatim term. Medical history will be summarized using 
frequencies and percentages according to the SOC and PT on all safety population cohorts. 
6.2.5. Migraine History 
Migraine history, including the number of years experiencing migraine, less than 15 headache 
days per month in the 3 months prior to screening, migraine history of 4-12 attacks per month in 
the 3 months prior to screening, presence of associated symptoms in migraines during screening 
(aura, nausea, photophobia, phonophobia, allodynia), triptan use, and pain relief with triptan use, 
will be summarized. For the subjects of the expansion cohort, migraine history will include the 
mean number of migraine attacks and headache days in the three months prior to screening. The 
number of migraine attacks and headache days prior to screening are reported on the CRF. 
Migraine history will be summarized for all safety population cohorts. 
6.2.6. Baseline Attack Symptoms 
The baseline (time 0) responses to pain severity, photophobia, phonophobia, and nausea for all 
treated attacks will be summarized by treatment for the mITT and Cohort 7 population. 
6.3. 
Safety Analysis 
The primary safety population will be the 6-Month Completers Mk2 safety population (Cohort 
1 ). Safety analyses will be conducted on all six safety population cohorts as defined in Section 2. 
All available data for subjects will be summarized for each population, i.e., if a subject is 
included in the 6-Month Completers Mk2 safety population but has data through Month 8 of the 
study, all of the data will be summarized for that subject. Selected clinical safety and tolerability 
data will be reported by treated migraine attacks. Selected clinical safety and tolerability data 
will be reported by use of STSlOl Mkl and Mk2 device. 
No inferential statistics will be performed; only summary statistics will be provided unless 
otherwise noted. All safety data reported/captured at a clinic visit will use the visit assigned in 
the database. No windows around the month will be applied. However, if the data is captured in 
the diary, then the study month windows will be used. 
All clinical safety and tolerability data will be listed by subject. 
6.3.1. Treatment Exposure 
Subjects may use up to 2 doses to treat a single migraine attack within 24 hours and can use up to 
12 doses per month. There were also 2 study drug devices (Mkl and Mk2) used during this 
study. All exposure summaries will be summarized by device and overall. 
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Treatment exposure will be summarized as follows: 
Page 14 
• 
Duration of exposure to treatment as defined in Section 3 using descriptive statistics 
• 
Study duration as defined in Section 3 using descriptive statistics 
• 
Frequency and percentage of subjects by treatment duration by month according to Table 
2 of Section 6.4.1. 
The number of doses taken will be summarized as follows: 
• 
The total number of doses of study medication from the Drug Accountability CRF 
• 
The total number of doses of study medication from the Drug Accountability CRF by 
visit month 
• 
The total number of doses of study medication from the eDiary 
• 
The total number of doses of study medication from the eDiary by study month 
The number of migraine attacks will be summarized as follows: 
• The total number of migraine attacks treated with study medication ( either 1 or 2 doses) 
during the study 
• The number of treated migraine attacks ( either 1 or 2 doses) by study month 
• The number of migraine attacks treated with one dose during the study 
• The number of migraine attacks treated with one dose by study month 
• The number of migraine attacks treated with a second dose during the study 
• The number of migraine attacks treated with a second dose by study month 
Subjects with a second dose within 2 hours of the first dose will be summarized for each cohort 
and broken out into occurring either in the first hour(:::;; 1 hour) or 1 -2 hours. 
The average number of treated migraine attacks per month will be derived for each subject based 
on their population inclusion. Therefore, the denominator for the 6-Month Completers safety 
populations will be 6 months, and the denominator for the 12-Month Completers safety 
populations will be 12 months. For the All Subjects safety populations, the denominator will be 
the difference in days between the reference end date and reference start date plus one and 
converted to months using 30.4375 (365.25/12). The subjects' average number of treated 
migraine attacks per month will be summarized using frequencies and percentages. 
Also summarized will be the distribution of subjects by maximum number of treated attacks in 
one month. 
A listing of the number of treated attacks per month by subject will also be provided along with a 
table summarizing the average number of treated attacks by month. 
Study month definitions will be based on the windowing found in Table 3 of Section 6.4.1. 
Study drug administration and drug accountability will be listed by subject. 
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6.3.2. Adverse Events 
Reported adverse events will be coded using MedDRA version 23.1. 
Page 15 
A treatment emergent adverse event is defined as an AE that begins after the dosing of study 
drug. When determining treatment emergent adverse events, if the start date is missing and the 
event is ongoing at the time of dosing, then the event will be considered treatment emergent. 
Treatment emergent adverse events will be summarized based on the number of subjects in each 
population. Multiple occurrences of an AE are counted only once per subject per system organ 
class and preferred term for summary tables. Treatment emergent AEs will also be summarized 
based on the number of treated migraine attacks for the subjects in each population. This 
summary will include the total number of events by SOC and PT. Therefore, all occurrences of 
an AE are counted per system organ class and preferred term. 
An overview of adverse events will be presented, which will include the number and percent of 
subjects who had at least one AE, TEAE, Serious TEAE, TEAE related to study drug, and 
maximum severity of TEAE. The same summary will be done for the number of events. 
The following TEAEs will be summarized by SOC, PT, and use ofMkl and Mk2 device: 
• 
Incidence of all TEAEs 
• 
Local TEAEs ( derived from a searchable list of preferred terms) 
• 
Cardiovascular TEAEs ( derived from a searchable list of preferred terms) 
• 
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 from study 
• 
Incidence of TEAEs leading to drug interruption 
For the 6-Month Completers (Mkl/Mk2) safety population (Cohort 4), subjects with a TEAE 
who used both Mkl and Mk2 devices will be summarized using frequencies and percentages. 
The proportions of subjects with a TEAE on Mkl and Mk2 will be analyzed using McNemar's 
test. 
Treatment emergent adverse events and local TEAEs will also be summarized over the time in 
study by months. The start date of the event will be used to determine when the event occurred 
within the study using Table 3 in Section 6.4.1. The summary will be displayed using the 
following intervals: 0 - < 3 months, 3 - < 6 months, 6 - < 9 months, and 9 - < 12 months, and 
12+ months. This summary will be performed for all six cohort safety populations. 
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Local TEAEs in subjects with a history of allergic rhinitis will be presented for all cohort safety 
populations also. History of allergic rhinitis is defined as subjects with any of the following 
medical history terms that are ongoing at the time of baseline: 
• 
Rhinitis 
• 
Rhinitis Allergic 
• 
Rhinitis Chronic 
A subset of treatment emergent adverse events in subjects who dosed twice within 2 hours will 
also be tabulated. Local treatment emergent adverse events will also be summarized by the 
number of doses taken and the timing of the second dose for Cohorts 1-3 only. 
The following AE tables will be summarized on Cohort 7: 
• 
Overview of AEs 
• 
TEAEs by SOC/PT 
• 
Related TEAEs. 
All data collected in the AE CRF will be included in data listings by subject. 
6.3.3. Assessment of Nasal Symptoms 
Observed and change from baseline values of Subjective Assessment of Nasal Symptoms will be 
summarized by visit (Month 3, 6, 12) using descriptive statistics. Shifts in Objective Assessment 
ofNasal Symptoms will be summarized at each visit (Months 1-6, 8, 10, 12) as compared to 
baseline. 
6.3.4. Physical Examination 
Physical examination findings will be presented in data listings by subject. 
6.3.5. Vital Signs 
Observed data at each visit and the change from baseline at the post baseline visit (Months 1-6, 
8, 10, 12) for vital signs will be summarized. 
Normal ranges for each vital sign parameter will be used to categorize the results as low 
(below the lower limit), normal (within the normal range), or high (above the upper limit). 
Frequency counts and percentages will be presented for these categorical data. 
The following normal ranges will be used in the summary of vital signs. 
• 
Systolic blood pressure: 90-160 mmHg (inclusive) 
• 
Diastolic blood pressure: 50-90 mmHg (inclusive) 
• 
Pulse: 50-100 beats/min.(inclusive) 
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• 
Temperature: 97.7-99.5 degrees F (36.5-37.5 degrees C) (inclusive) 
6.3.6. Electrocardiogram 
Page 17 
Electrocardiogram data is recorded in triplicate at each visit and will be averaged for summary 
purposes. Observed data at each visit and the change from baseline at the post baseline at Months 
3, 6, 8, 10, and 12 in ECG parameters, heart rate (HR), RR, PR, QRS, and QT corrected with the 
Fridericia's formula (QTcF), will be summarized. 
The ECG findings, as reported on the CRF, is also recorded in triplicate at each time point. For 
summary purposes, the worst finding will be selected. The number and percentage of subjects 
with clinically significant ECG findings as previously described will also be summarized at each 
post baseline visit in a shift table. 
6.3.7. Laboratory Parameters 
The observed data and change from baseline at the post baseline visits (Months 3, 6, 8, 10, and 
12) in hematology, serum chemistry and quantitative urinalysis test results will be summarized. 
For hematology and serum chemistry including calculated creatinine clearance, normal ranges 
for each parameter will be used to categorize the test results as low (value lower than the lower 
limit), normal (value within the normal range), or high (value higher than the upper limit). The 
flags provided in the vendor dataset will be used for summary. 
For qualitative urinalysis tests, the results will be tabulated as frequency counts and percentages. 
In addition, shifts from baseline to post baseline for each parameter will be summarized. 
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"). 
6.3.8. Smell Identification Test 
The olfactory function will be assessed using the SIT at baseline and Month 12. The test consists 
of 4 booklets of 10 odors each for a total of 40 items. The score is the number of odors correctly 
identified. Observed and change from baseline values will be summarized using descriptive 
statistics. The number of subjects with an absolute change from baseline of 5 or more will be 
summarized using frequencies and percentages. 
6.3.9. Sheehan Suicidality Tracking Scale 
The Sheehan Suicidality Tracking Scale will be performed at every visit in the study. A baseline 
score of 0 was needed to enter the study. This questionnaire was not included in the original 
schedule of evaluations; therefore, data will not be available on all subjects. The total score (as 
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reported in the database) will be summarized using descriptive statistics for each post baseline 
visit. 
6.3.10. Prior and Concomitant Medications and Therapies 
Concomitant medications and migraine prevention medication usage (as defined in Section 3) 
will be summarized using frequencies and percentages. Migraine prevention medication use is 
defined using the indication response of 'Migraine Prevention'. Prior medications are defined as 
medications that start and end before study drug dosing. Concomitant medications are defined as: 
(1) medications that start before study drug dosing and end after dosing or are ongoing at the 
time of dosing or (2) medications that start after study drug dosing. Prior and concomitant 
medications will be summarized separately. Concomitant migraine prevention medications will 
be summarized also. 
The World Health Organization Drug Dictionary (WHO Drug) version B3 September 2020 will 
be used to classify prior and concomitant medications by therapeutic class and generic name 
based on anatomical therapeutic chemical (ATC) class code level 3. lfthe ATC level 3 code is 
not available, then the next available ATC level will be used (i.e., ATC level 2 or 1 ). Subjects 
will only be counted one time in each unique ATC Class and generic name if multiple drugs are 
used by a subject. 
Concomitant procedures and non-drug therapies will be listed by subject. 
6.4. 
Efficacy Analysis 
The efficacy parameters will be recorded inane-diary by the subjects. Subjects may have several 
treated migraine attacks, and subjects may take a second dose after 2 hours for any attack. 
All efficacy analyses are exploratory, and there are no specified primary or secondary efficacy 
variables for this study. Definitions, summaries, and analyses for the efficacy parameters listed in 
Section 4 will be described in this section. The analysis for all endpoints will be based on the 
observed data for the mITT population. Since subjects may treat more than one migraine attack 
during the study, response rates or percentages will be based on the number of migraine attacks 
treated. 
6.4.1. 
Freedom from Headache Pain 
Headache pain severity will be collected at the onset of each migraine attack immediately before 
drug administration, at 30 minutes post dose, and at 1, 2, 4, 24, and 48 hours post dose. The 30 
minute and 1 hour time points were added after the start of the study and not all attacks have data 
at these timepoints. 
The endpoints for freedom from headache pain are: 
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• 
Attacks with freedom from headache pain at 30 minutes, 1, 2, 4, 24 and 48 hours post 
dose 
• 
Attacks with freedom from headache pain at 30 minutes, 1, 2, 4, 24, and 48 hours post 
dose by month 
The proportion of attacks free from headache pain at 2 hours post dose will be defined as attacks 
where the following is available: a baseline pain severity response, a non-missing response at 2 
hours post dose, freedom from headache pain as defined in Section 3, and no use of rescue 
medication or a second dose of study medication prior to 2 hours post dose. The percentage will 
be based on the number of treated migraine attacks with a response, i.e., a subject may be 
counted more than once in the summary. 
Freedom from headache pain at 30 minutes, 1, 4, 24, and 48 hours post dose will be defined in 
the same as 2 hours post dose; however, if a subject dosed a second time for an attack prior to the 
time point of interest (30 minute, 1, 4, 24, 48) then the subject's migraine attack is not included 
in subsequent analyses. 
The proportion of migraine attacks at each time point will also be summarized by month (1-12). 
Month will be derived using a window based on the Day 0 or Baseline visit date (Visit 2). 
Months 1 through 5 will be defined using 30-day increments with an additional 7-day allowance 
from the baseline date. Months 6 through 12 will be defined using 30-day increments with an 
additional 14-day allowance. The table below outlines the windows. 
Table 3: Month Window 
Month 
Target Day 
Window in Days 
1 
30 
0- 37 
2 
60 
38-67 
3 
90 
68-97 
4 
120 
98-127 
5 
150 
128-157 
6 
180 
158-194 
7 
210 
195-224 
8 
240 
225-254 
9 
270 
255-284 
10 
300 
285-314 
11 
330 
315-344 
12 
360 
345-374 
13 
390 
375-404 
14 
420 
405-434 
15 
450 
435-464 
16 
480 
465-494 
17 
510 
495-524 
18 
540 
>524 
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Migraine attacks will be slotted into each month based on the dates of the attacks. 
Page 20 
The proportion of pain free migraine attacks by month will also be summarized in the 6-Month 
Completers Mk2, 6-Month Completers Mkl/Mk2, 12-Month Completers Mk2, 12-Month 
Completers Mkl/Mk2 safety, and All Expansion Subjects populations. 
6.4.2. Freedom from MBS 
Most bothersome symptom will be collected at the onset of each migraine attack immediately 
before drug administration, at 30 minutes post dose, and at 1, 2, 4, 24, and 48 hours post dose. 
The 30 minute and 1 hour time points were added after the start of the study, and therefore, not 
all attacks will have these time points. 
The endpoints for freedom from MBS are: 
• 
Attacks with freedom from MBS at 30 minutes, 1, 2, 4, 24 and 48 hours post dose 
• 
Attacks with freedom from MBS at 30 minutes, 1, 2, 4, 24, and 48 hours post dose by 
month 
The proportion of attacks free from MBS at 2 hours post dose will be defined as attacks where 
the following is available: a baseline MBS response (photophobia, phonophobia, or nausea), the 
symptom selected at baseline is not present at 2 hours post dose, and no rescue medication use or 
a second dose of study medication prior to 2 hours post dose. The percentage will be based on 
the number of treated migraine attacks, i.e., a subject may be counted more than once in the 
summary. 
Freedom from MBS at 30 minutes, 1, 4, 24, and 48 hours post dose will be defined and 
summarized in the same manner as 2 hours post dose; however, if a subject dosed a second time 
for an attack prior to the time point of interest (30 minute, 1, 4, 24, 48) then the subject's 
migraine attack is not included in subsequent analyses. Summaries by study month will use the 
derived month windows described in section 6.4.1. 
The proportion ofMBS free migraine attacks by month will also be summarized in the 6-Month 
Completers Mk2, 6-Month Completers Mkl/Mk2, 12-Month Completers Mk2, 12-Month 
Completers Mkl/Mk2 safety, and All Expansion Subjects populations. 
6.4.3. Relief from Headache Pain 
Relief from headache pain will be derived from headach pain severity which is collected as noted 
in Section 6.4.1. Relief from headache pain at 2 hours post dose will be defined as attacks where 
the following is available: a baseline pain severity response, a non-missing response at 2 hours 
post dose, relief from headache pain as defined in Section 3, and no use of rescue medication or a 
second dose of study medication prior to 2 hours post dose. The percentage will be based on the 
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number of treated migraine attacks, i.e., a subject may be counted more than once in the 
summary. 
The endpoints for relief from headache pain are: 
• 
Attacks with relief from headache pain at 30 minutes, 1, 2, 4, 24 and 48 hours post dose 
• 
Attacks with relief from headache pain at 30 minutes, 1, 2, 4, 24, and 48 hours post dose 
by month 
Relief from headache pain at 30 minutes, 1, 4, 24, and 48 hours post dose will be defined and 
summarized in the same manner as relief from headache pain at 2 hours; however, if a subject 
dosed a second time for an attack prior to the time point of interest (30 minute, 1, 4, 24, 48) then 
the subject's migraine attack is not included in subsequent analyses. Summaries by study month 
will use the derived month windows described in section 6.4.1. 
The proportion of relief from headache pain migraine attacks by month will also be summarized 
in the 6-Month Completers Mk2, 6-Month Completers Mkl/Mk2, 12-Month Completers Mk2, 
12-Month Completers Mkl/Mk2 safety, and All Expansion Subjects populations. 
6.4.4. Freedom from Photophobia, Phonophobia, and Nausea 
Presence of photophobia, phonophobia, and nausea will be collected at the onset of each 
migraine attack immediately before drug administration (time 0), at 30 minutes post dose, and at 
1, 2, 4, 24, and 48 hours post dose. The 30 minute and 1 hour time points were added after the 
start of the study, and therefore, not all attacks will have these time points. 
The proportion of attacks with freedom from photophobia, phonophobia, and nausea will be 
summarized individually for each time point (30 minute, 1, 2, 4, 24, and 48 hours post dose). 
6.4.5. Sustained Freedom from Headache Pain and MBS 
Sustained freedom from headache pain is defined as free from headache pain at 2 hours post dose 
(as defined in Section 6.4.1) and remaining free of headache pain at 24 or 48 hours (as defined in 
Section 3). Rescue medication use will be based on observed data; therefore, if the subjects has 
no recorded rescue medications, then the subject is assumed to have no rescue medication use. 
Sustained freedom from headache pain at 24 and 48 hours will be analyzed overall and 
summarized by month using the windows described in Section 6.4.1. 
Sustained freedom from MBS is defined and summarized in the same manner as above using the 
derivation of freedom from MBS as described in Section 6.4.2. 
The proportion of sustained freedom from headache pain and MBS migraine attacks will also be 
summarized in the 6-Month Completers Mk2, 6-Month Completers Mkl/Mk2, 12-Month 
Completers Mk2, and 12-Month Completers Mkl/Mk2 safety populations. 
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6.4.6. Rescue Medications 
Page 22 
Rescue medications will be reported in the e-diary under the Headache Medication Diary 
category throughout the study. The number of subjects using rescue medications and the number 
of migraine attacks requiring rescue medications within 24 and 48 hours post dose will be 
summarized using frequencies and percentages. 
The number of subjects and the number of migraine attacks using a second dose of study 
medication within 24 and 48 hours post dose will also be summarized. 
These summaries will also be performed on the All Expansion Subjects Population. 
6.4.7. Frequency of Migraine Attacks 
Migraine attacks are logged in the subjects' diaries throughout the study. The number and 
percentage of migraine attacks treated with STS101, as well as the total number of migraine 
attacks reported will be summarized by month using the windows described in Table 2, Section 
6.4.1. 
6.4.8. Relapse in Headache Pain 
Headache relapse within 24 and 48 hours post dose will be defined as described in Section 3. 
Rescue medication or second dose use will not be considered a relapse. 
6.4.9. Functional Impairment Scale 
FIS will be collected at the onset of each migraine attack immediately before drug 
administration, at 30 minutes post dose, and at 1, 2, 4, 24, and 48 hours post dose. The 30 minute 
and 1 hour time points were added after the start of the study; therefore, data prior to the 2-hour 
time point will not be available for all subjects. 
The endpoints of interest for FIS are: 
• 
FIS distribution of attacks at 30 minutes, 1, 2, 4, 24, and 48 hours post dose 
• 
FIS distribution of attacks at 30 minutes, 1, 2, 4, 24, and 48 hours post dose by month 
The FIS distribution of attacks at each post dose time point will be summarized by month using 
the windows described in Table 2 of Section 6.4.1. 
6.4.10. 24-hour Migraine Quality of Life Questionnaire 
24-MQoL will be collected 24 hours after drug administration for one treated migraine attack per 
month. The questionnaire has 5 domains. They are work functioning, social functioning, 
energy/vitality, migraine symptoms, and feelings/concerns. The total score and domain 
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algorithms are defined in Section 3. The total score and domain scores will be summarized using 
descriptive statistics by month using the windows described in Section 6.4.1. 
6.4.11. Subject Impression Questions 
Subject impression questions were asked at Months 3, 6, and 12 and are listed below. 
• 
Patient Global Impression (PGI) 
• 
Ease of Use 
• 
Patient Likelihood of Use of Study Medication if it were available 
• 
Comparison of Study Medication with Previously Used Migraine Medication 
• 
Consistency of Study Medication Effect (Month 12 only) 
Responses to these questions will be summarized at each evaluation month using frequencies and 
percentages. 
6.4.12. Headache Impact Test 
The HIT-6 questionnaire will be performed at baseline, Months 3, 6, and 12 to assess the impact 
of the headaches on daily life. The total score will be derived as described in Section 3. The HIT-
6 score will be summarized using descriptive statistics for observed and change from baseline 
values at baseline and each evaluation month. 
The HIT-6 total score will also be derived as a categorical variable as defined in Section 3. The 
shifts in impact from baseline will also be summarized for each month. 
6.4.13. Healthcare Resource Utilization 
Healthcare resource utilization questions will be asked at baseline and at each post baseline visit. 
Subjects reported the number of times they used the following resources for migraines: 
• 
office-based consultations 
• 
office-based consultations with a specialist 
• 
visits to urgent care, emergency department, or infusion center 
• 
hospitalizations, overnight hospital/emergency department stays 
• 
diagnostic services, i.e., MRI, CT, other 
Each of these questions will be summarized using descriptive statistics. The change from 
baseline at each post baseline visit will also be included. Subject responses will be presented in a 
data listing. 
CONFIDENTIAL 
Final v4: September 19, 2022 


Satsuma Pharmaceuticals, Inc. - STSl0l-003 
Statistical Analysis Plan 
6.4.14. Subgroup Analyses 
Page 24 
Subgroup analyses will be conducted on the efficacy analyses of the freedom from headache pain 
at 2 hours, freedom from MBS at 2 hours, and relief from headache pain at 2 hours to gain 
insight of the nature and consistency of the treatment effect. Baseline migraine severity (Mild, 
Moderate, Severe) is the only planned subgroup. However, analysis by additional subgroups may 
be considered. 
6.5. 
Interim Analysis 
Two interim analyses are planned for this study. The first interim analysis will be conducted 
based on a data cut date of December 31, 2021. The second interim analysis will be conducted 
based on a data cut date of June 30, 2022. 
There are no formal statistical analyses performed in this study since it is an open-label study; 
therefore, there is no impact on the final analysis. 
7. 
TABLES, LISTINGS, AND FIGURES 
Data listings will be sorted by subject number and visit (if appropriate). All data recorded on the 
CRFs will be included in the listings as well as some derived information. The shells for the data 
listings will be primarily to show where specific data can be found. The variable spacing and 
overall presentation or layout of the listings may need to be altered once actual data is available. 
Tables will generally be presented with the parameter in the first column followed by treatment. 
Descriptive statistics such as mean, median, minimum, and maximum will generally be 
presented to one decimal place and standard deviation will be presented to two decimal places. 
The laboratory tables may vary for each test depending on the precision of the test. P-values, if 
applicable, will be presented to four decimal places. If a p-value is less than 0.0001 then it will 
be presented as <0.0001. 
A list of the tables, listings, and figures will be maintained outside of this document and may be 
amended as needed. 
CONFIDENTIAL 
Final v4: September 19, 2022 


Satsuma STS101-003 Final SAP 19Sep2022 
Final Audit Report 
2022-09-23 
Created: 
2022-09-20 
By: 
Shelia Ligozio (shelia.ligozio@instat.com) 
Status: 
Signed 
Transaction ID: 
CBJCHBCAABAAuCwGxdwtMjpV9GLCg0wsTD9rxrRZPcTI 
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